MicroRNA in cancer: New hopes for antineoplastic chemotherapy

Figures & data

Table I. Tumor-suppressor miRs.

miR	Targets	Tumor	Impact on metastasis	Description
miR-15/16	BCL2	CLL		BCL2 repression by these microRNAs induces apoptosis in a leukemic cell line model
	COX-2	Colon cancer		miR-16 as a central post-transcriptional regulator of COX-2 and shows the ability of elevated levels of HuR to antagonize miR-16 function
	CHEK1	Follicular lymphoma		Distinct microRNA profiles are associated with an increased proliferative capacity and a ‘late’ germinal center B-cell phenotype
	CEBPβ, CDC25a, CCNE1	Fibroblast		Upon cell cycle re-entry, the rapid decay of miR-16 alleviates repression of target genes, allowing proper resumption of the cell cycle
	VEGF, VEGFR2, FGFR1	Fibroblast		miR-16 plays important roles in regulating cell-intrinsic angiogenic activity of endothelial cells
	FGF2, FGFR1	Cancer-associated fibroblast		Down-regulation of miR-15 and miR-16 in cancer-associated fibroblasts (CAFs) promotes tumor growth and progression
	CCNE1			miR-15 and miR-16 families as novel transcriptional targets of E2F, which, in turn, modulates E2F activity
	FGFR1, PI3KCa, MDM4, VEGFa	Multiple myeloma		Deletion of miR-15/16 is commonly observed in early stages of multiple myeloma
	WIP1			Role of miR-16 in the regulation of Wip1 phosphatase in the DNA damage response and mammary tumorigenesis
	BMI-1	Ovarian cancer		Bmi-1 is down-regulated by miR-15a or miR-16 expression and leads to reduction in ovarian cancer cell proliferation and clonal growth
	CCND1, CCND2, CCNE1	Lung cancer		Overexpression of miR-15/16 induces arrest in G(1)-G(0)
miR-31	ITGA5, RDX, RhoA, FZD3, M-RIP, MMP16	Breast cancer	Suppresses	miR-31 uses multiple mechanisms to oppose metastasis
	SATB2	Cancer-associated fibroblast		New insights into tumor–stroma interaction and involvement of miR-31 in regulation of tumor cell motility
miR-34	SIRT1	Colon cancer		miR-34 suppression of SIRT1 leads to apoptosis only in colon cancer cells with wild-type p53
	BCL2, NOTCH, HMGA2			miR-34-mediated suppression of self-renewal is related to the direct modulation of the downstream targets Bcl-2, Notch, and HMGA2
	MYC	Fibroblast		During senescence, miR-34a targets the proto-oncogene MYC and co-ordinately controls a set of cell cycle regulators
	AXL	Lung cancer		Axl receptor is regulated by miR-34a and miR-199a/b, suppressed by promoter methylation in solid cancer
	MET	Ovarian cancer		MET is a critical effector of p53, and inhibition of MET may be an effective antimetastatic approach to treat cancers with p53 mutations
	NANOG, SOX2, MYCN	Embryonic fibroblast		Suppression of reprogramming by miR-34a due to repression of pluripotency genes
	SNAIL	Colon cancer		A new link between p53, miR-34, and Snail1 in the regulation of cancer cell EMT programs
miR-143/145	KRAS, RREB1	Pancreatic cancer		miR-143/miR-145 are suppressed by KRAS through RREB1, revealing a feed-forward mechanism that potentiates Ras signaling
	KRAS, MYC, CCND2, CDK6, E2F3	Colon cancer		EGFR suppresses miR-143 and miR-145 in murine models of colon cancer
	BCL2	Cervical cancer		Promotion of apoptosis by miR-143 through the suppression of BCL2
	PAI1	Bladder cancer		miR-145 and PAI1 as clinically relevant biomarkers in bladder cancer
