Abstract
Acinar cells of the pancreas produce the majority of enzymes required for digestion and make up >90% of the cells within the pancreas. Due to a common developmental origin and the plastic nature of the acinar cell phenotype, these cells have been identified as a possible source of β cells as a therapeutic option for Type I diabetes. However, recent evidence indicates that acinar cells are the main source of pancreatic intraepithelial neoplasias (PanINs), the predecessor of pancreatic ductal adenocarcinoma (PDAC). The conversion of acinar cells to either β cells or precursors to PDAC is dependent on reprogramming of the cells to a more primitive, progenitor-like phenotype, which involves changes in transcription factor expression and activity, and changes in their epigenetic program. This review will focus on the mechanisms that promote acinar cell reprogramming, as well as the factors that may affect these mechanisms.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1 . Analysis of pancreatic development using a cell lineage label. Exp. Cell Res. 247(1), 123–132 (1999).
- 2 Spatiotemporal patterns of multipotentiality in Ptf1a-expressing cells during pancreas organogenesis and injury-induced facultative restoration. Development 140(4), 751–764 (2013).•• By combining genetic lineage tracing and experimental pancreatitis models, this study identifies a population of PTF1A-expressing cells that maintain multipotent capabilities in the adult pancreas and give rise to acinar, duct and endocrine cell types.
- 3 In vivo reprogramming of pancreatic acinar cells to three islet endocrine subtypes. Elife 3, e01846 (2014).
- 4 Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma. Cancer Cell 22(6), 737–750 (2012).
- 5 . Exocrine pancreas trans-differentiation to hepatocytes‐‐a physiological response to elevated glucocorticoid in vivo. J. Steroid Biochem. Mol. Biol. 116(1–2), 76–85 (2009).
- 6 . Pancreatic inactivation of c-Myc decreases acinar mass and transdifferentiates acinar cells into adipocytes in mice. Gastroenterology 136(1), 309–319 e309 (2009).
- 7 . Recapitulation of elements of embryonic development in adult mouse pancreatic regeneration. Gastroenterology 128(3), 728–741 (2005).
- 8 . Numb regulates acinar cell dedifferentiation and survival during pancreatic damage and acinar-to-ductal metaplasia. Gastroenterology 145(5), 1088–1097 e1088 (2013).
- 9 . In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature 455(7213), 627–632 (2008).
- 10 Notch and Kras reprogram pancreatic acinar cells to ductal intraepithelial neoplasia. Proc. Natl Acad. Sci. USA 105(48), 18907–18912 (2008).
- 11 . The developmental capacity of nuclei taken from intestinal epithelium cells of feeding tadpoles. J. Embryol. Exp. Morphol. 10, 622–640 (1962).
- 12 Differentiation of pancreatic acinar cells to hepatocytes requires an intermediate cell type. Gastroenterology 138(7), 2519–2530 (2010).
- 13 Epigenetic reprogramming in mist1(-/-) mice predicts the molecular response to cerulein-induced pancreatitis. PLoS ONE 9(1), e84182 (2014).
- 14 . The absence of MIST1 leads to increased ethanol sensitivity and decreased activity of the unfolded protein response in mouse pancreatic acinar cells. PLoS ONE 6(12), e28863 (2011).
- 15 . Global burden of diabetes, 1995–2025: prevalence, numerical estimates, and projections. Diabetes Care 21(9), 1414–1431 (1998).
- 16 . Islet cell transplantation. Semin. Pediatr. Surg. 23(2), 83–90 (2014).
- 17 Notch signaling as gatekeeper of rat acinar-to-beta-cell conversion in vitro. Gastroenterology 136(5), 1750–1760 e1713 (2009).
- 18 . How to make a functional beta-cell. Development 140(12), 2472–2483 (2013).
- 19 Spontaneous induction of murine pancreatic intraepithelial neoplasia (mPanIN) by acinar cell targeting of oncogenic Kras in adult mice. Proc. Natl Acad. Sci. USA 105(48), 18913–18918 (2008).
- 20 . Cancer statistics, 2013. CA. Cancer J. Clin. 63(1), 11–30 (2013).
- 21 . Gene regulatory networks governing pancreas development. Dev. Cell 25(1), 5–13 (2013).
