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Review

Role of Epigenetics in Pancreatic Ductal Adenocarcinoma

ORCID Icon, ORCID Icon & ORCID Icon
Pages 89-110 | Received 13 May 2022, Accepted 30 Sep 2022, Published online: 17 Jan 2023

References

  • National Cancer Institute: Surveillance, Epidemiology, and End Results Program . Cancer stat facts: pancreatic cancer. https://seer.cancer.gov/statfacts/html/pancreas.html
  • Rahib L , SmithBD , AizenbergR , RosenzweigAB , FleshmanJM , MatrisianLM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res.74(11), 2913–2921 (2014).
  • Bailey P , ChangDK , NonesKet al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature531(7592), 47–52 (2016).
  • Roberts NJ , NorrisAL , PetersenGMet al. Whole genome sequencing defines the genetic heterogeneity of familial pancreatic cancer. Cancer Discov.6(2), 166–175 (2016).
  • Vincent A , HermanJ , SchulickR , HrubanRH , GogginsM. Pancreatic cancer. Lancet378(9791), 607–620 (2011).
  • Solomon S , DasS , BrandR , WhitcombDC. Inherited pancreatic cancer syndromes. Cancer J.18(6), 485–491 (2012).
  • Baylin SB , JonesPA. A decade of exploring the cancer epigenome – biological and translational implications. Nat. Rev. Cancer11(10), 726–734 (2011).
  • Bonasio R , TuS , ReinbergD. Molecular signals of epigenetic states. Science330(6004), 612–616 (2010).
  • Waddington CH . The epigenotype 1942. Int. J. Epidemiol.41(1), 10–13 (2012).
  • Berger SL , KouzaridesT , ShiekhattarR , ShilatifardA. An operational definition of epigenetics. Genes Dev.23(7), 781–783 (2009).
  • Chatterjee A , RodgerEJ , EcclesMR. Epigenetic drivers of tumourigenesis and cancer metastasis. Semin. Cancer Biol.51, 149–159 (2018).
  • Ciernikova S , EarlJ , GarciaBermejo ML , StevurkovaV , CarratoA , SmolkovaB. Epigenetic landscape in pancreatic ductal adenocarcinoma: on the way to overcoming drug resistance?Int. J. Mol. Sci.21(11), 4091 (2020).
  • Cancer Genome Atlas Research Network . Integrated genomic characterization of pancreatic ductal adenocarcinoma. Cancer Cell32(2), 185–203 (2017).
  • St Pierre R , KadochC. Mammalian SWI/SNF complexes in cancer: emerging therapeutic opportunities. Curr. Opin. Genet. Dev.42, 56–67 (2017).
  • Waddell N , PajicM , PatchAMet al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature518(7540), 495–501 (2015).
  • Kadoch C , CrabtreeGR. Mammalian SWI/SNF chromatin remodeling complexes and cancer: mechanistic insights gained from human genomics. Sci. Adv.1(5), e1500447 (2015).
  • Kadoch C , HargreavesDC , HodgesCet al. Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy. Nat. Genet.45(6), 592–601 (2013).
  • Zhang L , WangC , YuSet al. Loss of ARID1A expression correlates with tumor differentiation and tumor progression stage in pancreatic ductal adenocarcinoma. Technol. Cancer Res. Treat.17, 1533034618754475 (2018).
  • Xu S , TangC. The role of ARID1A in tumors: tumor initiation or tumor suppression?Front. Oncol.11, 745187 (2021).
  • Livshits G , Alonso-CurbeloD , MorrisJPTet al. Arid1a restrains Kras-dependent changes in acinar cell identity. Elife7, e352162018).
  • Wang SC , NassourI , XiaoSet al. SWI/SNF component ARID1A restrains pancreatic neoplasia formation. Gut68(7), 1259–1270 (2019).
  • Ferri-Borgogno S , BaruiS , McGeeAMet al. Paradoxical role of AT-rich interactive domain 1A in restraining pancreatic carcinogenesis. Cancers (Basel)12(9), 2695 (2020).
  • Hessmann E , JohnsenSA , SivekeJT , EllenriederV. Epigenetic treatment of pancreatic cancer: is there a therapeutic perspective on the horizon?Gut66(1), 168–179 (2017).
  • Jones S , ZhangX , ParsonsDWet al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science321(5897), 1801–1806 (2008).
