MicroRNA Signaling Pathway Network in Pancreatic Ductal Adenocarcinoma

Journal of Genetics and Genomics

Volumn 42, Issue 10, 2015, Pages 563-577

  Sun, Longhao ^a,c   Chua, Corrine Ying Xuan ^a,b   Tian, Weijun ^c   Zhang, Zhixiang ^c   Chiao, Paul J ^a,b   Zhang, Wei ^a,b,c  

^a UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER   (United States)

^b UNIVERSITY OF TEXAS   (United States)

^c TIANJIN MEDICAL UNIVERSITY   (China)

Author keywords

MicroRNA; Pancreatic ductal adenocarcinoma; Signaling pathway; Tumorigenesis

Indexed keywords

CYCLIN D1; K RAS PROTEIN; MICRORNA; MICRORNA 126; MICRORNA 143; MICRORNA 145; MICRORNA 206; MICRORNA 217; MICRORNA 96; SMAD4 PROTEIN; SONIC HEDGEHOG PROTEIN; TRANSFORMING GROWTH FACTOR BETA; UNCLASSIFIED DRUG; WNT PROTEIN;

APOPTOSIS; CANCER GROWTH; CARCINOGENESIS; CELL CYCLE REGULATION; CELL PROLIFERATION; GENE EXPRESSION; HUMAN; MITOSIS; NONHUMAN; PANCREAS ADENOCARCINOMA; REVIEW; TUMOR SUPPRESSOR GENE; WNT SIGNALING PATHWAY; GENETICS; PANCREAS CARCINOMA; PHYSIOLOGY; SIGNAL TRANSDUCTION;

CARCINOMA, PANCREATIC DUCTAL; HUMANS; MICRORNAS; SIGNAL TRANSDUCTION;

EID: 84946709697     PISSN: 16738527     EISSN: 18735533     Source Type: Journal    
DOI: 10.1016/j.jgg.2015.07.003     Document Type: Review

References (130)