- 22 . Direct evidence for the pancreatic lineage: NGN3+ cells are islet progenitors and are distinct from duct progenitors. Development 129(10), 2447–2457 (2002).
- 23 . A multipotent progenitor domain guides pancreatic organogenesis. Dev. Cell 13(1), 103–114 (2007).• One of the first studies to use a genetic lineage tracing model to show that all pancreatic cell types are derived from a multipotent progenitor cell. The study also indicates that this population transiently exists during development and that endocrine and duct cells share a closer developmental origin than duct and acinar cells.
- 24 Notch inhibits Ptf1 function and acinar cell differentiation in developing mouse and zebrafish pancreas. Development 131(17), 4213–4224 (2004).
- 25 . Exocrine ontogenies: on the development of pancreatic acinar, ductal and centroacinar cells. Semin. Cell Dev. Biol. 23(6), 711–719 (2012).
- 26 . The morphogenesis of the pancreatic mesenchyme is uncoupled from that of the pancreatic epithelium in IPF1/PDX1-deficient mice. Development 122(5), 1409–1416 (1996).
- 27 PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum. Development 122(3), 983–995 (1996).
- 28 The bHLH protein PTF1-p48 is essential for the formation of the exocrine and the correct spatial organization of the endocrine pancreas. Genes Dev. 12(23), 3752–3763 (1998).
- 29 . The role of the transcriptional regulator Ptf1a in converting intestinal to pancreatic progenitors. Nat. Genet. 32(1), 128–134 (2002).
- 30 . Pdx-1 and Ptf1a concurrently determine fate specification of pancreatic multipotent progenitor cells. Dev. Biol. 316(1), 74–86 (2008).
- 31 SOX9 is required for maintenance of the pancreatic progenitor cell pool. Proc. Natl Acad. Sci. USA 104(6), 1865–1870 (2007).
- 32 . Pancreas development is promoted by cyclopamine, a hedgehog signaling inhibitor. Proc. Natl Acad. Sci. USA 95(22), 13036–13041 (1998).
- 33 . Expression and misexpression of members of the FGF and TGFbeta families of growth factors in the developing mouse pancreas. Dev. Dyn. 226(4), 663–674 (2003).
- 34 . Notochord repression of endodermal Sonic hedgehog permits pancreas development. Genes Dev. 12(11), 1705–1713 (1998).
- 35 . All-trans retinoic acid suppresses exocrine differentiation and branching morphogenesis in the embryonic pancreas. Differentiation 75(1), 62–74 (2007).
- 36 . Notch signaling in the pancreas: patterning and cell fate specification. Wiley Interdiscip. Rev. Dev. Biol. 2(4), 531–544 (2013).
- 37 . Delivering the lateral inhibition punchline: it's all about the timing. Sci. Signal. 3(145), pe38 (2010).
- 38 Independent development of pancreatic alpha- and beta-cells from neurogenin3-expressing precursors: a role for the notch pathway in repression of premature differentiation. Diabetes 49(2), 163–176 (2000).
- 39 Control of endodermal endocrine development by Hes-1. Nat. Genet. 24(1), 36–44 (2000).
- 40 Notch signalling controls pancreatic cell differentiation. Nature 400(6747), 877–881 (1999).
- 41 . Activated Notch1 prevents differentiation of pancreatic acinar cells and attenuate endocrine development. Dev. Biol. 260(2), 426–437 (2003).
- 42 Notch-mediated patterning and cell fate allocation of pancreatic progenitor cells. Development 139(10), 1744–1753 (2012).
- 43 Ptf1a-mediated control of Dll1 reveals an alternative to the lateral inhibition mechanism. Development 139(1), 33–45 (2012).
- 44 Mind bomb 1 is required for pancreatic beta-cell formation. Proc. Natl Acad. Sci. USA 109(19), 7356–7361 (2012).
- 45 A Notch-dependent molecular circuitry initiates pancreatic endocrine and ductal cell differentiation. Development 139(14), 2488–2499 (2012).
- 46 . Ongoing Notch signaling maintains phenotypic fidelity in the adult exocrine pancreas. Dev. Biol. 362(1), 57–64 (2012).