  • von Figura G , FukudaA , RoyNet al. The chromatin regulator Brg1 suppresses formation of intraductal papillary mucinous neoplasm and pancreatic ductal adenocarcinoma. Nat. Cell Biol.16(3), 255–267 (2014).
  • Mann KM , WardJM , YewCCet al. Sleeping Beauty mutagenesis reveals cooperating mutations and pathways in pancreatic adenocarcinoma. Proc. Natl Acad. Sci. USA109(16), 5934–5941 (2012).
  • Chan-Seng-Yue M , KimJC , WilsonGWet al. Author correction: transcription phenotypes of pancreatic cancer are driven by genomic events during tumor evolution. Nat. Genet.52(4), 463 (2020).
  • Hayashi A , FanJ , ChenRet al. A unifying paradigm for transcriptional heterogeneity and squamous features in pancreatic ductal adenocarcinoma. Nat. Cancer1(1), 59–74 (2020).
  • Reiter JG , Makohon-MooreAP , GeroldJMet al. Minimal functional driver gene heterogeneity among untreated metastases. Science361(6406), 1033–1037 (2018).
  • Makohon-Moore AP , ZhangM , ReiterJGet al. Limited heterogeneity of known driver gene mutations among the metastases of individual patients with pancreatic cancer. Nat. Genet.49(3), 358–366 (2017).
  • McDonald OG , LiX , SaundersTet al. Epigenomic reprogramming during pancreatic cancer progression links anabolic glucose metabolism to distant metastasis. Nat. Genet.49(3), 367–376 (2017).
  • Zhao Y , YangM , WangSet al. An overview of epigenetic methylation in pancreatic cancer progression. Front. Oncol.12, 854773 (2022).
  • Baylin SB , JonesPA. Epigenetic determinants of cancer. Cold Spring Harb. Perspect. Biol.8(9), a019505 (2016).
  • Kelly TK , DeCarvalho DD , JonesPA. Epigenetic modifications as therapeutic targets. Nat. Biotechnol.28(10), 1069–1078 (2010).
  • Yi Z , WeiS , JinLet al. KDM6A regulates cell plasticity and pancreatic cancer progression by noncanonical activin pathway. Cell. Mol. Gastroenterol. Hepatol.13(2), 643–667 (2022).
  • Bazzichetto C , LuchiniC , ConciatoriFet al. Morphologic and molecular landscape of pancreatic cancer variants as the basis of new therapeutic strategies for precision oncology. Int. J. Mol. Sci.21(22), 8841 (2020).
  • Yang Q , ShenR , XuHet al. Comprehensive analyses of PBRM1 in multiple cancer types and its association with clinical response to immunotherapy and immune infiltrates. Ann. Transl. Med.9(6), 465 (2021).
  • Versemann L , HessmannE , UlisseM. Epigenetic Therapeutic Strategies to Target Molecular and Cellular Heterogeneity in Pancreatic Cancer. Visceral Medicine38(1), 11–19 (2022).
  • Shain AH , GiacominiCP , MatsukumaKet al. Convergent structural alterations define SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeler as a central tumor suppressive complex in pancreatic cancer. Proc. Natl Acad. Sci. USA109(5), E252–E259 (2012).
  • Jones PA , BaylinSB. The epigenomics of cancer. Cell128(4), 683–692 (2007).
  • Mathieu O , PicardG , TourmenteS. Methylation of a euchromatin-heterochromatin transition region inArabidopsis thalianachromosome 5 left arm. Chromosome Res.10(6), 455–466 (2002).
  • Wang SS , XuJ , JiKY , HwangCI. Epigenetic alterations in pancreatic cancer metastasis. Biomolecules11(8), 1082 (2021).
  • Thompson MJ , RubbiL , DawsonDW , DonahueTR , PellegriniM. Pancreatic cancer patient survival correlates with DNA methylation of pancreas development genes. PLOS ONE10(6), e0128814 (2015).
  • Mishra NK , SouthekalS , GudaC. Survival analysis of multi-omics data identifies potential prognostic markers of pancreatic ductal adenocarcinoma. Front. Genet.10, 624 (2019).
  • Sato N , ParkerAR , FukushimaNet al. Epigenetic inactivation of TFPI-2 as a common mechanism associated with growth and invasion of pancreatic ductal adenocarcinoma. Oncogene24(5), 850–858 (2005).
