Abstract
Chromosomal instability is a major pathway of sporadic colon carcinogenesis. Chromosome arm 1p appears to be one of the “hot spots” in the non-neoplastic mucosa that, when deleted, is associated with the initiation of carcinogenesis. Chromosome arm 1p contains genes associated with DNA repair, spindle checkpoint function, apoptosis, multiple microRNAs, the Wnt signaling pathway, tumor suppression, antioxidant activities, and defense against environmental toxins. Loss of 1p is dangerous since it would likely contribute to genomic instability leading to tumorigenesis. The 1p deletion-associated colon carcinogenesis pathways are reviewed at the molecular and cellular levels. Sporadic colon cancer is strongly linked to a high-fat/low-vegetable/low-micronutrient, Western-style diet. We also consider how selected dietary-related compounds (eg, excess hydrophobic bile acids, and low levels of folic acid, niacin, plant-derived antioxidants, and other modulatory compounds) might affect processes leading to chromosomal deletions, and to the molecular and cellular pathways specifically altered by chromosome 1p loss.
Introduction
Chromosomal instability is a major feature of sporadic colon carcinogenesis.Citation1–Citation11 Eighty-five percent of colorectal cancers are aneuploid, the remaining 15% being diploid.Citation5 Chromosome 1p deletions in colon tumors have been reported by laboratories from at least 15 countries around the world.Citation12–Citation49 Chromosome 1p deletions occur at an early stage of colon carcinogenesis,Citation21,Citation24,Citation26–Citation28,Citation30,Citation31,Citation33,Citation37,Citation39,Citation41–Citation45 and are strongly linked to karyotypic evolution during colon cancer development.Citation43
Many reports in the literature indicate that the macroscopically normal mucosa proximal or distal to a colon cancer exhibit aneuploidy (loss or gain of chromosomes or parts of chromosomes). Relevant to this review, Cianciulla et alCitation44 reported that deletions of chromosome 1p were simultaneously found in both the distant normal-appearing mucosa of 76% of patients who also harbored 1p deletions in their cancer. These findings indicate that the loss of chromosome 1p may be one of the “hot spots” among the numerous defects in the non-neoplastic mucosa associated with the possible initiation of colon carcinogenesis.Citation50–Citation70
The pioneering work of Paraskeva et alCitation71–Citation75 indicated the likely involvement of chromosome 1p loss in in vitro immortalizationCitation72,Citation74 and in the progression of adenomas to carcinomas.Citation75 The functional importance of loss of distal 1p in colon tumorigenesis was demonstrated in 1993 by Tanaka et alCitation76 who introduced chromosomal band 1p36 into colon carcinoma cells and found that their tumorigenicity was suppressed.
Chromosome 1p deletions can affect distinct pathways of sporadic colon carcinogenesis, including both chromosomal instability and chromosomal instability-negative pathways. The underlying mechanisms associated with the loss of chromosome 1p that may contribute to genomic instabilty and drive colon carcinogenesis are loss of genes associated with DNA repair, spindle checkpoint function, apoptosis, multiple microRNAs (miRNAs), the Wnt signaling pathway, tumor suppression, antioxidant activities, and defense against environmental toxins.Citation77,Citation78 Since centromeric instability and resulting telomeric fusions have been proposed as a mechanism for the loss of chromosome 1p,Citation79 the loss of genes located on chromosome 1p that function to ensure centromeric stability and telomere integrity, in turn, can exacerbate chromosomal instability throughout the genome. These 1p deletion-associated pathways that may lead to colon carcinogenesis will be reviewed at the molecular and cellular levels, and dietary factors that affect these pathways (eg, excess hydrophobic bile acids, and low levels of folic acid, niacin, plant-derived antioxidants, and other modulatory compounds) will be explored. It is likely that certain dietary factors prevent, initiate, or exacerbate genomic instability in colon epithelial cells and thus have importance for colon carcinogenesis.
Mechanisms of carcinogenesis associated with the loss of key genes on chromosome 1p
Chromosome 1, the longest human chromosome, is gene-dense with 3141 genes.Citation80 The genes located on chromosome 1 were identified with the assistance of the Weizmann Institute of Science websites:
GeneLoc (www.genecards.weizmann.ac.il/geneloc/index.shtml) and GeneCards – The Human Gene Compendium (www.genecards.org). Genes located on the p arm of chromosome 1 that are associated with protection against oxidative stress, DNA damage, mitotic perturbations, excessive cellular proliferation, development of apoptosis resistance, aberrant colonic cell differentiation, and environmental toxicity have been tabulated and the function of the gene products described (–). Since many of these genes have tumor suppressive capabilities, the simultaneous loss caused by a 1p deletion could initiate the formation of neoplastic clones and enhance tumorigenesis through Darwinian selection.Citation8
Table 1 DNA repair and DNA damage response genes
Table 8 Genes associated with protection against environmental and metabolic toxicity
Mechanisms protective against genomic instability
Cells with DNA damage, spindle damage, and dysfunctional telomeres signal DNA damage responses.Citation81–Citation84 These DNA damage responses include the activation of numerous checkpoints that arrest the damaged cells in the G1, S, G2, or M-phase of the cell cycle, depending upon the nature of the damage or dysfunction and the stage of the cell cycle of the target cell. DNA-damage checkpoints are activated following direct damage to DNA.Citation85–Citation91 Spindle assembly checkpoints are activated following damage to the mitotic machinery,Citation85,Citation92–Citation98 or as a result of DNA damage during mitosis.Citation99 Telomere checkpoints are activated by defective telomeres.Citation100–Citation106 These checkpoints prevent the damaged cell from completing DNA replication and mitosis until all damage is repaired (), and thus prevent 1) mutations that could be formed by replicating a damaged DNA template, 2) aneuploidy that could result from chromosome mis-segregation, and 3) telomere fusions that result in anaphase bridges, broken chromosomes, and translocations as a consequence of the well-known breakage–fusion–bridge cycles.Citation107–Citation114
Figure 1 The damaging effects of dietary factors and inflammatory conditions on the colonic epithelium. Damage to DNA, the mitotic spindle, and to telomeres is mediated through the generation of ROS (reactive oxygen species) and/or RNS (reactive nitrogen species). This damage results in the activation of spindle and DNA damage checkpoints, which delay mitosis until repairs are made.
However, cells with excessive direct DNA damage,Citation115–Citation122 massive chromosome loss or chromosomal imbalances,Citation123 prolonged activation or inhibition of the spindle checkpoint pathways,Citation122–Citation127 or excessively shortened or dysfunctional telomeres,Citation128–Citation140 initiate a cascade of molecular events that ultimately leads to either caspase-dependent cell death,Citation141–Citation143 caspase-independent cell death,Citation144 or a special form of apoptosis referred to as mitotic catastropheCitation145–Citation148 (). (Brightfield micrographs are shown in illustrating the cellular alterations that accompany apoptosis [], mitotic perturbation [], mitotic catastrophe [], and micronuclei formation [associated with aneuploidy] []). The cell-destructive and cell-protective pathways are downstream of a common signal transduction network that responds to DNA damage.Citation149 The repair/survival and non-repair/cell death pathways are probably activated simultaneously.Citation149 The repair, checkpoint, and cell death response to DNA damage are, however, well co-ordinated,Citation150 the interplay of positive and negative regulatory loops resulting in a delayed death response to DNA damage.Citation149
Figure 2 Excessive spindle damage, dysfunctional telomeres, or DNA damage can result in a prolonged cell cycle arrest which activates pro-cell death pathways. This activation of pro-cell death pathways leads to removal of cells with unrepaired damage to the mitotic spindle, the chromosome ends, and DNA and prevents the potential propagation of cells with many types of genomic instability.
Figure 3 Examples of cellular alterations that accompany apoptosis (A), mitotic perturbation during anaphase (B), mitotic catastrophe with complete chromosome/spindle disruption (C), and abundant micronuclei formation associated with aneuploidy (D). Panels A, B, and D are examples of HCT-116 cells treated with 10 μM camptothecin. Panel C represents cells treated with 5 μM phenstatin (drug obtained through courtesy of Dr GR. Pettit, Arizona State University) (cytospin preparations of Giemsa-stained cells; ×100 oil objective lens)
DNA repair and the DNA damage response (DDR) ()
The genes on chromosome 1p associated with DNA repair or the DNA damage response (DDR) include CLSN, DCL-RE1B (APOLLO), DDI2, GADD45α, MSH4, MUTYH, RAD54L, and TP73. The functions of these gene products are described in . The pathways that lead to the prevention of genomic instability are diagrammatically shown in . DNA damage elicits a well orchestrated and highly interactive series of events called the DDR, which causes cells to undergo growth arrest so that DNA damage can be adequately repaired. Although p53 mutation or loss of heterozygosity (LOH) is a late event in colon carcinogenesis,Citation151 the loss of p73 (found on chromosome 1p) through chromosomal deletion events may act early in colon carcinogenesis. P73 is an important isoform of the p53 family, since it performs many of the transcriptional functions of p53, and may even target the same genes as p53 during the DDR. In addition, TP73 has distinct transcriptional targets and harmonizes with p53 and p63 to maintain genomic stability.Citation152–Citation158 In addition to its role in growth arrest after DNA damage to allow DNA repair to take place, p73 plays an active role in spindle dynamics, mitotic exit and chromosomal stability. The PSRC1 (proline/serine-rich coiled-coil 1) gene found on chromosome 1p (see ) encodes a protein which is a direct transcriptional target of both p53 and p73.Citation159 PSRC1 functions as a microtubule destabilizing protein that controls spindle dynamics and mitotic progression by recruiting and regulating microtubule depolymerases.Citation160 Through its transcriptional activity, p73 is important for the M-to-G1 transition during mitosis.Citation161 Functional knock-out of p73 gene expression by small interfering RNAs alters mitotic progression, resulting in an increase of ana-telophase cells, the accumulation of aberrant late mitotic figures, and the appearance of abnormalities in the subsequent interphase.Citation161 This novel pathway involves the p73-mediated transcription of Kip2/p57, a cyclin-dependent kinase inhibitor, and the coordination of mitotic exit and transition to G1.Citation161,Citation162 Like p53, p73 has been confirmed to be a tumor suppressor.Citation163–Citation167 Therefore, a loss of p73 should have a major impact in the development of genomic instability during carcinogenesis.