- 47 . Early pancreatic development requires the vertebrate Suppressor of Hairless (RBPJ) in the PTF1 bHLH complex. Genes Dev. 21(20), 2629–2643 (2007).
- 48 Rbp-j regulates expansion of pancreatic epithelial cells and their differentiation into exocrine cells during mouse development. Dev. Dyn. 236(10), 2779–2791 (2007).
- 49 . Nr5a2 maintains acinar cell differentiation and constrains oncogenic Kras-mediated pancreatic neoplastic initiation. Gut 63(4), 656–664 (2014).
- 50 The nuclear hormone receptor family member NR5A2 controls aspects of multipotent progenitor cell formation and acinar differentiation during pancreatic organogenesis. Development 141(16), 3123–3133 (2014).
- 51 . Gata6 is required for complete acinar differentiation and maintenance of the exocrine pancreas in adult mice. Gut 62(10), 1481–1488 (2013).
- 52 . The plastic pancreas. Dev. Cell 26(1), 3–7 (2013).
- 53 Pancreatic exocrine duct cells give rise to insulin-producing beta cells during embryogenesis but not after birth. Dev. Cell 17(6), 849–860 (2009).
- 54 Preexisting pancreatic acinar cells contribute to acinar cell, but not islet beta cell, regeneration. J. Clin. Invest. 117(4), 971–977 (2007).
- 55 . Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation. Nature 429(6987), 41–46 (2004).
- 56 . AR42J-B-13 cell: an expandable progenitor to generate an unlimited supply of functional hepatocytes. Toxicology 278(3), 277–287 (2010).
- 57 Dexamethasone treatment induces the reprogramming of pancreatic acinar cells to hepatocytes and ductal cells. PLoS ONE 5(10), e13650 (2010).
- 58 . Glucagon-like peptide 1 and exendin-4 convert pancreatic AR42J cells into glucagon- and insulin-producing cells. Diabetes 48(12), 2358–2366 (1999).
- 59 Interplay of glucagon-like peptide-1 and transforming growth factor-beta signaling in insulin-positive differentiation of AR42J cells. Diabetes 53(11), 2824–2835 (2004).
- 60 Cross-talk between bone morphogenetic protein and transforming growth factor-beta signaling is essential for exendin-4-induced insulin-positive differentiation of AR42J cells. J. Biol. Chem. 280(37), 32209–32217 (2005).
- 61 Lineage tracing and characterization of insulin-secreting cells generated from adult pancreatic acinar cells. Proc. Natl Acad. Sci. USA 102(42), 15116–15121 (2005).
- 62 Transient cytokine treatment induces acinar cell reprogramming and regenerates functional beta cell mass in diabetic mice. Nat. Biotechnol. 32(1), 76–83 (2014).
- 63 . Suppression of Ptf1a activity induces acinar-to-endocrine conversion. Curr. Biol. 21(8), 712–717 (2011).
- 64 Lineage tracing evidence for transdifferentiation of acinar to duct cells and plasticity of human pancreas. Gastroenterology 141(2), 731–741, 741 e731–734 (2011).• The first study to use a genetic lineage tracing system to show human acinar cells, like rodent acinar cells, have the ability to be reprogrammed into duct cells.
- 65 . Pancreatic cell lineage analyses in mice. Endocrine 19(3), 267–278 (2002).
- 66 . What we have learned about pancreatic cancer from mouse models. Gastroenterology 142(5), 1079–1092 (2012).
- 67 . Pancreatic ductal adenocarcinoma and acinar cells: a matter of differentiation and development? Gut 61(3), 449–458 (2012).
- 68 Ras activity levels control the development of pancreatic diseases. Gastroenterology 137(3), 1072–1082, 1082 e1071–1076 (2009).
- 69 Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 4(6), 437–450 (2003).
- 70 Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. Genes Dev. 17(24), 3112–3126 (2003).
- 71 Inactivation of Smad4 accelerates Kras(G12D)-mediated pancreatic neoplasia. Cancer Res. 67(17), 8121–8130 (2007).
- 72 Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. Cancer Cell 11(3), 291–302 (2007).•• Showed the importance of pancreatic injury and inflammation to accelerating and enhancing PDAC in mouse models carrying a constitutively activated form of K-Ras.