  • Xiao Q , ZhouD , RuckiAAet al. Cancer-associated fibroblasts in pancreatic cancer are reprogrammed by tumor-induced alterations in genomic DNA methylation. Cancer Res.76(18), 5395–5404 (2016).
  • Ohlund D , Handly-SantanaA , BiffiGet al. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J. Exp. Med.214(3), 579–596 (2017).
  • Pan X , ZhengL. Epigenetics in modulating immune functions of stromal and immune cells in the tumor microenvironment. Cell. Mol. Immunol.17(9), 940–953 (2020).
  • Laird PW , Jackson-GrusbyL , FazeliAet al. Suppression of intestinal neoplasia by DNA hypomethylation. Cell81(2), 197–205 (1995).
  • Zhang JJ , ZhuY , ZhuYet al. Association of increased DNA methyltransferase expression with carcinogenesis and poor prognosis in pancreatic ductal adenocarcinoma. Clin. Transl. Oncol.14(2), 116–124 (2012).
  • Hong L , SunG , PengLet al. The interaction between miR 148a and DNMT1 suppresses cell migration and invasion by reactivating tumor suppressor genes in pancreatic cancer. Oncol. Rep.40(5), 2916–2925 (2018).
  • Xie VK , LiZ , YanYet al. DNA-methyltransferase 1 induces dedifferentiation of pancreatic cancer cells through silencing of Kruppel-like factor 4 expression. Clin. Cancer Res.23(18), 5585–5597 (2017).
  • Zagorac S , AlcalaS , FernandezBayon Get al. DNMT1 inhibition reprograms pancreatic cancer stem cells via upregulation of the miR-17-92 cluster. Cancer Res.76(15), 4546–4558 (2016).
  • Clinicaltrials.gov . NCT01845805. https://clinicaltrials.gov/ct2/show/NCT01845805
  • Clinicaltrials.gov . NCT02959164. https://clinicaltrials.gov/ct2/show/NCT02959164
  • Jing W , SongN , LiuYet al. DNA methyltransferase 3a modulates chemosensitivity to gemcitabine and oxaliplatin via CHK1 and AKT in p53 deficient pancreatic cancer cells. Mol. Med. Rep.17(1), 117–124 (2018).
  • Jing W , SongN , LiuYPet al. DNMT3a promotes proliferation by activating the STAT3 signaling pathway and depressing apoptosis in pancreatic cancer. Cancer Manag. Res.11, 6379–6396 (2019).
  • Wang LH , HuangJ , WuCRet al. Downregulation of miR 29b targets DNMT3b to suppress cellular apoptosis and enhance proliferation in pancreatic cancer. Mol. Med. Rep.17(2), 2113–2120 (2018).
  • Ito S , ShenL , DaiQet al. Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science333(6047), 1300–1303 (2011).
  • Li J , WuX , ZhouYet al. Decoding the dynamic DNA methylation and hydroxymethylation landscapes in endodermal lineage intermediates during pancreatic differentiation of hESC. Nucleic Acids Res.46(6), 2883–2900 (2018).
  • Fujikura K , AlruwaiiZI , HaffnerMCet al. Downregulation of 5-hydroxymethylcytosine is an early event in pancreatic tumorigenesis. J. Pathol.254(3), 279–288 (2021).
  • Morris JPT , YashinskieJJ , KocheRet al. α-Ketoglutarate links p53 to cell fate during tumour suppression. Nature573(7775), 595–599 (2019).
  • Cimmino L , AifantisI. Alternative roles for oxidized mCs and TETs. Curr. Opin. Genet. Dev.42, 1–7 (2017).
  • Eyres M , LanfrediniS , XuHet al. TET2 drives 5hmc marking of GATA6 and epigenetically defines pancreatic ductal adenocarcinoma transcriptional subtypes. Gastroenterology161(2), 653–668 e616 (2021).
  • Wu J , LiH , ShiMet al. TET1-mediated DNA hydroxymethylation activates inhibitors of the Wnt/β-catenin signaling pathway to suppress EMT in pancreatic tumor cells. J. Exp. Clin. Cancer Res.38(1), 348 (2019).
  • Bhagat TD , Von AhrensD , DawlatyMet al. Lactate-mediated epigenetic reprogramming regulates formation of human pancreatic cancer-associated fibroblasts. Elife8, e50663 (2019).