1. Arlt A., Müerköster S.S., Schäfer H. Targeting apoptosis pathways in pancreatic cancer. Cancer Lett. 2013, 332:346-358.
2. Bai S., Cao X. A nuclear antagonistic mechanism of inhibitory Smads in transforming growth factor-beta signaling. J. Biol. Chem. 2002, 277:4176-4182.
3. Bleeker F.E., Felicioni L., Buttitta F., Lamba S., Cardone L., Rodolfo M., Scarpa A., Leenstra S., Frattini M., Barbareschi M., Grammastro M.D., Sciarrotta M.G., Zanon C., Marchetti A., Bardelli A. AKT1 (E17K) in human solid tumours. Oncogene 2008, 27:5648-5650.
4. Brabletz T., Jung A., Spaderna S., Hlubek F., Kirchner T. Opinion: migrating cancer stem cells-an integrated concept of malignant tumour progression. Nat. Rev. Cancer 2005, 5:744-749.
5. Broderick J.A., Zamore P.D. MicroRNA therapeutics. Gene Ther. 2011, 18:1104-1110.
6. Burk U., Schubert J., Wellner U., Schmalhofer O., Vincan E., Spaderna S., Brabletz T. A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells. EMBO Rep. 2008, 9:582-589.
7. Cai B., An Y., Lv N., Chen J., Tu M., Sun J., Wu P., Wei J., Jiang K., Miao Y. miRNA-181b increases the sensitivity of pancreatic ductal adenocarcinoma cells to gemcitabine in vitro and in nude mice by targeting BCL-2. Oncol. Rep. 2013, 29:1769-1776.
8. Chan S.L., Chan S.T., Chan E.H., He Z.X. Systemic treatment for inoperable pancreatic adenocarcinoma: review and update. Chin. J. Cancer 2014, 33:267-276.
9. Chang T.C., Wentzel E.A., Kent O.A., Ramachandran K., Mullendore M., Lee K.H., Feldmann G., Yamakuchi M., Ferlito M., Lowenstein C.J., Arking D.E., Beer M.A., Maitra A., Mendell J.T. Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. Mol. Cell 2007, 26:745-752.
10. Chen W.Y., Liu W.J., Zhao Y.P., Zhou L., Zhang T.P., Chen G., Shu H. Induction, modulation and potential targets of miR-210 in pancreatic cancer cells. Hepatobiliary Pancreat. Dis. Int. 2012, 11:319-324.
11. Chen Z., Chen L.Y., Dai H.Y., Wang P., Gao S., Wang K. miR-301a promotes pancreatic cancer cell proliferation by directly inhibiting Bim expression. J. Cell. Biochem. 2012, 113:3229-3235.
12. Croce C.M., Calin G.A. miRNAs, cancer, and stem cell division. Cell 2005, 122:6-7.
13. Croce C.M. Causes and consequences of microRNA dysregulation in cancer. Nat. Rev. Genet. 2009, 10:704-714.
14. Deng J., He M., Chen L., Chen C., Zheng J., Cai Z. The loss of miR-26a-mediated post-transcriptional regulation of cyclin E2 in pancreatic cancer cell proliferation and decreased patient survival. PLoS One 2013, 8:e76450.
15. Ding X.M. MicroRNAs: regulators of cancer metastasis and epithelial-mesenchymal transition (EMT). Chin. J. Cancer 2014, 33:140-147.
16. Dong J., Zhao Y.P., Zhou L., Zhang T.P., Chen G. Bcl-2 upregulation induced by miR-21 via a direct interaction is associated with apoptosis and chemoresistance in MIA PaCa-2 pancreatic cancer cells. Arch. Med. Res. 2011, 42:8-14.
17. Dosch J.S., Pasca di Magliano M., Simeone D.M. Pancreatic cancer and hedgehog pathway signaling: new insights. Pancreatology 2010, 10:151-157.
18. Druz A., Chen Y.C., Guha R., Betenbaugh M., Martin S.E., Shiloach J. Large-scale screening identifies a novel microRNA, miR-15a-3p, which induces apoptosis in human cancer cell lines. RNA Biol. 2013, 10:287-300.
19. Farhana L., Dawson M.I., Murshed F., Das J.K., Rishi A.K., Fontana J.A. Upregulation of miR-150* and miR-630 induces apoptosis in pancreatic cancer cells by targeting IGF-1R. PLoS One 2013, 8:e61015.
20. Frampton A.E., Krell J., Jacob J., Stebbing J., Castellano L., Jiao L.R. Loss of miR-126 is crucial to pancreatic cancer progression. Expert Rev. Anticancer Ther. 2012, 7:881-884.
21. Franke T.F. PI3K/Akt: getting it right matters. Oncogene 2008, 27:6473-6488.
22. Fulda S. Evasion of apoptosis as a cellular stress response in cancer. Int. J. Cell Biol. 2010, 2010:370835.
23. Gironella M., Seux M., Xie M.J., Cano C., Tomasini R., Gommeaux J., Garcia S., Nowak J., Yeung M.L., Jeang K.T., Chaix A., Fazli L., Motoo Y., Wang Q., Rocchi P., Russo A., Gleave M., Dagorn J.C., Iovanna J.L., Carrier A., Pébusque M.J., Dusetti N.J. Tumor protein 53-induced nuclear protein 1 expression is repressed by miR-155, and its restoration inhibits pancreatic tumor development. Proc. Natl. Acad. Sci. USA 2007, 104:16170-16175.
24. Gregory P.A., Bert A.G., Paterson E.L., Barry S.C., Tsykin A., Farshid G., Vadas M.A., Khew-Goodall Y., Goodall G.J. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat. Cell Biol. 2008, 10:593-601.