- 73 . Acute pancreatitis markedly accelerates pancreatic cancer progression in mice expressing oncogenic Kras. Biochem. Biophys. Res. Commun. 382(3), 561–565 (2009).
- 74 . Pancreatic cancer in chronic pancreatitis; aetiology, incidence, and early detection. Best Pract. Res. Clin. Gastroenterol. 24(3), 349–358 (2010).
- 75 . Models of acute and chronic pancreatitis. Gastroenterology 144(6), 1180–1193 (2013).
- 76 . Autocrine Sonic hedgehog attenuates inflammation in cerulein-induced acute pancreatitis in mice via upregulation of IL-10. PLoS ONE 7(8), e44121 (2012).
- 77 . Expression of transforming growth factor-beta 1 in chronic pancreatitis. Digestion 56(3), 237–241 (1995).
- 78 Adult pancreatic acinar cells dedifferentiate to an embryonic progenitor phenotype with concomitant activation of a senescence programme that is present in chronic pancreatitis. Gut 60(7), 958–966 (2011).
- 79 . Activation of protein kinase Cdelta leads to increased pancreatic acinar cell dedifferentiation in the absence of MIST1. J. Pathol. 228(3), 351–365 (2012).
- 80 . Secretagogues differentially activate endoplasmic reticulum stress responses in pancreatic acinar cells. Am. J. Physiol. Gastrointest. Liver Physiol. 292(6), G1804–1812 (2007).
- 81 . Mice lacking the transcription factor Mist1 exhibit an altered stress response and increased sensitivity to caerulein-induced pancreatitis. Am. J. Physiol. Gastrointest. Liver Physiol. 292(4), G1123–1132 (2007).
- 82 . Drinking and driving pancreatitis: links between endoplasmic reticulum stress and autophagy. Autophagy 7(7), 783–785 (2011).
- 83 . Redifferentiation and apoptosis of pancreatic cells during acute pancreatitis. Int. J. Pancreatol. 20(2), 77–84 (1996).
- 84 . An operational definition of epigenetics. Genes Dev. 23(7), 781–783 (2009).
- 85 . Transgenerational epigenetic inheritance: myths and mechanisms. Cell 157(1), 95–109 (2014).
- 86 . Chromatin modifications and their function. Cell 128(4), 693–705 (2007).
- 87 . Bmi1 lineage tracing identifies a self-renewing pancreatic acinar cell subpopulation capable of maintaining pancreatic organ homeostasis. Proc. Natl Acad. Sci. USA 106(17), 7101–7106 (2009).
- 88 Derepression of Polycomb targets during pancreatic organogenesis allows insulin-producing beta-cells to adopt a neural gene activity program. Genome Res. 20(6), 722–732 (2010).
- 89 . Chromatin “prepattern” and histone modifiers in a fate choice for liver and pancreas. Science 332(6032), 963–966 (2011).•• Provides that first evidence that differences in histone modifications precede changes in gene expression linked to either pancreatic or liver development. For example, specific histone modifications that are linked to repression or activation are observed in cells destined to become hepatocytes prior to overt differentiation.
- 90 Global identification of transcriptional regulators of pluripotency and differentiation in embryonic stem cells. Nucleic Acids Res. 40(17), 8199–8209 (2012).
- 91 A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125(2), 315–326 (2006).•• Genes that are marked by both active and repressive histone modifications are deemed to be bivalent in nature. This study showed genes that promote specific developmental fates are bivalently marked in ES cells, allowing for rapid activation in response to appropriate cues promoting differentiation.
- 92 . Visualization of multivalent histone modification in a single cell reveals highly concerted epigenetic changes on differentiation of embryonic stem cells. Nucleic Acids Res. 41(15), 7231–7239 (2013).
- 93 Mll2 is required for H3K4 trimethylation on bivalent promoters in embryonic stem cells, whereas Mll1 is redundant. Development 141(3), 526–537 (2014).
- 94 H3K4 tri-methylation provides an epigenetic signature of active enhancers. EMBO J. 30(20), 4198–4210 (2011).
- 95 . Identification of cis regulatory features in the embryonic zebrafish genome through large-scale profiling of H3K4me1 and H3K4me3 binding sites. Dev. Biol. 357(2), 450–462 (2011).