Figure 4 DNA damage causes several downstream molecular and cellular events. The DNA damage response involves several DNA repair proteins and transcription factors that allow the cell cycle to be arrested at several points to enhance genomic stability. All of the genes associated with these damage response pathways that are also found on chromosome 1p are highlighted in red, and reference to the appropriate tables (contain functions of gene products) in the text is provided below. The large number of molecular and cellular events affected by the loss of chromosome 1p is apparent.
Abbreviations: DDR, DNA damage response; ROS, reactive oxygen species; RNS, reactive nitrogen species.
Table 2 Mitosis-related and spindle checkpoint genes
Table 6 Tumor suppressor genes
Table 7 Genes associated with antioxidant function
Since base excision repair (BER) removes damage that would otherwise be mutagenic in mammalian cells,Citation168–Citation170 BER is one of the most important DNA repair pathways in the gastrointestinal tract. BER ameliorates environmentally induced DNA damage in addition to the alkylation, oxidation, and deamination events that occur during normal metabolic processes.Citation171,Citation172 A critical enzyme in the base excision repair pathway is MUTYH (MutY homolog or A/G-specific adenine DNA glycosylase), whose germline mutation is a known cause of MAP (MutYH-associated polyposis), a recently described autosomal recessive colorectal adenoma predisposition syndrome with a very high risk of colorectal cancer.Citation173 Myh deficiency enhances intestinal tumorigenesis in multiple intestinal neoplasia (ApcMin/+) mice.Citation174 Interestingly, Myh deficiency in mice has a larger effect on tumor initiation than on progression in the small bowel.Citation174 Since 1p deletions are observed in the human non-neoplastic mucosa of patients with colon cancer,Citation44 it is possible that Myh-deficient field defects may initiate the process of colon carcinogenesis in humans as it does in the mouse model. Since MUTYH-null mouse embryonic stem cells exhibit a mutator phenotype,Citation175 the loss of MUTYH can affect multiple pathways associated with colon carcinogenesis. The role of MUTYH in the repair of oxidative DNA damage begins with the formation of 8-oxo-guanine (8-oxoG) (see ), which then causes a mispairing of the oxidized guanine base with adenine upon DNA replication. Mismatch repair processes are activated and MUTYH excises adenine leaving an apurinic (AP) site resulting, after AP endonuclease action, in a DNA single strand (ss) break.Citation176–Citation180 The activity of MUTYH, in conjunction with other glycosylases and the spontaneous generation of AP sites, may be quite extensive, since about 9000 AP sites/cell occur daily.Citation168 The AP site is then correctly repaired by the sequential action of several enzymes which catalyze template-directed insertion of one or a few nucleotides at the previously damaged site.Citation172
In addition to their role in DNA repair or the DDR, MUTYH and p73 play important roles in the death of cells that experience either excessive oxidative DNA damage or chromosomal instability. The MUTYH-mediated cell death pathway is described in the next section followed by a section on the p73-mediated cell death pathway, which utilizes part of the MUTYH pathway in its mediation of cell death in response to excessive mitotic perturbation.
MUTYH/PARP/AIF pathway of cell death
MUTYH-mediated cell death has, as a central player, the activation of PARP-1 [poly(ADP-ribose) polymerase-1] (). Excessive DNA ss breaks caused by the action of MUTYH and AP endonuclease in the nucleus results in the activation of PARP-1, which attaches polymers of ADP-ribose to proteins, thereby opening up the chromatin to allow access of DNA repair proteins.Citation181,Citation182 PARP initially serves as a survival protein facilitating the rapid repair of DNA strand breaks, and also prevents DNA degradation, in part, by inhibiting the activity of deoxyribonucleases through the process of poly(ADP) ribosylation.Citation183 Since the synthesis of ADP-ribose polymers consumes nicotinamide adenine dinucleotide (NAD+),Citation184 and NAD+ is largely found in mitochondria where it participates in the production of ATP (bottom right side of ), sustained PARP activation will consume energy reserves, resulting in cell death, usually through the process of necrosis.Citation185–Citation188 A marked deficiency in energy reserves may cause the ATP-dependent Na+/K+ transport proteins, which maintain ionic balance, to fail, resulting in cell swelling and lysis of the cell,Citation189 one of the hallmarks of necrosis.Citation190
Figure 5 The mechanisms by which excessive activity of MUTYH and AP endonucleases can lead to cell death through the activation of PARP and the generation of toxic poly(ADP)ribose (PAR) polymers and mitochondrial DNA (mtDNA) damage (see text for detailed description).
In addition to the above energy catastrophe caused by excessive PARP activity in the nucleus, persistent single-stranded gaps in newly replicated DNA initiated by the action of MUTYH in mitochondria can result in the fragmentation and depletion of mitochondrial DNA (mtDNA)Citation191,Citation192 accompanied by the loss of mitochondrial function culminating in cell deathCitation191,Citation193 (bottom right side of ). Dysfunctional mitochondria can release Ca++ into the cytosol which can activate calpains, causing Bax activation, lysosomal rupture, and the release of cathepsins into the cytosolCitation191,Citation194 resulting in a caspase-independent mode of cell death. Calpain activation can also result in Bax activation, followed by Bax oligomerization and mitochondrial damage, resulting in the loss of the mitochondrial membrane potential.
There is another unique mechanism that can lead to PARP-mediated cell death after excessive MUTYH activity, in addition to the fragmentation of mtDNA, energy catastrophe and calpain/lysosomal rupture/cathepsin pathways of mitochondrial failure described above. The main product of PARP-1 activity is the generation of polymers of ADP-ribose (PAR). Although these polymers are usually covalently bound to proteins, free PAR polymers are themselves toxicCitation195–Citation197 and function as a death signal.Citation197–Citation199 The PAR polymers bind to mitochondria and induce the release of tAIF (truncated apoptosis-inducing factor) from the mitochondria into the cytosolCitation199 (lower left side of ). tAIF is then translocated to the nucleus where it binds to DNA,Citation200–Citation202 causes DNA condensationCitation203 and recruits DNA degrading factors (eg, endogenous endo- and exo-nucleases) resulting in DNA degradationCitation198,Citation204 (upper left side of ). This series of events is part of an intricate program of caspase-independent cell death,Citation203–Citation213 and is currently an active area of research.
Several mechanisms have been proposed to explain how tAIF is released from the mitochondria into the cytosol.Citation210,Citation214 Prior to truncation, AIF is embedded in the inner mitochondrial membrane,Citation215 and the release of AIF requires its cleavageCitation215,Citation216 from a 62 kDa AIF mitochondrial form to a truncated 57 kDa soluble AIF form (tAIF).Citation217,Citation218 Calpain-I, which is activated by Ca++,Citation219 and Ca++-independent cathepsins B, L, and SCitation218,Citation220 can cleave intramitochondrial AIF.Citation221–Citation223 The calpains and cathepsins can truncate AIF in the same position at Gly102/Leu103.Citation218 Calpain-I, however, appears to be the critical enzyme regulating AIF processing in which the AIF pathway is important for cell death.Citation219 Oxidative modifcation of AIF markedly increases the susceptibility of AIF to calpain-I-mediated processing, most probably through the exposure of a normally hidden calpain cleavage site.Citation219 Since the PAR polymer is a highly negatively charged molecule, it could depolarize mitochondria leading to opening of the mitochondrial membrane permeability transition pore (MPTP) followed by the release of tAIF.Citation197,Citation199 PAR polymers of increasing complexity and molecular weight are more toxic than simple PAR polymers of low molecular weight.Citation197 The PAR polymer could also bind to PAR polymer binding proteins associated with mitochondria, which then release AIF.Citation199,Citation224–Citation226 This results in AIF cleavage producing a tAIF, which is soluble and enters the cytosol. The release of tAIF may also be caused by a significant but not excessive decrease in NAD+ (as a result of PARP activity), ATP, and the mitochondrial membrane potential, resulting in the opening of the MPTP (mitochondrial permeability transition pore).Citation186,Citation196,Citation211 The release of tAIF may also be caused by other caspase-independent pathways involving molecules that are often found in the downstream execution phase of apoptosis, such as tBid (truncated Bid),Citation227–Citation229 Bax oligomers (formed after activation of Bax by Ca++-dependent calpains),Citation211,Citation217 Bak,Citation230 and Bim-EL.Citation231,Citation232 The activation of PARP also activates other stress-response pathways such as the RIP/TRAF2/JNK pathway,Citation233–Citation235 which may be responsible, in part, for generation of tBidCitation228 and the phosphorylation of Bim-EL. The phosphorylation of Bim-EL releases Bim-EL from sequestration by the microtubular dynein motor complex,Citation236 allowing it to bind to bcl-2,Citation231 thereby enhancing the cell death process.