  • Hendrich B , BirdA. Identification and characterization of a family of mammalian methyl-CpG binding proteins. Mol. Cell. Biol.18(11), 6538–6547 (1998).
  • Pandey S , PruittK. Functional assessment of MeCP2 in Rett syndrome and cancers of breast, colon, and prostate. Biochem. Cell Biol.95(3), 368–378 (2017).
  • Pandey S , SimmonsGEJr , Malyarchuk , S , CalhounTN , PruittK. A novel MeCP2 acetylation site regulates interaction with ATRX and HDAC1. Genes Cancer6(9-10), 408–421 (2015).
  • Jorgensen HF , BirdA. MeCP2 and other methyl-CpG binding proteins. Ment. Retard. Dev. Disabil. Res. Rev.8(2), 87–93 (2002).
  • Wang H , LiJ , HeJet al. Methyl-CpG-binding protein 2 drives the Furin/TGF-beta1/Smad axis to promote epithelial–mesenchymal transition in pancreatic cancer cells. Oncogenesis9(8), 76 (2020).
  • Guo X , LiK , JiangWet al. RNA demethylase ALKBH5 prevents pancreatic cancer progression by posttranscriptional activation of PER1 in an m6A-YTHDF2-dependent manner. Mol. Cancer19(1), 91 (2020).
  • Tang B , YangY , KangMet al. m 6 A demethylase ALKBH5 inhibits pancreatic cancer tumorigenesis by decreasing WIF-1 RNA methylation and mediating Wnt signaling. Mol. Cancer19(1), 3 (2020).
  • Marmorstein R , TrievelRC. Histone modifying enzymes: structures, mechanisms, and specificities. Biochim. Biophys. Acta1789(1), 58–68 (2009).
  • Ono H , BassonMD , ItoH. P300 inhibition enhances gemcitabine-induced apoptosis of pancreatic cancer. Oncotarget7(32), 51301–51310 (2016).
  • Chugh R , SangwanV , PatilSPet al. A preclinical evaluation of minnelide as a therapeutic agent against pancreatic cancer. Sci. Transl. Med.4(156), 156ra139 (2012).
  • McGinn O , GuptaVK , DauerPet al. Inhibition of hypoxic response decreases stemness and reduces tumorigenic signaling due to impaired assembly of HIF1 transcription complex in pancreatic cancer. Sci. Rep.7(1), 7872 (2017).
  • Modi S , GiriB , GuptaVKet al. Minnelide synergizes with conventional chemotherapy by targeting both cancer and associated stroma components in pancreatic cancer. Cancer Lett.537, 215591 (2022).
  • Hou P , KapoorA , ZhangQet al. Tumor microenvironment remodeling enables bypass of oncogenic KRAS dependency in pancreatic cancer. Cancer Discov.10(7), 1058–1077 (2020).
  • Qin H , NiyongereSA , LeeSJ , BakerBJ , BenvenisteEN. Expression and functional significance of SOCS-1 and SOCS-3 in astrocytes. J. Immunol.181(5), 3167–3176 (2008).
  • Hu G , HeN , CaiCet al. HDAC3 modulates cancer immunity via increasing PD-L1 expression in pancreatic cancer. Pancreatology19(2), 383–389 (2019).
  • Sherman MH , YuRT , TsengTWet al. Stromal cues regulate the pancreatic cancer epigenome and metabolome. Proc. Natl Acad. Sci. USA114(5), 1129–1134 (2017).
  • Shinke G , YamadaD , EguchiHet al. Role of histone deacetylase 1 in distant metastasis of pancreatic ductal cancer. Cancer Sci.109(8), 2520–2531 (2018).
  • Krauß L , UrbanBC , HastreiterSet al. HDAC2 facilitates pancreatic cancer metastasis. Cancer Res.82(4), 695–707 (2022).
  • Strahl BD , AllisCD. The language of covalent histone modifications. Nature403(6765), 41–45 (2000).
  • Jang MK , MochizukiK , ZhouM , JeongHS , BradyJN , OzatoK. The bromodomain protein Brd4 is a positive regulatory component of P-TEFb and stimulates RNA polymerase II-dependent transcription. Mol. Cell19(4), 523–534 (2005).
  • Mazur PK , HernerA , MelloSSet al. Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma. Nat. Med.21(10), 1163–1171 (2015).
  • Hyun K , JeonJ , ParkK , KimJ. Writing, erasing and reading histone lysine methylations. Exp. Mol. Med.49(4), e324 (2017).