	PRC1, PLK1	Liposarcoma		The down-regulation of PRC1 and its docking partner PLK1 suggests that miR-143 inhibits cytokinesis in these cells
	MLL-AF4	ALL		Therapeutic promise of up-regulating miR-143 expression for MLL-AF4 B-cell ALL
	MMP-13	Osteosarcoma		Down-regulation of miR-143 correlates with the lung metastasis of human osteosarcoma cells by promoting cellular invasion, probably via MMP-13 up-regulation
	ERK5	Burkitt lymphoma		miRs-143 and -145 may be useful as biomarkers that differentiate B-cell malignant cells from normal cells
Let-7 family	KRAS	Lung cancer		The let-7 family negatively regulates let-60/RAS in C. elegans and lung tumors
	HMGA2			Chromosomal translocations associated with human tumors disrupt repression of high mobility group A2 (Hmga2) by let-7 miRNA
	MYC	Burkitt lymphoma		Dysregulation of let-7 participates in genesis and maintenance of Burkitt lymphoma and other MYC-dysregulated cancers
	IMP-1			Let-7-oncofetal proteins could be novel therapeutic targets and potential biomarkers for cancer treatment
	DICER			Existence of a regulatory loop to regulate the equilibrated state of Dicer and various miRNAs
	CDC-34	Fibroblast		Let-7 represses Cdc34, stabilizes Wee1 kinase, and increases a fraction of cells in G(2)/M in primary fibroblasts
	IL6	Breast cancer		Inflammation activates a positive feedback loop that maintains the epigenetic transformed state
	E2F2, CCND2	Prostate cancer		Let-7a acts as a tumor suppressor in prostate cancer by down-regulating E2F2 and CCND2
	BCL-XL	Liver cancer		Let-7 suppresses Bcl-xL expression in hepatocellular carcinomas and potentiates sorafenib-induced apoptosis
	PLCγ1	Breast cancer		Tumor-suppressor function by negatively regulating EGF-driven cell invasion, viability, and cell cycle progression in breast cancer
miR-200 family	ZEB1, ZEB2	Breast cancer	Suppresses	Down-regulation of the miR-200 family may be an important step in tumor progression
	ERRFI-1	Bladder cancer		miR-200 is sufficient to restore EGFR dependency at least in some of the mesenchymal bladder cancer cells
	ZEB1, CTNNB1	Nasopharyngeal carcinoma		The inhibitory effects of miR-200a on cell growth, migration, and invasion are mediated by distinct targets and pathways
	BMI-1	Pancreatic cancer		ZEB1 links EMT and stemness maintenance by suppressing the miR-200 family and thereby promotes migration
	PLCγ1	Breast cancer		Tumor-suppressor function by negatively regulating EGF-driven cell invasion, viability, and cell cycle progression in breast cancer
	FAP1			miR-200c sensitizes cells to apoptosis mediated by CD95
	SUZ12	Breast cancer		The miR-200b-Suz12-cadherin pathway is important for cancer stem cell growth and invasive ability
	FLT1/VEGFR1	Lung cancer		miR-200 suppresses lung adenocarcinoma metastasis by targeting Flt1 in tumor cells
	JAG1, MALM2, MALM3			These findings explain increased Notch signaling in some types of cancers, where mutations in Notch pathway genes are rare
	FN1, LEPR, NTRK2, ARHGAP19	Breast and endometrial cancer		miR-200c actively represses a program of mesenchymal and neuronal genes involved in cell motility and anoikis resistance
	p38α	Ovarian cancer		miR-200a-dependent stress signature correlates with improved survival of patients in response to treatment

Table II. OncomiRs in action.