Mechanisms that interfere with tAIF release include the 1) degradation of the PAR polymer by PARG (PAR glycohydrolase),Citation237 2) inhibition of tAIF translocation to the nucleus by Bcl-2, Bcl-xl, HSP70, or Iduna, and 3) interference of transcription of the AIF gene by BNIP3.Citation238 PARG, Bcl-2, Bcl-xl, HSP70, Iduna, and BNIP3 have been shown to be upregulated during carcinogenesis, consistent with the development of tumor cell resistance to cell death. In addition, pro-cell death molecules involved in this MUTYH/PARP/AIF pathway, such as AIF, Bid, Bax, Bak, and Bim-EL, have been reported to be downregulated during carcinogenesis. Thus, overall, MUTYH likely has an important role in the death of cells exposed to excessive reactive oxygen species/reactive nitrogen species (ROS/RNS)-induced DNA damage, and interference with the MUTYH cell death pathway is associated with carcinogenesis.
P73 and caspase-dependent cell death
Like p53, p73 is responsible for the induction of apoptosis in response to excessive DNA damage that cannot be repaired.Citation239 P73 has the ability to upregulate the transcription of numerous classic apoptosis-related genes such as caspases 3, 6, and 8, Bcl-2 family members, and death receptors (). In order for p73 to function as a transcription factor, it must be phosphorylated. The c-Abl kinase, activated by DNA damage, phosphorylates and activates p73 on tyrosine 99.Citation240 The stress-induced mitogen-activated protein kinase, p38 MAPK, phosphorylates and activates p73 on threonine residues.Citation239 The degradation of p73 by the E3 ubiquitin-like protein, Itch, is prevented by the Yes-associated protein, YAP. E2F1, p53, and c-jun (located on chromosome 1p; and ) may also have a role in p73 activation in different cell types.Citation241,Citation242 One mechanism by which p73 induces apoptosis includes the transcription of PUMA (p53 upregulated modulator of apoptosis), which in turn causes Bax translocation to the mitochondria with the release of cytochrome c.Citation243 A second mechanism involves the transcription of scotin, which causes endoplasmic reticulum (ER) stress and subsequent apoptosis.Citation244,Citation245 Unlike p53, a direct role of p73 in the apoptotic process (eg, mitochondrial translocation and perturbation) has not been verified. The role of p73 in the regulation of the miRNA processing complex will be discussed in the section “MiRNAs and miRNA processing”. As noted above, loss of p73 through chromosome 1p deletion occurs early in colon carcinogenesis, contrary to the loss of p53 which is a late event.
Figure 6 The possible mechanisms by which p73 transcription and activation can lead to cell death through classic apoptotic mechanisms. Definitions of proteins not included in the main text: PERP (p53 apoptosis effector related to PMP22; tetraspan membrane protein and component of intercellular desmosome junctions); p53AIPI (p53 apoptosis-inducing protein 1; promoter activated by acetylated p73); FAS (CD95) (member 6 of the TNF receptor superfamily which contains a death domain); TNFR1 (member 1A of the TNF receptor superfamily); TRAIL-R1 (member 10A of the TNF receptor superfamily); TRAIL-R2 (member 10B of the TNF receptor superfamily; death receptor 5); PIG3 (p53-induced gene 3 protein; quinone oxidoreductase involved in the generation of ROS and cell death).
Mitosis-related and spindle checkpoint function ()
There are 24 genes on chromosome 1p whose gene products affect many different aspects of the mitotic process, and include kinases, phosphatases, centromere proteins, centrosome proteins, cyclins, regulatory mitotic proteins, motor spindle proteins, regulators of chromosomal condensation, a mitosis-related transcription factor, a deacetylase, and a major spindle checkpoint protein (). The large number of mitosis-related genes that are lost if there is a chromosome 1p deletion could potentially be responsible for colon cancer initiation and progression, since cancer epidemiology studies show that abnormal expression of mitosis-related genes is frequent in different tumor types.Citation246,Citation247 Mitotic checkpoints, and specifically the spindle assembly checkpoint, are major targets for tumor-associated alterations.Citation247 The mitotic spindle assembly checkpoint is essential for ensuring that all chromosomes are properly aligned on the metaphase plate, with every chromosome attached to a spindle microtubule by its kinetochore to prevent aneuploidy.Citation97 If these processes fail to occur and the cell undergoes a prolonged mitotic arrest (), the cell may be eliminated through caspase-dependent or caspase-independent cell death mechanismsCitation147 to ensure genomic stability ().
Figure 7 The different cellular fate following spindle, telomere and DNA damage during mitosis. Cells with excessive genomic damage can undergo caspase-dependent cell death (CDMCD) or caspase-independent mitotic cell death (CIMCD). DNA-damaged cells may, however, exit from mitosis by defying cell death pathways through a process referred to as mitotic slippage. These preneoplastic cells with DNA damage and chromosomal abnormalities can then be clonally expanded to produce a tumor and eventually develop into a malignancy through continued cycles of damage to the genome.
Oxidative stress is a major factor that can induce disturbances in spindle organization,Citation248,Citation249 induce centrosome amplification, cause proteolysis of the anaphase inhibitor securin and mitotic cyclins,Citation250 affect components of the anaphase-promoting complex,Citation251 and override the spindle checkpoint,Citation250 thereby affecting chromosomal stability. During the process of mitosis, direct oxidative damage to chromosomes resulting in double-strand breaks, or oxidative damage to telomeres can activate p53 () or p73 (), major DNA damage response proteins that elicit apoptosis through multiple caspase-dependent mechanisms. In addition, caspase-independent mitotic cell death can also occur during a mitotic catastrophe (, ), which is a prestage to distinct modes of cell death that may be caspase-dependent or caspase-independent.Citation148
The length of time that a spindle is destabilized may determine the mode and timing of cell death after mitotic exit.Citation123,Citation124,Citation126 It has been suggested that prolonged mitotic delay can lead to the decay of anti-apoptotic messenger RNAs (mRNAs)Citation252,Citation253 and/or the gradual accumulation of pro-apoptotic signals.Citation252,Citation254 Of the 24 mitosis-related genes (), the products of 7 genes have dual-role mitosis/pro-apoptotic functions. These dual-role mitosis/pro-apoptotic genes include APITD1, CCNL2, CDC2L2, CDC42, E2F2, KIF1B, and PLK3 (). Cells may become genomically unstable if they evade mitotic checkpoints through a process referred to as mitotic slippage, mitotic arrest slippage, or mitotic checkpoint slippageCitation255–Citation263 (). With mitotic slippage, the cell exits mitosis prematurely, carrying broken chromosomes, abnormal numbers of chromosomes, and unrepaired DNA damage into the daughter cells. In addition to loss of pro-apoptotic proteins, it has been reported that the gradual loss of the checkpoint effector, cyclin B, releases the mitotic arrest induced by spindle disruptive agents, despite the continued presence of spindle damage and upstream checkpoint proteins.Citation14,Citation258,Citation260 In order for a DNA-damaged cell to survive after mitotic slippage, it must evade both apoptosis in the subsequent G1 phase of the cell cycleCitation124 () and reproductive cell death that can follow centrosome amplification and the generation of tetraploid cellsCitation264 ().
Thus, a decrease in pro-apoptotic mitotic/cell cycle-related genes located on chromosome 1p (APITD1, CCNL2, CDC2L2, CDC42, E2F2, KIF1B, PLK3) () may result in resistance to cell death, a critical event that drives tumorigenesis.Citation52,Citation54,Citation265–Citation267
Apoptosis-related genes ()
Seven genes associated with apoptosis are located on chromosome 1p. Bcl-10 and Bcl2L15 are Bcl-2 family members, THAP3 is a zinc-coordinating DNA-binding protein, DNA fragmentation factor A (DFFA) and B (DFFB) are the two subunits of DFF, caspase-9 is a major initiator caspase in the apoptotic proteolytic cascade, and TNFRSF25 is a death domain-containing receptor related to TNFR-1 and CD95 (Apo-1/Fas). The deletion of 3 of these genes would have important implications for carcinogenesis through the increase in apoptosis resistance, and will be discussed in some detail.