- 96 Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science 298(5595), 1039–1043 (2002).
- 97 . The functions of E(Z)/EZH2-mediated methylation of lysine 27 in histone H3. Curr. Opin. Genet. Dev. 14(2), 155–164 (2004).
- 98 . Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein. Genes Dev. 16(22), 2893–2905 (2002).
- 99 Ezh1 and Ezh2 maintain repressive chromatin through different mechanisms. Mol. Cell 32(4), 503–518 (2008).
- 100 Polycomb protein Ezh2 regulates pancreatic beta-cell Ink4a/Arf expression and regeneration in diabetes mellitus. Genes Dev. 23(8), 975–985 (2009).
- 101 Dynamics of genomic H3K27me3 domains and role of EZH2 during pancreatic endocrine specification. EMBO J. 33(19), 2157–2170 (2014).
- 102 . Regulation of the Drosophila engrailed gene by Polycomb repressor complex 2. Mech. Dev. 126(5–6), 443–448 (2009).
- 103 EZH2 couples pancreatic regeneration to neoplastic progression. Genes Dev. 26(5), 439–444 (2012).•• Targeted deletion of Ezh2 in the mouse pancreas affects the ability of acinar cells to progress to PanINs suggesting that the PRC2 complex plays a role in enhancing K-Ras initiation of PDAC.
- 104 Loss of Dnmt1 catalytic activity reveals multiple roles for DNA methylation during pancreas development and regeneration. Dev. Biol. 334(1), 213–223 (2009).
- 105 Zebra fish Dnmt1 and Suv39h1 regulate organ-specific terminal differentiation during development. Mol. Cell. Biol. 26(19), 7077–7085 (2006).
- 106 Organ-specific requirements for Hdac1 in liver and pancreas formation. Dev. Biol. 322(2), 237–250 (2008).
- 107 Histone deacetylase 3 (hdac3) is specifically required for liver development in zebrafish. Dev. Biol. 317(1), 336–353 (2008).
- 108 . Histone deacetylase 1 is required for exocrine pancreatic epithelial proliferation in development and cancer. Cancer Biol. Ther. 11(7), 659–670 (2011).
- 109 . The constitutive active/androstane receptor facilitates unique phenobarbital-induced expression changes of genes involved in key pathways in precancerous liver and liver tumors. Toxicol. Sci. 110(2), 319–333 (2009).
- 110 . Role of Notch signalling pathway in cancer and its association with DNA methylation. J. Genet. 92(3), 667–675 (2013).
- 111 . Notch1 intracellular domain increases cytoplasmic EZH2 levels during early megakaryopoiesis. Cell Death Dis. 3, e380 (2012).
- 112 . Chemokine gene expression in rat pancreatic acinar cells is an early event associated with acute pancreatitis. Gastroenterology 113(6), 1966–1975 (1997).
- 113 . NF-kappaB activation in pancreas induces pancreatic and systemic inflammatory response. Gastroenterology 122(2), 448–457 (2002).
- 114 Fibroblast growth factor 21 reduces the severity of cerulein-induced pancreatitis in mice. Gastroenterology 137(5), 1795–1804 (2009).
- 115 . Expression of genes associated with dedifferentiation and cell proliferation during pancreatic regeneration following acute pancreatitis. Pancreas 7(6), 712–718 (1992).
- 116 Long-term ethanol consumption alters pancreatic gene expression in rats: a possible connection to pancreatic injury. Pancreas 33(1), 68–76 (2006).
- 117 . Hypertriglyceridemia aggravates ER stress and pathogenesis of acute pancreatitis. Hepatogastroenterology 59(119), 2318–2326 (2012).
- 118 . A gene complex controlling segmentation in Drosophila. Nature 276(5688), 565–570 (1978).
- 119 . Transcriptional regulation by Polycomb group proteins. Nat Struct. Mol. Biol. 20(10), 1147–1155 (2013).
- 120 . Bmi1 is required for regeneration of the exocrine pancreas in mice. Gastroenterology 143(3), 821–831 e821–822 (2012).
- 121 The epigenetic regulators Bmi1 and Ring1B are differentially regulated in pancreatitis and pancreatic ductal adenocarcinoma. J. Pathol. 219(2), 205–213 (2009).