miR	Targets	Tumor	Impact on metastasis	Description
miR-106a ∼ 363, miR-106b ∼ 25	BIM, p21	Gastric cancer		The miR-106b-25 cluster is involved in E2F1 post-transcriptional regulation and may play a key role in the development of TGFβ resistance in gastric cancer
	E2F1	Prostate cancer		microRNA expression becomes altered with the development and progression of prostate cancer. Some of these microRNAs regulate the expression of cancer-related genes in prostate cancer cells
	PTEN	Prostate cancer		Proto-oncogenic miRNA-dependent network for PTEN regulation
miR-21	PTEN	Cholangiocarcinoma	Promotes	miR-21 modulates gemcitabine-induced apoptosis by phosphatase and the tensin homolog deleted on chromosome 10 (PTEN)-dependent activation of PI3-kinase signaling
	TPM1	Breast cancer		Suppression of miR-21 can inhibit tumor growth
	PDCD4	Breast cancer		The tumor suppressor protein programmed cell death 4 (PDCD4) is regulated by miR-21, and it has been demonstrated that PDCD4 is a functionally important target for miR-21 in breast cancer cells
	SPRY1			miR-21-null mice show a significant reduction in papilloma formation compared with wild-type mice due to the up-regulation of its tumor-suppressor targets
	RECK, TIMP3	Glioblastoma		The inhibition of miR-21 provides a novel therapeutic approach for ‘physiological’ modulation of multiple proteins whose expression is deregulated in cancer
	p63, JMY, TOPORS, TP53BP2, DAXX, HNRPK, TGFβRII	Glioblastoma		miR-21 targets multiple important components of p53, transforming growth factor-β (TGFβ), and mitochondrial apoptosis tumor-suppressive pathways
	MARKS	Prostate cancer		miR-21 could promote apoptosis resistance, motility, and invasion in prostate cancer cells
	ANP32A, SACA4	Prostate cancer
miR-10a/10b	HOXB1, HOXB3	Pancreatic cancer	Promotes	miR-10a is a key mediator of metastatic behavior in pancreatic cancer that regulates metastasis via suppression of HOXB1 and HOXB3
	HOXD10	Breast cancer		TWIST transcription factor induces expression of a specific microRNA that suppresses its direct target and in turn activates another pro-metastatic gene, leading to tumor cell invasion and metastasis
	KLF4	Esophageal cancer		A significant correlation of miR-10b level with cell motility and invasiveness
	TIAM1	Breast cancer		A mechanism for the regulation of Tiam1-mediated Rac activation in breast cancer cells
	Nf1	Ewing's sarcoma		miR-10b may play an important role in NF1 tumorigenesis through targeting neurofibromin and RAS signaling
miR-107/103	DICER	Breast cancer	Promotes	Dicer inhibition drifts epithelial cancer toward a less-differentiated, mesenchymal fate to foster metastasis
miR-9	PRDM1/Blimp-1	Lymphomas	Promotes	miRNA-mediated down-regulation of PRDM1/Blimp-1 may contribute to the phenotype maintenance and pathogenesis of lymphoma cells by interfering with normal B-cell terminal differentiation
	CDH1	Breast cancer
	CAMTA	Glioblastoma		miR-9 is highly expressed in glioblastoma cancer stem cells and reduces the levels of CAMTA tumor-suppressor
miR-17–92	TSP-1, CTGF	Colon	Promotes	Up-regulated in colonocytes coexpressing K-Ras, c-Myc and p53 impaired activity
	E2F2, E2F3	Prostate/Burkitt lymphoma/testis carcinoma/		Presence of an autoregulatory feedback loop between E2F factors and miR-17/92
	BIM, PTEN	c-Myc-induced lymphoma		Transgenic mice with higher expression of miR-17/92 in lymphocytes
	HIF1α	Lung cancer		Intricate and finely tuned circuit involving c-myc, miR-17/92, and HIF1α
	PTPRO	Cervix tumor cell line		PTPRO gene is co-regulated by both E2F1 and miR-17/92 at transcriptional and post-transcriptional level, respectively
	p63	Myeloid cells		miR-92 increases cell proliferation by negative regulation of an isoform of the cell cycle regulator p63
	BIM, PTEN, PRKAA1, PPP2R5e	T-cell acute lymphoblastic leukemia		Functional genomics approach reveals a co-ordinate clamp-down on several regulators of phosphatidylinositol-3-OH kinase-related survival signals by the leukemogenic miR-19
	JAK1	Endothelial cells		The miR-17/92 family may provide an interesting therapeutic perspective specifically to enhance therapeutic angiogenesis