Table 3 Apoptosis-related genes
DFF is a heterodimeric protein composed of a catalytically active 40 kD subunit, DFFB (CAD [caspase-activated DNase]), and an inhibitory 45 kD subunit, DFFA (ICAD [inhibitor of CAD]).Citation268,Citation269 When bound to DFFB, DFFA inhibits the nuclease activity of DFFB.Citation268,Citation269 During apoptosis, caspase-3 cleaves DFFA at amino acids 117 and 224 and dissociates it from DFFB, thereby releasing the inhibition of DFFB.Citation270 DFFB activity results in chromatin condensationCitation271 and the formation of the typical crescents and margination of chromatin that are characteristic of classic apoptotic cells at the ultrastructural level.Citation190,Citation266,Citation272–Citation276 Characteristic ultrastructural features of apoptotic cells treated with a ROS-generating and DNA-damaging agent are shown in . At the molecular level, the action of DFF on DNA results in the initial cleavage of DNA into 50- to 300-kb long fragments,Citation277,Citation278 representing the dismemberment of the higher order organization of chromatin into chromosomal loop domains, and the fragmentation of DNA into oligonucleosomal sized fragments that form a “ladder” on agarose gel electrophoresis.Citation279 The importance of DFF in suppressing tumorigenesisCitation280 was demonstrated by Yan et alCitation281 using DFF40-null mice. DFF-deficient cells exhibit significant increases in mutation, chromosomal instability, and survival compared with wild-type control cells.Citation281 This is probably a result of the inhibition of cell death of DNA-damaged cells resulting from the failure to undergo DNA fragmentation.Citation282,Citation283 DFF is reported to avoid chromosome instability in a p53-independent manner.Citation284 Irradiation of cells with a caspase-resistant form of DFFA led to increased clonogenic survival of cells with increased chromosomal aberrations and aneuploidy.Citation284 The ability of DFF to maintain chromsosomal stability appears to be the result of the DNA fragmentation-induced death of cells with excessive DNA damage.Citation284 Although DFFB has intrinsic DNAse activity, both DFFA and DFFB are required to generate DNase activity,Citation140,Citation269 and must be co-expressed.Citation280 DFFA has been postulated to stabilize the synthesis of DFFB,Citation270,Citation271 or mediate the correct folding and chromatin localization of DFFB.Citation271 The absence of DFF results in an increased frequency of cell transformation and enhanced susceptibility to radiation-induced carcinogenesis, indicating that DFF is a tumor suppressor.Citation280 Recently, it has been reported that the expression of DFFA protein, but not DFFA mRNA, is regulated by a specific miRNA, miR-145, suggesting a mechanism of translational regulation.Citation285 The regulation of DFFB by miRNA has not been investigated, and, so far, none of the miRNAs found on chromosome 1p () have been determined to have DFFA or DFFB as target mRNAs for translational regulation.
Figure 8 Transmission electron micrographs of HCT-116 cells reacted with 0.5 mM sodium deoxycholate for 2 hours. A) Normal cell (arrow 1) with prominent nucleolus and dispersed chromatin; arrow 2 points to a cell in early apoptosis, showing margination of chromatin, a nucleolus showing nucleolar segregation, and an increase in electron density compared with the normal cell; arrow 3 points to a cell in a late stage of apoptosis showing condensed chromatin, a marked increase in electron density compared with the cell above, and apoptotic body formation. B) Apoptotic cell in a late stage of apoptosis showing condensed chromatin (including crescent formation), an increase in electron density, and cytoplasmic vacuole (V) formation. (Uranyl acetate, lead citrate stains.)
Table 4 MicroRNAs (miRNAs) and components of the miRNA processing complex
Caspase-9 is a member of the family of cysteine-aspartic acid-specific proteases (caspases), and is also referred to as Apaf-3 (apoptotic protease-activating factor 3). In the presence of cytochrome c and dATP, Apaf-1 binds to procaspase-9Citation286 via a CARD (caspase activation recruitment domain),Citation287 forming a complex referred to as the apoptosome.Citation286,Citation288,Citation289 The cellular oxidative state can affect apoptosome formation by promoting an interaction between caspase-9 and Apaf-1 via disulfide formation.Citation290 In the apoptosome, caspase-9 is activated to process other downstream caspases, including caspase-3 and caspase-2.Citation291 Caspase-9 plays an important role in apoptosis induced by genotoxic stress.Citation292,Citation293 The caspase-9-induced apoptotic pathway can result from mitochondrial membrane depolarization, formation of the apoptosome, and the activation of multiple caspases, including caspase-3 and caspase-2.Citation294 Loss of caspase-9 is therefore important to carcinogenesis, since it can result in apoptosis resistance and the propagation of DNA-damaged cells.Citation295 If caspase-9 is lost, caspase-3 cannot be activated, and thus cannot cleave many substrates including DFFA, an essential endonuclease in apoptosis (see previous page). Similarly, if caspase-9 is lost, caspase-2 may not be activated. Caspase-2 plays a specific role in genotoxic stress-induced apoptosis in some cell types.Citation296,Citation297 (However, there is another pathway for activation of caspase-2. Activation of p53 by DNA damage can result in the p53-mediated transcription of the death domain protein PIDD [p53-induced protein with a death domain], which, together with RAIDD or RIP1, can form a multiprotein complex called the PIDDosomeCitation298–Citation300 which then activates caspase-2Citation298). DNA damage can also activate caspase-2 through the activation of c-Abl.Citation301 C-Abl binds directly to caspase-9, phosphorylates it on Tyr-153, which then results in the autocleavage and activation of caspase-9 resulting in the apoptosis of excessively DNA-damaged cells.Citation301 Caspase-9 also mediates apoptosis caused by ER stress.Citation302 ER stress first activates caspase-12,Citation302 which is located on the outer membrane of the ER;Citation303 caspase 12 then activates caspase-9 through a cytochrome c-independent mechanism.Citation302 In some cells, ER stress can result in caspase-8 activation, formation of tBid, mitochondrial damage, release of cytochrome c and the activation of caspase-9 through the formation of the apoptosome.Citation304 Therefore, ER stress can activate caspase-9 through both mitochondrial-independent and -dependent mechanisms.
MiRNAs and miRNA processing ()
miRNAs are evolutionarily conserved, endogenous, small (21 to 24 nucleotides) non-coding RNAs cleaved from 70 to 100 nucleotide hairpin-shaped precursors that reduce translation and stability of target mRNAs through RISC (RNA interference effector complex)-mediated mRNA degradation and translational suppression via sequence-recognition interactions with the 3′ untranslated region of their targeted mRNAs.Citation305–Citation315 The diverse cellular functions affected by miRNAsCitation306,Citation316,Citation317 is underscored by the prediction that thousands of genes are potential miRNA targets.Citation318–Citation320 At least 800 different miRNAs predicted by computational scanning in the human genome have been documented (http://microrna.sanger.ac.uk). Individual miRNAs have the potential to downregulate large numbers of target mRNAs with seed region complementary sites in their 3′ untranslated regions.Citation321–Citation323 It has been speculated that miRNAs could regulate ∼30% of the human genome.Citation306 MiRNAs function in proliferation, cell cycle control, the prevention of replicative stress, differentiation, and apoptosis.Citation324–Citation333 More than half of the known human miRNAs are located at fragile sites, as well as at sites of LOH, amplification, and common breakpoint regions, which are particular genomic regions that are prone to alteration in cancer cells.Citation327 The overexpression or underexpression of miRNAs as a result of chromosomal additions or deletions, respectively, in individual cells can have dramatic effect on hundreds to thousands of target genes. It is, therefore, not surprising that aberrant expression of miRNAs is associated with cancerous tissues,Citation334–Citation340 and that characteristic miRNA expression profiles are features of certain human cancers.Citation341–Citation350 Impaired miRNA processing enhances cellular transformation and tumorigenesis,Citation351,Citation352 and certain miRNAs are even classified as tumor suppressors and oncogenes.Citation353–Citation355 Alterations in a series of specific miRNAs have been associated with the age of onset of colon cancer, the growth of colon cancer cells, and certain stages of colon carcinogenesis.Citation344,Citation356–Citation369 Human colon cancer profiles from 80 colon tumors and 28 samples of normal mucosa show differential miRNA expression depending on mismatch repair status and are characteristic of undifferentiated proliferative states.Citation367 Examination of the genomic regions containing differentially expressed miRNAs revealed that they were also differentially methylated in colon cancer at a far greater rate than would be expected by chance.Citation367 MiRNA profiles could accurately predict microsatellite status in a set of 39 colon cancer studied by Lanza and colleagues.Citation370 This is probably a reflection of the presence or near absence of chromosomal instabilty in the respective microsatellite stable vs unstable cancers.Citation371
There are 20 miRNAs and 3 components of the miRNA processing complex (Argonaute proteins 1,3,4) encoded on chromosome 1p (). One of the 20 miRNAs, miR-34a, is known to be regulated by p53.Citation309,Citation330,Citation372–Citation376 Tarasov et alCitation375 evaluated the differential regulation of 74 miRNAs by p53; 50 miRNAs were either positively or negatively regulated by p53, miR-34a showing the highest fold increase (33.4 fold). Although the 20 miRNAs found on chromosome 1p can have pleiotropic effects on cells, miR-34a is the most well studied for its role in cell cycle arrest and apoptosis in response to DNA damage.Citation309,Citation330,Citation374,Citation377,Citation378 The miR-34 family of miRNAs is one of only 18 mammalian miRNA familiesCitation379 that are present in flies and worms.Citation309 It is probable that links between p53 and the miRNA-34 family may have arisen early in the evolution of the stress-related p53 network.Citation309 Because of its central role in preventing carcinogenesis, miR-34a has been classified as a tumor suppressor.Citation372,Citation377 MiR-34a has numerous downstream targets, including bcl-2 (major anti-apoptotic protein), NOTCH1, Delta1 (ligand for NOTCH1), NOTCH2 (found on chromosome 1p), CDK4, CDK6, Cyclin D1, Cyclin E2, c-Met, MYCN, SIRT1 and E2F3.Citation319,Citation362,Citation374,Citation375,Citation377,Citation380–Citation384 The inhibition of NOTCH1 by miR-34a would enhance apoptosis since NOTCH1 is known to inhibit p53 activityCitation385,Citation386 and to have an anti-apoptotic roleCitation387,Citation388 in tumorigenesis. The inhibition of SIRT1 by miR-34a contributes to p53-dependent apoptosisCitation389 through deacetylating and stabilizing p53 leading to an increase in p21 and PUMA.Citation384 The E2F3 transcription factor is not known to have a role in apoptosis; however, it is a novel repressor of the ARF/p53 pathwayCitation390 and a potent transcriptional inducer of cell-cycle progression.Citation377 Therefore, the downregulation of E2F3 by miRNA-34a would have a growth inhibitory effect.Citation362,Citation374 MYCN has important roles in both cell proliferation and apoptosis, and MYCN amplification is almost always associated with the loss of chromosome 1p36.Citation382 It is probable that the effects of miR-34a on cellular molecular pathways is widespread, since enforced expression of 34A shows a dramatically altered gene expression profile with upregulation of 532 mRNA transcripts and downregulation of 681 mRNA transcripts highly enriched for those genes that regulate cell-cycle progression, apoptosis (BCL2, BIRC3 [baculoviral IAP repeat-containing 3], DcR3 [decoy receptor 3]), DNA repair, and angiogenesis.Citation330 In conclusion, although p53 is a late event in colon carcinogenesis, the deletion of a major downstream target of p53, miR-34a, as a result of chromosomal 1p deletion, could have dramatic effects on colon tumorigenesis.