- 122 Implications of enhancer of zeste homologue 2 expression in pancreatic ductal adenocarcinoma. Hum. Pathol. 41(9), 1205–1209 (2010).
- 123 Context-specific regulation of NF-kappaB target gene expression by EZH2 in breast cancers. Mol. Cell 43(5), 798–810 (2011).
- 124 EZH2 oncogenic activity in castration-resistant prostate cancer cells is Polycomb-independent. Science 338(6113), 1465–1469 (2012).
- 125 BMI1 is recruited to DNA breaks and contributes to DNA damage-induced H2A ubiquitination and repair. Mol. Cell. Biol. 31(10), 1972–1982 (2011).
- 126 Epigenomic comparison reveals activation of “seed” enhancers during transition from naive to primed pluripotency. Cell Stem Cell 14(6), 854–863 (2014).•• Identified epigenetic changes at gene enhancer regions that predated changes in gene expression or changes in the differentiation status of stem cells. These changes reflect an epigenetic re-programming that predates actual cell reprogramming and suggests that epigenetic changes may initiate this process.
- 127 . Silencing of the Fibroblast Growth Factor 21 gene is an underlying cause of acinar cell injury in mice lacking MIST1. Am. J. Physiol. Endocrinol. Metab. 306(8), E916–E928 (2014).
- 128 . The bHLH transcription factor Mist1 is required to maintain exocrine pancreas cell organization and acinar cell identity. J. Cell Biol. 155(4), 519–530 (2001).
- 129 . miR-106b-25/miR-17–92 clusters: polycistrons with oncogenic roles in hepatocellular carcinoma. World J. Gastroenterol. 20(20), 5962–5972 (2014).
- 130 MicroRNA-99 family targets AKT/mTOR signaling pathway in dermal wound healing. PLoS ONE 8(5), e64434 (2013).
- 131 . Modeling microRNA-transcription factor networks in cancer. Adv. Exp. Med. Biol. 774, 149–167 (2013).
- 132 Hypoxia pathways and cellular stress activate pancreatic stellate cells: development of an organotypic culture model of thick slices of normal human pancreas. PLoS ONE 8(9), e76229 (2013).
- 133 . Conversion of Human Pancreatic Acinar Cells Toward a Ductal-Mesenchymal Phenotype and the Role of Transforming Growth Factor beta and Activin Signaling. Pancreas 43(7), 1083–1092 (2014).
- 134 . A novel 2-step culture model for long-term in vitro maintenance of human pancreatic acinar cells. Pancreas 43(5), 762–767 (2014).
- 135 . Alcohol/cholecystokinin-evoked pancreatic acinar basolateral exocytosis is mediated by protein kinase C alpha phosphorylation of Munc18c. J. Biol. Chem. 282(17), 13047–13058 (2007).
- 136 Ethanol differentially regulates NF-kappaB activation in pancreatic acinar cells through calcium and protein kinase C pathways. Am. J. Physiol. Gastrointest. Liver Physiol. 286(2), G204–G213 (2004).
- 137 . Ethanol augments elevated-[Ca2+]C induced trypsin activation in pancreatic acinar zymogen granules. Biochem. Biophys. Res. Commun. 350(3), 593–597 (2006).
- 138 DNA methylation alterations in the pancreatic juice of patients with suspected pancreatic disease. Cancer Res. 66(2), 1208–1217 (2006).
- 139 Hypermethylation of HIC1 promoter and aberrant expression of HIC1/SIRT1 might contribute to the carcinogenesis of pancreatic cancer. Ann. Surg. Oncol. 20(Suppl. 3), S301–S311 (2013).
- 140 Aberrant methylation of CpG islands in intraductal papillary mucinous neoplasms of the pancreas. Gastroenterology 123(1), 365–372 (2002).
- 141 Multiple genes are hypermethylated in intraductal papillary mucinous neoplasms of the pancreas. Mod. Pathol. 21(12), 1499–1507 (2008).
- 142 Expression of DNMT1 and DNMT3a are regulated by GLI1 in human pancreatic cancer. PLoS ONE 6(11), e27684 (2011).