	HBP1	Breast cancer		The miR-17/92 cluster plays an important role in breast cancer cell invasion and migration by suppressing HBP1 and subsequently activating Wnt/β-catenin
	p21(WAF1)	Ras-induced senescent fibroblasts		Disruption of senescence by miR-17/92 or its miR-17/20a components leads to enhanced oncogenic transformation by activated Ras in primary human cells
	TGFβII SA4	Glioblastoma		miR-17/92 attenuates the TGFβ signaling pathway to shut down clusterin expression, thereby stimulating angiogenesis and tumor cell growth
	MnSOD, GPX2, TRXR2	Prostate		miR-17/92 may suppress tumorigenicity of prostate cancer through inhibition of mitochondrial antioxidant enzymes
miR-221/222	p27^kip1	Glioblastoma, prostate and thyroid carcinoma	Promotes	Certain cancer cell lines require high activity of miR-221/222 to maintain low p27^kip1 levels and continuous proliferation
	p57^kip2	Normal fibroblast		Up-regulation of miR-221/222 is tightly linked to the initiation of S phase with growth factor signaling pathways that stimulate cell proliferation
	PTEN, TIMP3	Non-small cell lung cancer and hepatocellular carcinoma		miR-221/222, by targeting PTEN and TIMP3 tumor suppressors, induce TRAIL resistance and enhance cellular migration. The MET oncogene is involved in miR-221/222 activation through the c-Jun transcription factor
	FOXO3A	Breast cancer		The miR-221/222 cluster targets FOXO3A to suppress p27^kip1 also at a transcriptional level
	KIT	Endothelial cells		Interaction between miR-222 and c-Kit is likely to be part of a complex circuit that controls the ability of endothelial cells to form new capillaries
	ESR1	Breast cancer		Modulation of ERα is associated with antiestrogen therapy
	PUMA	Glioblastoma		miR-221/222 directly regulate apoptosis by targeting PUMA in glioblastoma
	TRSP1	Breast cancer		miR-221/222 promote EMT and contribute to the more aggressive clinical behavior of basal-like breast cancers
	PTPμ	Glioblastoma		miR-221/222 regulate glioma tumorigenesis at least in part through the control of PTPμ protein expression
	DICER	Breast cancer		Dicer is low in ERα-negative breast cancers, since such cells express high miR-221/222
	APAF1	Non-small cell lung cancer		miR-221/222 are modulated by both epidermal growth factor (EGF) and MET receptors, and, by targeting APAF1, miR-221/222 are responsible for gefitinib resistance
miR-155	SOCS1	Breast cancer		miR-155 is an oncomiR in breast cancer, and it has been suggested that miR-155 may serve as a bridge between inflammation and cancer
	CEBPB, PU.1, CUTL1, PICALM	AML		miR-155 as a contributor to physiological GM expansion during inflammation and to certain pathological features associated with AML
	BACH1, ZIC3			The induction of miR-155 by EBV contributes to EBV-mediated signaling in part through the modulation of transcriptional regulatory factors
	ETS1, MEIS1	Human cord blood CD34+		miR-155 is required for megakaryocytic proliferation and differentiation
	C-MAF	Lymphocytes		bic/microRNA-155 plays a key role in the homeostasis and function of the immune system
	HGAL	Diffuse large B-cell lymphoma		Cell dissemination and aggressiveness is a phenotype of DLBCL typically expressing high levels of miR-155 and lacking HGAL expression
	JMJD1A	Nasopharyngeal carcinoma		Up-regulation of miR-155 is partly driven by LMP1 and LMP2A, and results in down-regulation of JMJD1A, associated with N stage and poor prognosis
	WEE1	Breast cancer		miR-155 enhances mutation rates by decreasing the efficiency of DNA safeguard mechanisms by targeting of cell cycle regulators such as WEE1
	TP53INP1	Pancreatic cancer		TP53INP1 expression is repressed by the oncogenic micro RNA miR-155, which is overexpressed in pancreatic carcinoma cells
	SMAD1, SA5, HIVEP2, CEBPB, RUNX2, MYO10			Role for miR-155 in controlling BMP-mediated cellular processes
	FOXO3a	Breast cancer		Molecular links between miR-155 and FOXO3a affect cell survival and response to chemotherapy in breast cancer
	hMSH2, hMSH6, and hMLH1	Colon cancer		Inactivation of mismatch repair is induced by miR-155
	SMAD5	Diffuse large B-cell lymphoma		Highlighted a hitherto unappreciated role of SA5 in lymphoma biology and defined a unique mechanism used by cancer cells to escape TGFβ's growth-inhibitory effects