MiR-101 is a miRNA that, like 34a, is pro-apoptoticCitation391 and considered to be a tumor suppressor.Citation391,Citation392 The nomenclature of miR-101-1 () and miR-101-2 is based on the fact that miR-101-1 is produced from a genomic locus on chromosome 1p31 and miR-101-2 from a genomic locus on chromosome 9p24.Citation392 Loss of heterozygosity at both 1p and 9p are known to be associated with cancer.Citation392 The mechanism by which miR-101 induces apoptosis is by targeting and decreasing the expression of the multifaceted anti-apoptotic protein Mcl-1 (myeloid cell leukemia sequence 1).Citation391 Mcl-1 undergoes rapid turnover which may serve as a convergence point for signals that affect global translation, thereby coupling translation to cell survival and the apoptotic machinery.Citation393 (The DNA damage response can also result in Mcl-1 destruction and the initiation of apoptosis.Citation394,Citation395) Mcl-1 specifically inhibits apoptosis, in part, by sequestering the pro-apoptotic Bim, Bak, tBid, and Noxa, in an inactive state. Since Mcl-1 can interact with tBid and inhibit its induction of cytochrome c release, it plays an important role in resistance to TRAIL and TNFα-induced apoptosis.Citation396,Citation397 Therefore, Mcl-1 can inhibit apoptosis induced by both the death receptor (extrinsic) and mitochondrial (intrinsic) pathways. Mcl-1 is targeted for proteasome-mediated degradation by the E3 ubiquitin ligase MULECitation398 and is rapidly degraded with a half-life of 30 minutes to 3 hours.Citation393 Its short half-life relates to the presence of a long proline-, glutamic acid-, serine-, and threonine-rich (PEST) region upstream of the Bcl-2 homology domains.Citation398 The inhibition of translation with cycloheximide can cause the rapid degradation of Mcl-1 within 30 minutes, thereby triggering the apoptotic machinery through the release of Bim and the activation of Bak and Bax.Citation393 Although full-length Mcl-1 does not interact with Bax, the caspase-mediated cleavage of Mcl-1 at Asp127 generates a fragment that induces apoptosis through direct interaction with Bax.Citation399 Phosphorylation of Mcl-1 can affect its function and degradation.Citation400 The phosphorylation of Mcl-1 is prominent in cells that accumulate in the G2/M phase of the cell cycle as a result of exposure to microtubule disrupting agents, and in synchronized cells passing through this phase.Citation401 This phosphorylation, especially at serine 64, enhances the anti-apoptotic function of Mcl-1,Citation400 thereby allowing cells to properly align their chromosomes prior to anaphase. In colorectal mucosa, the Mcl-1 protein is found in the apical cells of the crypt,Citation402,Citation403 whereas the distribution is more diffuse in the malignant cells.Citation403
In addition to the development of apoptosis resistance, the loss of miR-101 also leads to cancer progression through the overexpression of histone methytransferase EZH2 (enhancer of zeste homolog 2), a polycomb group member, with concomitant dysregulation of epigenetic pathways.Citation392,Citation404 MiR-101 also represses the expression of FOS (v-fos FBJ murine osteosarcoma viral oncogene homolog) oncogene, a key component of the AP-1 (activator protein-1) transcription factor, MYCN (a gene amplified in many tumors), and COX-2, an enzyme involved in the production of prostaglandins from the metabolism of arachidonic acid.Citation405 Enhanced expression of miRNA-101 also has an effect on the late stages of cancer, since it inhibits invasion and migration.
The p53/p63/p73 family of tumor suppressors are known to regulate the major components of the miRNA processing complex,Citation164,Citation406 which include Drosha-DGCR8, Dicer-TRBP2, and Argonaute proteins. Drosha (RNASEN) is an RNAse III endonuclease; DGCR8 is a double stranded RNA binding protein; DICER contains an RNA helicase motif required for the formation of RISC (RNA induced silencing complex); TRBP2 (trans-activation-responsive RNA binding protein 2) is a component of the miRNA loading complex (composed of DICER1, AGO2, and TRBP2) required for the formation of RISC. Argonaute proteins are endonucleases that aid in the maturation of pre-miRNAs of 60 to 70 nucleotides to mature miRNAs of 21 to 24 nucleotides; the tethering to mRNA mimics the miRNA-mediated repression of protein synthesis.Citation164,Citation407,Citation408 There are 8 members of the Argonaute family in the human genome;Citation409 4 belong to the PIWI subfamily and are expressed mainly in the testis, whereas the other 4 belong to the elF2C/AGO subfamily and are expressed in a variety of adult tissues. Ago1 and Ago2 (catalytic engine of RISC) reside in 3 complexes with distinct DICER and RNA-induced proteins involved in RNA metabolism.Citation410 Three of the 4 members of the elF2C/AGO subfamily are found in a tandem cluster of closely related Argonaute non-nucleolytic proteins,Citation411 Ago1, Ag3, and Ago4 on chromosome 1p (). Therefore, loss of chromosome 1p should have a major impact on the process of miRNA processing in the affected cells.
A family of miRNAs on chromosome 1p of particular interest to colon carcinogenesis is the miR-200 family, which includes miR-200a, -200b, and -429 (). These 3 family members are all encoded on a 7.5-kb polycistronic primary miRNA transcript and help determine the epithelial phenotype of cancer cells through the regulation of the Wnt/β-catenin signaling pathway.Citation412,Citation413 Wnt growth factors activate a cascade of intracellular events, known as the canonical Wnt pathway, which ultimately leads to a coordinated proliferation, differentiation, and sorting of the epithelial cell population that forms the colonic crypts.Citation414 In colorectal cancer, epithelial cells that acquire mutations in the Wnt/β-catenin signaling pathway gain inappropriate proliferative capabilities mimicking the effect of a permanent Wnt stimulation.Citation414 Beta-catenin is a transcription factor that translocates to the nucleus and activates target genes involved in stimulation of the cell cycle and inhibition of apoptosis. E-cadherin binds directly to β-catenin in the cytoplasm, which restricts the movement of β-catenin to the nucleus. ZEB1 and ZEB2 are proteins that repress the transcription of E-cadherin. Members of the miR-200 family were found to directly target the mRNA of ZEB1 and ZEB2,Citation412,Citation415–Citation418 upregulate E-cadherin expression in cancer cell lines, and reduce cellular motility.Citation412 Conversely, downregulation of one miR-200 family member that was tested, miR-200a, was shown to promote tumor growth by reducing E-cadherin and activating the Wnt/β-catenin signaling pathway.Citation413 Cancer progression has some similarities with embryonic development and wound healing, in which a process of epithelial-to-mesenchymal transition (EMT) occurs.Citation419 Although the EMT normally occurs as a process of stem cell differentiation, the EMT that occurs during carcinogenesis involves a change from a differentiated tumor to a more invasive dedifferentiated tumor.Citation412,Citation419,Citation420
The loss of the miR-200 family of miRNAs, coupled with the loss of 4 proteins associated with the Wnt/β-catenin signaling pathway ( below), and the loss of the pro-apoptotic miR-34a and the miRNA transcriptional protein, p73, should have a significant impact on the initiation and progression of colon cancer.