  • Raynal NJ , SiJ , TabyRFet al. DNA methylation does not stably lock gene expression but instead serves as a molecular mark for gene silencing memory. Cancer Res.72(5), 1170–1181 (2012).
  • Schneider G , KrämerOH , SchmidRM , SaurD. Acetylation as a transcriptional control mechanism – HDACs and HATs in pancreatic ductal adenocarcinoma. J. Gastrointest. Cancer42(2), 85–92 (2011).
  • Zhang H , PandeyS , TraversMet al. Targeting CDK9 reactivates epigenetically silenced genes in cancer. Cell175(5), 1244–1258.e1226 (2018).
  • Kretz AL , SchaumM , RichterJet al. CDK9 is a prognostic marker and therapeutic target in pancreatic cancer. Tumour Biol.39(2), 1010428317694304 (2017).
  • Gupta VK , SharmaNS , DurdenBet al. Hypoxia-driven oncometabolite L-2HG maintains stemness–differentiation balance and facilitates immune evasion in pancreatic cancer. Cancer Res.81(15), 4001–4013 (2021).
  • Cao R , WangL , WangHet al. Role of histone H3 lysine 27 methylation in polycomb-group silencing. Science298(5595), 1039–1043 (2002).
  • Jin X , YangC , FanPet al. CDK5/FBW7-dependent ubiquitination and degradation of EZH2 inhibits pancreatic cancer cell migration and invasion. J. Biol. Chem.292(15), 6269–6280 (2017).
  • Bednar F , SchofieldHK , CollinsMAet al. Bmi1 is required for the initiation of pancreatic cancer through an Ink4a-independent mechanism. Carcinogenesis36(7), 730–738 (2015).
  • van Vlerken LE , KieferCM , MorehouseCet al. EZH2 is required for breast and pancreatic cancer stem cell maintenance and can be used as a functional cancer stem cell reporter. Stem Cells Transl. Med.2(1), 43–52 (2013).
  • Proctor E , WaghrayM , LeeCJet al. Bmi1 enhances tumorigenicity and cancer stem cell function in pancreatic adenocarcinoma. PLOS ONE8(2), e55820 (2013).
  • Chen NM , NeesseA , DyckMLet al. Context-dependent epigenetic regulation of nuclear factor of activated T cells 1 in pancreatic plasticity. Gastroenterology152(6), 1507–1520 e1515 (2017).
  • Patil S , SteuberB , KoppW et al. EZH2 regulates pancreatic cancer subtype identity and tumor progression via transcriptional repression of GATA6 . Cancer Res.80(21), 4620–4632 (2020).
  • Andricovich J , PerkailS , KaiY , CasasantaN , PengW , TzatsosA. Loss ofKDM6Aactivates super-enhancers to induce gender-specific squamous-like pancreatic cancer and confers sensitivity to BET inhibitors. Cancer Cell33(3), 512–526 e518 (2018).
  • Welstead GG , CreyghtonMP , BilodeauSet al. X-linked H3K27me3 demethylase Utx is required for embryonic development in a sex-specific manner. Proc. Natl Acad. Sci. USA109(32), 13004–13009 (2012).
  • Lan F , BaylissPE , RinnJL et al. A histone H3 lysine 27 demethylase regulates animal posterior development. Nature449(7163), 689–694 (2007).
  • Creyghton MP , ChengAW , WelsteadGGet al. Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc. Natl Acad. Sci. USA107(50), 21931–21936 (2010).
  • Zhang X , ChoiPS , FrancisJMet al. Identification of focally amplified lineage-specific super-enhancers in human epithelial cancers. Nat. Genet.48(2), 176–182 (2016).
  • Yun M , WuJ , WorkmanJL , LiB. Readers of histone modifications. Cell Res.21(4), 564–578 (2011).
  • Mathison AJ , KerkettaR , de AssuncaoTMet al. Kras(G12D) induces changes in chromatin territories that differentially impact early nuclear reprogramming in pancreatic cells. Genome Biol.22(1), 289 (2021).
  • Nicolle R , BlumY , MarisaLet al. Pancreatic adenocarcinoma therapeutic targets revealed by tumor–stroma cross-talk analyses in patient-derived xenografts. Cell Rep.21(9), 2458–2470 (2017).