- 143 . DNMT3B gene amplification predicts resistance to DNA demethylating drugs. Genes Chromosomes Cancer 50(7), 527–534 (2011).
- 144 Association of increased DNA methyltransferase expression with carcinogenesis and poor prognosis in pancreatic ductal adenocarcinoma. Clin. Transl. Oncol. 14(2), 116–124 (2012).
- 145 Down-regulation of MicroRNA-494 via Loss of SMAD4 Increases FOXM1 and beta-Catenin Signaling in Pancreatic Ductal Adenocarcinoma Cells. Gastroenterology 147(2), 485–497 e418 (2014).
- 146 miR-212 promotes pancreatic cancer cell growth and invasion by targeting the hedgehog signaling pathway receptor patched-1. J. Exp. Clin. Cancer Res. 33, 54 (2014).
- 147 MicroRNA-135a inhibits cell proliferation by targeting Bmi1 in pancreatic ductal adenocarcinoma. Int. J. Biol. Sci. 10(7), 733–745 (2014).
- 148 miR-211 modulates gemcitabine activity through downregulation of ribonucleotide reductase and inhibits the invasive behavior of pancreatic cancer cells. Nucleosides Nucleotides Nucleic Acids 33(4–6), 384–393 (2014).
- 149 . Clinical potential of microRNAs in pancreatic ductal adenocarcinoma. Pancreas 40(8), 1165–1171 (2011).
- 150 Pancreatic cancers epigenetically silence SIP1 and hypomethylate and overexpress miR-200a/200b in association with elevated circulating miR-200a and miR-200b levels. Cancer Res. 70(13), 5226–5237 (2010).
- 151 Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer. Science 322(5908), 1695–1699 (2008).
- 152 Carcinogenesis of intraductal papillary mucinous neoplasm of the pancreas: loss of microRNA-101 promotes overexpression of histone methyltransferase EZH2. Ann. Surg. Oncol. 19(Suppl. 3), S565–S571 (2012).
- 153 Prognostic relevance of hTERT mRNA expression in ductal adenocarcinoma of the pancreas. Neoplasia 10(9), 973–976 (2008).
- 154 BRCA1 and BRCA2 germline mutations are frequently demonstrated in both high-risk pancreatic cancer screening and pancreatic cancer cohorts. Cancer 120(13), 1960–1967 (2014).
- 155 Nuclear protein 1 promotes pancreatic cancer development and protects cells from stress by inhibiting apoptosis. J. Clin. Invest. 122(6), 2092–2103 (2012).
- 156 The chromatin regulator Brg1 suppresses formation of intraductal papillary mucinous neoplasm and pancreatic ductal adenocarcinoma. Nat. Cell Biol. 16(3), 255–267 (2014).
- 157 A small molecule that directs differentiation of human ESCs into the pancreatic lineage. Nat. Chem Biol. 5(4), 258–265 (2009).
- 158 Adenosine kinase inhibition selectively promotes rodent and porcine islet beta-cell replication. Proc. Natl Acad. Sci. USA 109(10), 3915–3920 (2012).
- 159 Salivary transcriptomic biomarkers for detection of resectable pancreatic cancer. Gastroenterology 138(3), 949–957 e941–947 (2010).
- 160 A microRNA meta-signature for pancreatic ductal adenocarcinoma. Expert Rev. Mol. Diagn. 14(3), 267–271 (2014).
- 161 Radionuclide labeling and evaluation of candidate radioligands for PET imaging of histone deacetylase in the brain. Bioorg. Med. Chem. Lett. 23(24), 6700–6705 (2013).
- 162 . Targeting histone deacetylase in lung cancer for early diagnosis: (18)F-FAHA PET/CT imaging of NNK-treated A/J mice model. Am. J. Nucl. Med. Mol. Imaging 4(4), 324–332 (2014).
- 163 . Targeting epigenetic regulation of miR-34a for treatment of pancreatic cancer by inhibition of pancreatic cancer stem cells. PLoS ONE 6(8), e24099 (2011).
- 164 Coordinated silencing of MYC-mediated miR-29 by HDAC3 and EZH2 as a therapeutic target of histone modification in aggressive B-Cell lymphomas. Cancer Cell 22(4), 506–523 (2012).