Table 5 Genes associated with the Wnt signaling pathway
Wnt/β-catenin signaling pathway ()
The Wnt signaling pathway is critical for the differentiation and sorting of the epithelial cell population necessary for the organization of the colonic crypts and for the regulation of crypt cell renewal and homeostasis.Citation414,Citation421 Wnt signaling is initiated by the binding of extracellular Wnt factors to receptors on the cell surface, which triggers a signaling cascade that leads to the accumulation of β-catenin.Citation414,Citation422 In the absence of Wnt signals, β-catenin is degraded by a multicomplex complex composed, in part, of APC (adenomatous polyposis coli), GSK3β (glycogen synthase kinase-3-beta), and the scaffold proteins Axin1 and Axin2/conductin,Citation423–Citation425 forming the β-catenin destruction box. This destruction box is responsible for the GSK3β-mediated phosphorylation of β-catenin and its subsequent degradation by the ubiquitin-proteasome pathway. The Wnt signals block this phosphorylation and degradation, resulting in the accumulation of β-catenin. Cytoplasmic β-catenin accumulation and translocation to the nucleus allows β-catenin to associate with TCF/LEF (T cell factor/lymphocyte enhancer factor) transcription factors which target genes that enhance cell survival and proliferation (ie, c-myc, cyclin D1).Citation426–Citation428 Mutations in APC, β-catenin, Axin1, or ICAT (inhibitor of beta-catenin and Tcf-interacting protein) result in the deregulated accumulation of β-catenin and the constitutive activation of Wnt signaling,Citation429–Citation431 a major cause of cancer, including colorectal cancer.Citation418,Citation424,Citation425,Citation432
There are 4 genes located on chromosome 1p that are directly involved in the Wnt signaling pathway (CTNNBIP1, DVL1, WNT2B, and WNT4) (). WNT2B and WNT4 are secreted signaling factors and Dvl1 is a cytoplasmic molecule that associates with Frat-1 to activate the Wnt signaling pathway. The loss of these positive regulators of the Wnt signaling pathway as a result of a chromosomal 1p deletion may contribute to the dysregulation of crypt organization that could initiate the carcinogenic process.Citation433 CTNNBIP1/ICAT (), on the other hand, is a negative protein regulator of the Wnt signaling pathway. ICAT disrupts β-catenin–TCF interactions,Citation434–Citation436 thereby downregulating gene expression associated with proliferation and cell survival. The crystallographic structure of ICAT indicates the mechanism by which ICAT interferes with β-catenin function. The NH2-terminal domain of ICAT binds to armadillo repeats 10–12 of β-catenin, whereas the COOH-terminal domain of ICAT binds to the groove formed by armadillo repeats 5–9.Citation435,Citation437 The armadillo repeats 5–9 are crucial for the binding of β-catenin to both TCF and E-cadherin.Citation438 The importance of ICAT in the prevention of carcinogenesis is underscored by the fact that ICAT is a multipotent inhibitor of β-cateninCitation438 by interfering with the binding of β-catenin to TCF, cadherins, and APC, with consequences for transcription, cell adhesion, and cytoskeletal function.Citation438–Citation440 The cytoplasmic and nuclear location of ICAT, using an immunohistochemical approach, is consistent with a broader role for ICAT than previously reported.Citation440
In addition to the effects on transcription and cell adhesion, ICAT can function as a pro-cell death molecule in certain situations. Overexpression of ICAT in colorectal tumor cells results in growth arrest and cell death, and serves to eliminate cells with a constitutively activated Wnt signaling pathway.Citation441 Using flow cytometry, the cell death was evidenced by a sub-G1 peak of the cell cycle, and the forced entry of cells into an illegitimate DNA synthetic phase without having undergone a prior mitosis (enhanced trypan exclusion of >4N cells).Citation441 Transgenic mice expressing ICAT also make activated T cells (dependent on β-catenin–TCF signaling for survivalCitation442,Citation443) highly susceptible to apoptosis (using annexin V staining), by reducing the expression of BclxL below a critical threshold.Citation436 The mechanism by which ICAT reduces BclxL expression is not known at the present time.
Since chromosomal instability is a major feature of colon carcinogenesis, it is appropriate to consider the role of the Wnt signaling pathway in mitotic control and aberrant Wnt signaling in the generation of chromosomal aberrations. A precedent for exploring the role of aberrant Wnt signaling in chromosomal instability are the findings that 1) multiple signaling pathways converge to orient the mitotic spindle in Caenorhabditis elegans embryos;Citation444 2) APC and EB1 (a microtubule-associated protein) have the ability to maintain proper spindle positioning in the developing nervous system of Drosophila;Citation445,Citation446 3) binding of APC protein to microtubules increases microtubule stability and is regulated by GSK3β;Citation447 4) APC has a role in chromosome segregation;Citation448 5) β-catenin is a component of the mammalian mitotic spindle and functions to ensure proper centrosome separation and subsequent establishment of a bipolar spindle;Citation449 6) GSK3β has a role in mitotic spindle dynamics and chromosome alignment,Citation450 and localizes to the centrosome and specialized cytoskeletal structures;Citation451 7) dishevelled genes are involved in mitotic progression in cooperation with polo-like kinase 1;Citation452 and 8) conductin/axin2 and Wnt signaling regulates centrosome cohesion.Citation453 It is now well established that aberrant Wnt/β-catenin signaling can induce chromosomal instability in cancer, including colon cancer.Citation454–Citation458 An understanding of the mechanisms by which specific components of the Wnt signaling pathway affect mitosis, mitotic slippage and other aspects of the cell cycle, including interaction with spindle checkpoint proteins, needs to be experimentally determined.
Tumor suppressors ()
Experiments involving somatic cell fusion and chromosome segregation established the concept that certain genes are capable of suppressing tumorigenesis.Citation459,Citation460 Tumor suppressors are genes whose miRNA or protein products reduce the formation of tumors and prevent malignant progression by decreasing proliferation, regulating the cell cycle, maintaining chromosome integrity, enhancing DNA repair, inducing apoptosis, and, by reducing angiogenesis, invasion, migration, and cell adhesion. Classic tumor suppressor genes that, when deleted or mutated, contribute to tumorigenesis in many types of tumors include p53, RB, INK4a (p16), and ARF.Citation461 In colorectal cancer, mutations and LOH of the tumor suppressor, APC, can affect both the initiation and progression of cancer, whereas the loss of p53 is a late event. Therefore, when the loss of chromosome 1p became associated with many types of cancer, including colon cancer, several groups began the quest to identify the specific tumor suppressor gene or genes located on 1p.Citation462–Citation467 Several genomic loci were identified as “hot spots” for tumor suppressor genes, which included 1p36 and 1p34. It became evident that many genes, both inside and outside of these “hot spots”, could be classified as tumor suppressors; 26 tumor suppressor genes, their genomic loci, and the function of their gene products are listed in . (Note: 11 genes classified as tumor suppressors in are not listed in other tables [– and ]).
Several tumor suppressors are haploinsufficient,Citation468 and cell cycle regulatory tumor suppressor genes seem especially dosage-sensitive.Citation469 These findings indicate that the loss of only one copy of a gene in a diploid cell could have a biologic effect.Citation469 Such a loss could contribute to cellular transformation, with the process of selection driving clonal expansion of pre-neoplastic cells.Citation8
Certain tumor suppressors play a more prominent role in tumorigenesis than others in particular tissue types. However, it is probable that the loss of numerous tumor suppressor genes as a result of a chromosomal deletion probably plays a prominent role in the initiation and progression of cancer through a “combination” of different and/or complementary adverse cellular and molecular events.Citation461,Citation467
Antioxidants ()
Four genes on chromosome 1p are associated with defense against oxidative stress (). Two of these (peroxiredoxin 1 [PRDX1] and endoplasmic reticulum protein ERP19 [TXNDC12]) utilize reducing equivalents provided through the thioredoxin system, and 2 (glutamate-cysteine ligase [modifier subunit] or GCLM and glutathione peroxidase 7 [GPX7]) utilize glutathione. One of the most important genes associated with oxidative stress is glutamate-cysteine ligase (GCL) (also called gamma-glutamylcysteine synthetase), the first rate limiting enzyme of glutathione synthesis.Citation470,Citation471 This enzyme requires coupled ATP hydrolysis to form an amide bond between the γ-carboxyl group of glutamate and the amino group of cysteine to form γ-glutamylcysteine. The enzyme consists of a heavy catalytic subunit (73 kDa) and a light (31 kDa) regulatory subunit (GCLM); the light chain or modifier subunit is found on chromosome 1p. It has been known for the past 2 decades that the ultimate formation of glutathione is required for intestinal function.Citation472 The long-term ingestion of reduced glutathione has recently been shown to suppress the accelerating effect of a beef tallow diet on colon carcinogenesis in rats.Citation473 The specific importance of GCLM to protection against oxidative stress is underscored in GCLM (−/−) knock-out mice, which are severely compromised in the oxidative stress response.Citation474
GCL can be increased by oxidative stress or glutathione depletionCitation475,Citation476 through the inhibition of SHP-1Citation477 and the activation of jun N-terminal kinase (JNK).Citation477,Citation478 The increase in GCL can protect against mitochondrial injury and numerous cellular processes that are depend on the generation of glutathione, such as cell cycle progression, inhibition of caspases (protection against apoptosis), activity of detoxification enzymes (see GSTM genes in ; discussed below), and DNA repair.Citation479–Citation482 Recent studies indicate that a reduced state of proteins in the nucleus is an important environment that induces heterochromatin formationCitation482 and the regulation of histones and PARP activities.Citation483
Defense against environmental and metabolic toxicity ()
Chromosome 1p contains 19 genes associated with protection against toxins/carcinogens derived from the environment, dietary/cooking-derived components, and metabolism (). These genes consist of 2 arylacetamide deacetylase-like enzymes, 4 members of the aldo-keto reductase family, 6 members of the cytochrome P450 family of polypeptides, all 5 members of the mu class of glutathione-S-transferases (GSTs), and 2 metal response element binding transcription factors. A compilation of the 10 most significant transcripton factors capable of targeting the 5′-upstream promoter regions of these 19 genes (GeneCards [SABiosciences’ database; UCSC Genome Browser]) indicates the possible involvement of 95 distinct transcription factors that control their expression. In addition, the Wnt/beta-catenin signaling pathway has been shown to activate various P450 family and GST mu class enzymes in mouse models.Citation484 Since transcription factors respond to different cellular demands and stresses, the presence of these genes on chromosome 1p indicates that the loss of this chromosome arm could compromise the cell’s ability to respond to a variety of environmental toxins/carcinogens that could damage DNA.