  • Knudsen ES , BalajiU , MannakeeBet al. Pancreatic cancer cell lines as patient-derived avatars: genetic characterisation and functional utility. Gut67(3), 508–520 (2018).
  • Witkiewicz AK , BalajiU , EslingerCet al. Integrated patient-derived models delineate individualized therapeutic vulnerabilities of pancreatic cancer. Cell Rep.16(7), 2017–2031 (2016).
  • Collisson EA , BaileyP , ChangDK , BiankinAV. Molecular subtypes of pancreatic cancer. Nat. Rev. Gastroenterol. Hepatol.16(4), 207–220 (2019).
  • Lomberk G , BlumY , NicolleRet al. Distinct epigenetic landscapes underlie the pathobiology of pancreatic cancer subtypes. Nat. Commun.9(1), 1978 (2018).
  • Collisson EA , SadanandamA , OlsonPet al. Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nat. Med.17(4), 500–503 (2011).
  • Moffitt RA , MarayatiR , FlateELet al. Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma. Nat. Genet.47(10), 1168–1178 (2015).
  • Weissmueller S , ManchadoE , SaborowskiMet al. Mutant p53 drives pancreatic cancer metastasis through cell autonomous PDGF receptor β signaling. Cell157(2), 382–394 (2014).
  • Diaferia GR , BalestrieriC , ProsperiniEet al. Dissection of transcriptional and cis -regulatory control of differentiation in human pancreatic cancer. EMBO J.35(6), 595–617 (2016).
  • Somerville TDD , XuY , MiyabayashiKet al. TP63-mediated enhancer reprogramming drives the squamous subtype of pancreatic ductal adenocarcinoma. Cell Rep.25(7), 1741–1755 e1747 (2018).
  • Kloesch B , IonaszV , PaliwalSet al. A GATA6 -centred gene regulatory network involving HNFs and DeltaNp63 controls plasticity and immune escape in pancreatic cancer. Gut71(4), 766–777 (2022).
  • Lomberk G , DusettiN , IovannaJ , UrrutiaR. Emerging epigenomic landscapes of pancreatic cancer in the era of precision medicine. Nat. Commun.10(1), 3875 (2019).
  • Matsui M , CoreyDR. Non-coding RNAs as drug targets. Nat. Rev. Drug. Discov.16(3), 167–179 (2017).
  • Mortoglou M , TabinZK , ArisanED , KocherHM , Uysal-OnganerP. Non-coding RNAs in pancreatic ductal adenocarcinoma: new approaches for better diagnosis and therapy. Transl. Oncol.14(7), 101090 (2021).
  • Cech TR , SteitzJA. The noncoding RNA revolution – trashing old rules to forge new ones. Cell157(1), 77–94 (2014).
  • Yu J , LiA , HongSM , HrubanRH , GogginsM. MicroRNA alterations of pancreatic intraepithelial neoplasias. Clin. Cancer Res.18(4), 981–992 (2012).
  • Bartel DP . MicroRNAs: genomics, biogenesis, mechanism, and function. Cell116(2), 281–297 (2004).
  • Carthew RW , SontheimerEJ. Origins and mechanisms of miRNAs and siRNAs. Cell136(4), 642–655 (2009).
  • Borchert GM , LanierW , DavidsonBL. RNA polymerase III transcribes human microRNAs. Nat. Struct. Mol. Biol.13(12), 1097–1101 (2006).
  • Pillai RS , BhattacharyyaSN , FilipowiczW. Repression of protein synthesis by miRNAs: how many mechanisms?Trends Cell Biol.17(3), 118–126 (2007).
  • Berezikov E , PlasterkRH. Camels and zebrafish, viruses and cancer: a microRNA update. Hum. Mol. Genet.14(2), R183–R190 (2005).
  • Hussain SP . Pancreatic cancer: current progress and future challenges. Int. J. Biol. Sci.12(3), 270–272 (2016).
  • Gilles ME , HaoL , HuangLet al. Personalized RNA medicine for pancreatic cancer. Clin. Cancer Res.24(7), 1734–1747 (2018).
  • MacKenzie TN , MujumdarN , BanerjeeSet al. Triptolide induces the expression of miR-142-3p: a negative regulator of heat shock protein 70 and pancreatic cancer cell proliferation. Mol. Cancer Ther.12(7), 1266–1275 (2013).
  • Calin GA , SevignaniC , DumitruCDet al. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc. Natl Acad. Sci. USA101(9), 2999–3004 (2004).