It is of interest that all 5 genes of the mu class of GSTs are located on chromosome 1p. The 5 genes are arranged in tandem in the physical order 5′-M4-M2-M1-M5-M3-3′.Citation485,Citation486 The M4-M2-M1-M5 sequence in the gene cluster is oriented in a head-to-tail orientation, whereas the M3 gene is oriented tail-to-tail with respect to the adjacent M5 gene, and is therefore transcribed in the reverse orientation relevant to the other 4 GST mu genes.Citation485 This GST mu gene cluster functions in the detoxification of electrophilic compounds by conjugating glutathione to a wide number of endogenous and exogenous toxins/carcinogens.Citation487 Genetic polymorphisms in GSTM1 increase susceptibility to gastric and colorectal adenocarcinomas.Citation488 In addition, about 70% of human loci is deleted for GSTM1 and 50% of the human population is homozygous deleted for GSTM1.Citation485 This deletion is a result of unequal crossing-over between the two 2.3 kb repeated regions in the intergenic regions that flank the GSTM1 gene. Homozygous deletion of GSTM1 results in increased baseline chromosomal aberrations in lymphocytes among smokers, indicating the role of epoxides and other reactive metabolites of polycyclic aromatic hydrocarbons in inducing genomic instability in these compromised cells.Citation489 All 5 GSTM genes have distinct promoter regions that respond to a different array of transcription factors. Therefore, the loss of chromosome 1p would compromise cellular defenses against toxins/carcinogens, especially in individuals harboring the GSTM1 deletion or other specific polymorphisms.
Development of resistance to cell death and the propagation of cells with DNA damage and chromosomal defects (summary)
We have described in this review how the combination of the persistent damage to a cell’s genome with the inability of that cell to adequately repair the damage or die in response to the excessive damage, is a dangerous situation which can result in clonal selection and the development of colon carcinogenesis. The molecular and cellular mechanisms that are associated with the death of cells are most complex, and include both caspase-dependent and caspase-independent processes. Listed in – are 27 pro-apoptotic/pro-cell death genes found on chromosome 1p, whose simultaneous loss caused by a chromosome 1p deletion could have a major impact on the development of resistance to cell death. In , we extract from those tables the specific genes whose products contribute to cell death. Caspase-9 and both subunits of DNA fragmentation factor are on the downstream execution phase of apoptosis, and the consequences of their loss are obvious. However, the loss of other gene products (eg, TP73, miR-34a) can have pleiotropic effects on cell death pathways because of multiple transcriptional or translational targets. In addition, TP73, KIF1B, and E2F2 are classified as haploinsufficient genes, with loss of function implied with the presence of only 1 allele.Citation490 Some gene products have dual DNA repair/pro-cell death functions (eg, MUTYH) and dual mitosis/pro-cell death functions (KIF1B). One can see () that, in addition to classic pro-apoptotic genes, there are dual role cell survival/pro-cell death genes, DNA damage-response genes, various tumor suppressor genes, genes associated with mitosis, miR-NAs, Wnt signaling, and protection against the generation of peroxides. The mechanism of action of these 27 genes in the control of cell fate is an active area of investigation and beyond the scope of this review. This detailed study of the implications of the loss of chromosome 1p serve as an example of how specific chromosomal deletions can have a major impact on carcinogenesis.
Table 9 Summary of pro-cell death genes on chromosome 1p
Role of dietary factors in colon carcinogenesis (Citation491–Citation538)
In this section we first address what alteration in specific dietary factors can lead to the loss of chromosome segments or entire chromosome arms in general to produce loss of heterozygosity. Second, we will consider how the consequences of the loss of genes located on chromosome 1p might be affected by pro-carcinogenic and anti-carcinogenic dietary factors. Our approach is to show how specific dietary factors may influence the molecular and cellular processes affected by chromosome 1p loss that were described in previous sections. Links of diet to any of the specific genes lost by the 1p deletion (see –) are listed in .
Table 10 Preventive effects of dietary factors on processes and signaling pathways associated with genes located on chromosome 1p
Diets high in fat,Citation473,Citation539–Citation547 but low in fiber,Citation540,Citation548–Citation551 low in vegetable intake,Citation552–Citation555 and micronutrient deficientCitation556–Citation560 induce oxidative stress and DNA damage and adversely affect many molecular pathways that prevent genomic instability and apoptosis resistance, 2 major processes that, together, enhance the development of sporadic colon cancer.
The effects of diet likely occur early in the carcinogenesis process, since an altered vegetable intake is known to affect pivotal carcinogenesis pathways in the colonic mucosa from adenoma patients and controls.Citation561 Although 2 alleles are associated with each gene, and the loss of 1 allele may be compensated for by the other, many genes are reported to be haploinsufficient, including those associated with the mitotic checkpoint.Citation562 It is relevant that TP73, KIF1B, and E2F2, found on chromosome 1p, have also been reported to be haploinsufficient,Citation490,Citation563,Citation564 and could have dramatic consequences for colon tumorigenesis if only 1 allele is expressed in colonic epithelial cells. It is possible that many other genes may be found to be haploinsufficient in the future, since a map of 1079 probable haploinsufficient genes has been compiled by systematic identification of genes unambiguously and repeatedly compromised by copy number variation among 8458 apparently healthy individuals.Citation565 Those genes with a high probability of exhibiting haploinsufficiency were enriched among genes implicated in human dominant diseases and among genes causing abnormal phenotypes in heterozygous knockout mice.Citation565 In addition, the loss of several genes on the same chromosome arm that affect a particular molecular pathway (see –) may together have a significant effect on that pathway, although the loss of a single gene may have little effect. Specific dietary factors may decrease the protein levels of certain genes through post-translational mechanisms (eg, proteasomal degradation), thereby inducing a functional pseudo-biallelic loss of a gene, one through a physical loss of the chromosomal segment harboring that gene, and the other an actual degradation of the gene product.
Although dietary factors may affect many processes associated with carcinogenesis, we will evaluate specific factors associated with oxidative stress/inflammation, since these genotoxic processes are known to have major effects on the initiation and progression of cancer, including colon cancer.Citation566–Citation578 Direct damage to DNA, assessed by immunohistochemical staining of 8-oxoG, correlates with poor survival in colorectal cancer.Citation579 ROS can cause excessive DNA double strand breaks, resulting in the loss of chromosome segments or entire arms, depending on the location of the break. In addition, several DNA repair proteins are degraded through an oxidative mechanism,Citation580,Citation581 thereby affecting DNA repair and increasing susceptibility to cancer.Citation582 Oxidative stress can affect spindle organization, induce centrosome amplification, cause proteolysis of components of the anaphase-promoting complex, and override the spindle checkpoint, thereby affecting chromosomal stability. Therefore, oxidative stress can induce a mutator phenotype in affected cells.Citation583 The big question is what dietary factors contribute directly to oxidative DNA damage and aneuploidy (alteration in the number of whole chromosomes or chromosomal segments). We now address several dietary factors that may be associated with these forms of genomic instability. Although the literature on dietary factors associated with genomic instability is substantial, we have chosen to discuss the effects of a high-fat diet, folate deficiency, and niacin deficiency, since the molecular and cellular mechanisms associated with the overabundance or deficiency of these factors have been especially well studied.