  • Volinia S , CalinGA , LiuCGet al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc. Natl Acad. Sci. USA103(7), 2257–2261 (2006).
  • Hampton T . MicroRNAs linked to pancreatic cancer. JAMA297(9), 937 (2007).
  • Szafranska AE , DavisonTS , JohnJet al. MicroRNA expression alterations are linked to tumorigenesis and non-neoplastic processes in pancreatic ductal adenocarcinoma. Oncogene26(30), 4442–4452 (2007).
  • Hong TH , ParkIY. MicroRNA expression profiling of diagnostic needle aspirates from surgical pancreatic cancer specimens. Ann. Surg. Treat Res.87(6), 290–297 (2014).
  • Hanahan D , WeinbergRA. Hallmarks of cancer: the next generation. Cell144(5), 646–674 (2011).
  • Bhat SA , AhmadSM , MumtazPTet al. Long non-coding RNAs: mechanism of action and functional utility. Noncoding RNA Res.1(1), 43–50 (2016).
  • Chen X , YanCC , ZhangX , YouZH. Long non-coding RNAs and complex diseases: from experimental results to computational models. Brief. Bioinform.18(4), 558–576 (2017).
  • Kung JT , ColognoriD , LeeJT. Long noncoding RNAs: past, present, and future. Genetics193(3), 651–669 (2013).
  • Muller S , RaulefsS , BrunsPet al. Next-generation sequencing reveals novel differentially regulated mRNAs, lncRNAs, miRNAs, sdRNAs and a piRNA in pancreatic cancer. Mol. Cancer14, 94 (2015).
  • Li X , DengSJ , ZhuSet al. Hypoxia-induced lncRNA- NUTF2P3-001 contributes to tumorigenesis of pancreatic cancer by derepressing the miR-3923/ KRAS pathway. Oncotarget7(5), 6000–6014 (2016).
  • Kim K , JutooruI , ChadalapakaGet al. HOTAIR is a negative prognostic factor and exhibits pro-oncogenic activity in pancreatic cancer. Oncogene32(13), 1616–1625 (2013).
  • Castro-Piedras I , VartakD , SharmaMet al. Identification of novel MeCP2 cancer-associated target genes and post-translational modifications. Front. Oncol.10, 576362 (2020).
  • Sharma NS , GnamlinP , DurdenBet al. Long non-coding RNA GAS5 acts as proliferation ‘brakes’ in CD133 + cells responsible for tumor recurrence. Oncogenesis8(12), 68 (2019).
  • Raimondi S , MaisonneuveP , LowenfelsAB. Epidemiology of pancreatic cancer: an overview. Nat. Rev. Gastroenterol. Hepatol.6(12), 699–708 (2009).
  • Herman JG , UmarA , PolyakKet al. Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc. Natl Acad. Sci. USA95(12), 6870–6875 (1998).
  • Ottini L , RizzoloP , SiniscalchiEet al. Gene promoter methylation and DNA repair capacity in monozygotic twins with discordant smoking habits. Mutat. Res. Genet. Toxicol. Environ. Mutagen.779, 57–64 (2015).
  • Besingi W , JohanssonA. Smoke-related DNA methylation changes in the etiology of human disease. Hum. Mol. Genet.23(9), 2290–2297 (2014).
  • Jin T , HaoJ , FanD. Nicotine induces aberrant hypermethylation of tumor suppressor genes in pancreatic epithelial ductal cells. Biochem. Biophys. Res. Commun.499(4), 934–940 (2018).
  • Hussain M , RaoM , HumphriesAEet al. Tobacco smoke induces polycomb-mediated repression of Dickkopf-1 in lung cancer cells. Cancer Res.69(8), 3570–3578 (2009).
  • Vrijens K , BollatiV , NawrotTS. MicroRNAs as potential signatures of environmental exposure or effect: a systematic review. Environ. Health Perspect.123(5), 399–411 (2015).
  • Zhao X , ZhuS , LiJ , LongD , WanM , TangW. Epigenetic changes in inflammatory genes and the protective effect of cooked rhubarb on pancreatic tissue of rats with chronic alcohol exposure. Biomed. Pharmacother.146, 112587 (2022).
  • Ni XG , BaiXF , MaoYLet al. The clinical value of serum CEA, CA19-9, and CA242 in the diagnosis and prognosis of pancreatic cancer. Eur. J. Surg. Oncol.31(2), 164–169 (2005).