A high-fat diet derived from beef tallow or corn oil (eg, linoleic acid, palmitic acid) is one of the major causes of sporadic colon cancer. Long-chain nonesterified (“free”) fatty acids (FFA) and some of their derivatives and metabolites can modify the intracellular production of ROS, in particular superoxide anions and hydrogen peroxide, in part, through their interference with the mitochondrial electron transport chain.Citation584 FFA can also interfere with the glutathione system and stimulate the generation of superoxide anions from phagocytic NADPH oxidases.Citation584 Chronic exposure of cells to FFA (eg, palmitic acid) can also alter miRNA expression (eg, miR-34a, miR-146).Citation585
The genotoxicity associated with a high-fat diet is also caused, in part, by high concentrations of hydrophobic bile acids released into the gastrointestinal tract in response to high-fat meals where they act as detergents to aid in the digestion of fats. Our research group showed that deoxycholic acid (a major hydrophobic bile acid in the human colon) induces ROSCitation586–Citation589 in vitro, and oxidative DNA damage,Citation590 sessile adenomas,Citation591 and colon cancerCitation592 in dietary-related mouse models. In addition to the bile acid-induced formation of 8-oxoG in guanine bases of DNA and the induction of DNA strand breaks (activation of γ-H2AXCitation593 and PARPCitation594), we have shown that deoxycholic acid affects genomic instability at the chromosomal level.Citation595 Evidence indicating the induction of chromosomal damage by deoxycholic acid include the formation of micronuclei and aberrant mitoses, attenuation of activation of the nocodazole-induced spindle checkpoint, and decrease in protein expression of major spindle checkpoint proteins (eg, Mad2, BubR1, securin). The dramatic effect of deoxycholic acid on the process of mitosis is underscored by the finding that deoxycholic acid modulates 71 mitosis-related genes at the mRNA and/or protein levels in vitro and in vivo using mouse models.Citation8 The induction by hydrophobic bile acids of both DNA and chromosomal damage indicates that hydrophobic bile acids are endogenous carcinogens that, at high pathophysiologic concentrations, are capable of contributing to the initiation and progression of colon cancer.Citation8,Citation189,Citation595–Citation597 In addition to causing genomic instability, deoxycholic acid can activate survival pathways (eg, NF-κBCitation594 and autophagyCitation598), which allow for the survival and selection of cells with genomic instability.Citation8,Citation599
Coffee drinkers have a lower incidence of cancer, including that of the colon and rectum.Citation600–Citation603 One coffee compound that we found to prevent the formation of bile acid-induced proximal colon cancer in a mouse model is chlorogenic acid (CGA), the ester of caffeic acid with quinic acid.Citation592 CGA is one of the most abundant polyphenols in the human diet, with coffee, fruits (eg, blueberry, strawberry, raspberry, apple), and vegetables (eg, eggplants, potato, carrot, tomato) as its major sources.Citation493,Citation604 CGA and its metabolites are likely responsible, in part, for the lower risk of rectal cancer associated with the consumption of decaffeinated coffee in 2 large prospective cohort studies.Citation603 One possible mechanism by which polyphenols can reduce colon cancer in this model is through the reduction in deoxycholic acid levels.Citation605 In this study, Han et alCitation605 report that when rats on a high-fat diet (30% beef tallow) received dietary curcumin (component of the Indian spice turmeric) or caffeic acid (metabolite of CGA), the fecal concentration of deoxycholic acid was substantially reduced. In addition, dietary supplementation of this high-fat diet with caffeic acid, catechin (plant polyphenol), rutin (citrus flavonoid glycoside), and ellagic acid (plant polyphenol) significantly reduced the levels of fecal lithocholic acid, a second major hydrophobic bile acid and risk factor for colon cancer.Citation605
The induction of double-strand breaks is a major cause of the production of chromosomal fragments and the deletion of hundreds to thousands of genes. An important DNA repair protein in preventing large chromosomal deletions is Parp-1Citation606 (). DNA strand breakage is directly caused by ROS (which would be enhanced due to the loss of genes encoding antioxidant proteins in the chromosome 1p deletion []) or as a result of the activity of base excision repair enzymes (see ). Strand breakage activates Parp-1, which is involved with opening up chromatin and allowing DNA repair processes to occur, including base excision repair, single-strand and double-strand repair (). Shibata et alCitation606 carried out mutation analysis using Parp-1 knockout (Parp−/−) mice, and found that PARP deficiency enhanced deletion mutations, especially >1 kbp. A dietary micronutrient whose deficiency has a major effect on PARP activity is niacin (vitamin B3) obtained from meat and corn. The term niacin refers to nicotinic acid and nicotinamide, which are both used by humans to form NAD+. PARP-1 utilizes NAD+ to make poly(ADP-ribose) needed for poly(ADP-ribosyl)ation of proteins. In keeping with the protective effect of PARP, we determined that pre-treatment of cells in vitro with nicotinic acid and nicotinamide protected against bile acid-induced apoptosis,Citation607 presumably by enhancing PARP-mediated DNA repair of bile acid-induced DNA damage and replenishing the NAD+ levels in mitochondria. In addition, we showed that pre-treatment of cells with nicotinic acid and nicotinamide upregulated the mRNA levels of the glycolytic enzymes, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and glucose-6-phosphate dehydrogenase (G6PD).Citation608 GAPDH and G6PD may protect against oxidative stress, in part through the generation of the reduced pyridine nucleotides, NADH and NADPH, respectively, from NAD+.Citation608 Niacin supplementation was even reported to improve pellagra (severe niacin deficiency) in a patient with Crohn’s disease,Citation609 a pre-cancerous inflammatory conditionCitation610 associated with oxidative DNA damage.Citation611 Pellagra most probably developed in these Crohn’s disease patients through a combination of intestinal malabsorption of niacin/nicotinic acidCitation612,Citation613 and the high demand for NAD+ that accompanies DNA damage-induced PARP-1 activity (see ). Work from our laboratory indicated that CGA and its metabolites, caffeic acid, m-coumaric acid, and 3-(m-hydroxyphenyl) propionic acid, increased PARP-1 protein expression.Citation493 The modulation of PARP-1 protein levels by CGA may explain, in part, the colon cancer preventive properties of CGA when added as a supplement to the bile acid-induced colon cancer mouse model.Citation592
The mechanisms by which chromosome segments are deleted and translocated can be most complex. Deletions and translocations can arise from centromeric instability and telomeric instability.Citation7,Citation614 and have been proposed as possible mechanisms for chromosomal aberrations associated with chromosome 1.Citation615–Citation617 Centromeric instability can result from hypomethylation or acetylation of pericentromeric heterochromatin, resulting in decondensation/uncoiling/disruption of the centromereCitation618–Citation620 and loss of the affected chromosome arms. Telomeric instability is characterized by telomeric fusions, formation of anaphase bridges during mitosis, broken chromosomes upon the stress of cell division, and fusion of chromosomal fragments to chromosome ends. This cycle of chromosomal abberations is referred to as breakage–fusion–bridge cycles.Citation107–Citation114,Citation621 Six genes found on chromosome 1p (APITD1, CCDC28B, CDCA8, HDAC1, KIF2C, RCC2) are associated with centomeres (see ), and whose loss would affect centromeric instability. A deficiency of HDAC1, for example, has been reported to disrupt pericentromeric heterochromatin.Citation622 In addition to its role in the repair of interstrand cross-links,Citation623 APOLLO (aka DCLRE1B [DNA cross-link repair 1 B]) is also involved in the protection of telomeres (see ). APOLLO is stabilized when bound to the telomere-binding protein TRF2, and protects human telomeres in S phaseCitation624 (). A reduced level of APOLLO results in an increased number of telomere-induced DNA damage foci and telomeric fusions in S-phase,Citation624 suggesting that APOLLO contributes to a processing step associated with the replication of chromosome ends. Hydrophobic bile acids, probably through the generation of oxidative stress, can modulate 71 genes associated with mitosisCitation8 and decrease the protein expression of 3 major spindle checkpoint proteins (eg, Mad2, BubR1, securin).Citation8 These alterations in gene expression, coupled with direct oxidative damage to components of the mitotic apparatus, may be responsible, in part, for the observed bile acid-induced mitotic aberrations.Citation595 It is, therefore, possible that bile acids may contribute to the loss of chromosome 1p through its effects on centromere instability and telomeric fusions.
Another mechanism by which large chromosomal deletions can occur is through folic acid deficiency.Citation625,Citation626 Folic acid can attenuate the loss of heterozygosity of the DCC tumor suppressor gene in the colonic mucosa of patients with colorectal adenomas,Citation625 indicating that folic acid deficiency can affect allelic deletion and associated micronuclei formation.Citation627,Citation628 Folates are a group of water-soluble B vitamins (obtained from leafy, green vegetables, the whole grain quinoa, and lentils) whose deficiency contributes to colon cancer.Citation629–Citation633 Folates maintain DNA stability through their ability to donate one-carbon units for cellular metabolism and particularly for DNA biosynthesis, repair, and methylation.Citation629,Citation633 Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in one-carbon metabolism. MTHFR catalyzes a unidirectional reaction that determines the balance between cellular availability of 5,10-methylenetetrahydrofolate, used for thymidylate and purine synthesis, and methyltetrahydrofolate used for biological methylation.Citation629 Folate deficiency, therefore, enhances carcinogenesis by impairing normal methylation and nucleotide synthesis, and creates an imbalance between the partitioning of cellular folates into these two pathways. Inhibition of folate metabolism results in excessive uracil misincorporation into DNACitation633,Citation634 with approximately 4 million uracil bases/cell.Citation559 The repair of 2 adjacent uracil residues on opposite strands of DNA can result in a double-strand break, leading to chromosomal breakage and aneuploidy.Citation558,Citation629,Citation634 Folate deficiency also induces hypomethylation and inhibits DNA excision repair in immortalized normal human colon epithelial cellsCitation633 and in the rat colon.Citation635
Recent studies have implicated folate deficiency in the modulation of miRNA expression.Citation497,Citation636 Using microarrays of 385 known human miRNAs, it was determined that folate deficiency in vitro in cultured cells induced a statistically significant fold-change in 24 miRNAs.Citation636 One of these miRNAs was miR-34a, which is found on chromosome 1p and involved in p53-mediated signaling (see and the section on MiRNA and MiRNA Processing). MiRNAs were also determined to be altered in patients on a folate-deficient diet.Citation636 In addition to folate deficiency, polymorphisms of MTHFR and altered folate levels are associated with colon cancer risk.Citation637–Citation640 The fact that MTHFR is located on chromosome 1p at 1p36.22 indicates that the loss of this chromosome arm, coupled with folate deficiency, can have major effects on genomic instability.
In this section we have considered how dietary factors such as niacin, folic acid, and a low-fat diet associated with low bile acid levels, together with antioxidants that protect against oxidative DNA damage (), might affect the processes relevant to carcinogenesis that are altered by chromosome 1p loss. In addition to a deficiency in dietary factors that prevent oxidative DNA damage, a deficiency of certain dietary factors that modulate DNA repair proteins, miRNA expression, antioxidant enzymes, defenses against environmental toxicity, and the Wnt signaling pathway () can exacerbate the effects of the loss of chromosome 1p. An understanding of the complex molecular and cellular pathways that are affected by dietary factors is an enormous undertaking, but one that has become a focus of colon cancer prevention.
Acknowledgements
This work was supported in part by NIH 5 R01 CA119087, Arizona Biomedical Research Commission Grant #0803, VA Merit Review Grant 0142 of the Southern Arizona Veterans Affairs Health Care System and Biomedical Diagnostics and Research, Inc., Tucson, Arizona.
Disclosure
The authors declare no conflicts of interest.
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