  • Sato N , FukushimaN , MaitraAet al. Discovery of novel targets for aberrant methylation in pancreatic carcinoma using high-throughput microarrays. Cancer Res.63(13), 3735–3742 (2003).
  • Natale F , VivoM , FalcoG , AngrisanoT. Deciphering DNA methylation signatures of pancreatic cancer and pancreatitis. Clin. Epigenetics11(1), 132 (2019).
  • Shen SY , SinghaniaR , FehringerGet al. Sensitive tumour detection and classification using plasma cell-free DNA methylomes. Nature563(7732), 579–583 (2018).
  • Cohen JD , JavedAA , ThoburnCet al. Combined circulating tumor DNA and protein biomarker-based liquid biopsy for the earlier detection of pancreatic cancers. Proc. Natl Acad. Sci. USA114(38), 10202–10207 (2017).
  • Cohen JD , LiL , WangYet al. Detection and localization of surgically resectable cancers with a multi-analyte blood test. Science359(6378), 926–930 (2018).
  • Guler GD , NingY , KuCJet al. Detection of early stage pancreatic cancer using 5-hydroxymethylcytosine signatures in circulating cell free DNA. Nat. Commun.11(1), 5270 (2020).
  • Song CX , YinS , MaLet al. 5-Hydroxymethylcytosine signatures in cell-free DNA provide information about tumor types and stages. Cell Res.27(10), 1231–1242 (2017).
  • Li W , ZhangX , LuXet al. 5-Hydroxymethylcytosine signatures in circulating cell-free DNA as diagnostic biomarkers for human cancers. Cell Res.27(10), 1243–1257 (2017).
  • Turchinovich A , WeizL , LangheinzA , BurwinkelB. Characterization of extracellular circulating microRNA. Nucleic Acids Res.39(16), 7223–7233 (2011).
  • Wang H , PengR , WangJ , QinZ , XueL. Circulating microRNAs as potential cancer biomarkers: the advantage and disadvantage. Clin. Epigenetics10, 59 (2018).
  • Yonemori K , SekiN , IdichiTet al. The microRNA expression signature of pancreatic ductal adenocarcinoma by RNA sequencing: anti-tumour functions of the microRNA-216 cluster. Oncotarget8(41), 70097–70115 (2017).
  • Kawaguchi T , KomatsuS , IchikawaDet al. Clinical impact of circulating miR-221 in plasma of patients with pancreatic cancer. Br. J. Cancer108(2), 361–369 (2013).
  • Lee EJ , GusevY , JiangJ et al. Expression profiling identifies microRNA signature in pancreatic cancer. Int. J. Cancer120(5), 1046–1054 (2007).
  • Kunovsky L , TesarikovaP , KalaZet al. The use of biomarkers in early diagnostics of pancreatic cancer. Can. J. Gastroenterol. Hepatol.2018, 5389820 (2018).
  • Yu Y , TongY , ZhongA , WangY , LuR , GuoL. Identification of serum microRNA-25 as a novel biomarker for pancreatic cancer. Medicine (Baltimore)99(52), e23863 (2020).
  • Yang SZ , XuF , ZhouT , ZhaoX , McDonaldJM , ChenY. The long non-coding RNAHOTAIRenhances pancreatic cancer resistance to TNF-related apoptosis-inducing ligand. J. Biol. Chem.292(25), 10390–10397 (2017).
  • Liu JH , ChenG , DangYW , LiCJ , LuoDZ. Expression and prognostic significance of lncRNAMALAT1in pancreatic cancer tissues. Asian Pac. J. Cancer Prev.15(7), 2971–2977 (2014).
  • Pang EJ , YangR , FuXB , LiuYF. Overexpression of long non-coding RNAMALAT1is correlated with clinical progression and unfavorable prognosis in pancreatic cancer. Tumour Biol.36(4), 2403–2407 (2015).
  • Young MR , WagnerPD , GhoshSet al. Validation of biomarkers for early detection of pancreatic cancer: summary of the Alliance of Pancreatic Cancer Consortia for Biomarkers for Early Detection workshop. Pancreas47(2), 135–141 (2018).
  • Singhi AD , KoayEJ , ChariST , MaitraA. Early detection of pancreatic cancer: opportunities and challenges. Gastroenterology156(7), 2024–2040 (2019).