25. Greither T., Grochola L.F., Udelnow A., Lautenschläger C., Würl P., Taubert H. Elevated expression of microRNAs 155, 203, 210 and 222 in pancreatic tumors is associated with poorer survival. Int. J. Cancer 2010, 126:73-80.
26. Guo R., Wang Y., Shi W.Y., Liu B., Hou S.Q., Liu L. MicroRNA miR-491-5p targeting both TP53 and Bcl-XL induces cell apoptosis in SW1990 pancreatic cancer cells through mitochondria mediated pathway. Molecules 2012, 17:14733-14747.
27. Hamada S., Satoh K., Fujibuchi W., Hirota M., Kanno A., Unno J., Masamune A., Kikuta K., Kume K., Shimosegawa T. MiR-126 acts as a tumor suppressor in pancreatic cancer cells via the regulation of ADAM9. Mol. Cancer Res. 2012, 10:3-10.
28. Hamada S., Masamune A., Miura S., Satoh K., Shimosegawa T. MiR-365 induces gemcitabine resistance in pancreatic cancer cells by targeting the adaptor protein SHC1 and pro-apoptotic regulator BAX. Cell. Signal. 2014, 26:179-185.
29. Hao J., Zhang S., Zhou Y., Hu X., Shao C. MicroRNA 483-3p suppresses the expression of DPC4/Smad4 in pancreatic cancer. FEBS Lett. 2011, 585:207-213.
30. Hao J., Zhang S., Zhou Y., Liu C., Hu X., Shao C. MicroRNA 421 suppresses DPC4/Smad4 in pancreatic cancer. Biochem. Biophys. Res. Commun. 2011, 406:552-557.
31. Harazono Y., Muramatsu T., Endo H., Uzawa N., Kawano T., Harada K., Inazawa J., Kozaki K. miR-655 is an EMT-suppressive microRNA targeting ZEB1 and TGFBR2. PLoS One 2013, 8:e62757.
32. Hata A., Davis B.N. Control of microRNA biogenesis by TGFbeta signaling pathway-A novel role of Smads in the nucleus. Cytokine Growth Factor Rev. 2009, 20:517-521.
33. He D., Miao H., Xu Y., Xiong L., Wang Y., Xiang H., Zhang H., Zhang Z. MiR-371-5p facilitates pancreatic cancer cell proliferation and decreases patient survival. PLoS One 2014, 9:e112930.
34. Hidalgo M. Pancreatic cancer. N. Engl. J. Med. 2010, 362:1605-1617.
35. Hu Y., Ou Y., Wu K., Chen Y., Sun W. MiR-143 inhibits the metastasis of pancreatic cancer and an associated signaling pathway. Tumour Biol. 2012, 33:1863-1870.
36. Huang F., Tang J., Zhuang X., Zhuang Y., Cheng W., Chen W., Yao H., Zhang S. MiR-196a promotes pancreatic cancer progression by targeting nuclear factor kappa-B-inhibitor alpha. PLoS One 2014, 9:e87897.
37. Huang T., Alvarez A., Hu B., Cheng S.Y. Noncoding RNAs in cancer and cancer stem cells. Chin. J. Cancer 2013, 32:582-593.
38. Hui C.C., Angers S. Gli proteins in development and disease. Annu. Rev. Cell Dev. Biol. 2011, 27:513-537.
39. Ivanovska I., Ball A.S., Diaz R.L., Magnus J.F., Kibukawa M., Schelter J.M., Kobayashi S.V., Lim L., Burchard J., Jackson A.L., Linsley P.S., Cleary M.A. MicroRNAs in the miR-106b family regulate p21/CDKN1A and promote cell cycle progression. Mol. Cell. Biol. 2008, 28:2167-2174.
40. Izumchenko E., Chang X., Michailidi C., Kagohara L., Ravi R., Paz K., Brait M., Hoque M.O., Ling S., Bedi A., Sidransky D. The TGFβ-miR200-MIG6 pathway orchestrates the EMT-associated kinase switch that induces resistance to EGFR inhibitors. Cancer Res. 2014, 74:3995-4005.
41. Jiang J., Yu C., Chen M., Zhang H., Tian S., Sun C. Reduction of miR-29c enhances pancreatic cancer cell migration and stem cell-like phenotype. Oncotarget 2015, 6:2767-2778.
42. Jiao L.R., Frampton A.E., Jacob J., Pellegrino L., Krell J., Giamas G., Tsim N., Vlavianos P., Cohen P., Ahmad R., Keller A., Habib N.A., Stebbing J., Castellano L. MicroRNAs targeting oncogenes are down-regulated in pancreatic malignant transformation from benign tumors. PLoS One 2012, 7:e32068.
43. Jones S., Zhang X., Parsons D.W., Lin J.C., Leary R.J., Angenendt P., Mankoo P., Carter H., Kamiyama H., Jimeno A., Hong S.M., Fu B., Lin M.T., Calhoun E.S., Kamiyama M., Walter K., Nikolskaya T., Nikolsky Y., Hartigan J., Smith D.R., Hidalgo M., Leach S.D., Klein A.P., Jaffee E.M., Goggins M., Maitra A., Iacobuzio-Donahue C., Eshleman J.R., Kern S.E., Hruban R.H., Karchin R., Papadopoulos N., Parmigiani G., Vogelstein B., Velculescu V.E., Kinzler K.W. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 2008, 321:1801-1806.
44. Kapinas K., Kessler C., Ricks T., Gronowicz G., Delany A.M. miR-29 modulates Wnt signaling in human osteoblasts through a positive feedback loop. J. Biol. Chem. 2010, 285:25221-25231.
45. Kang M.H., Reynolds C.P. Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy. Clin. Cancer Res. 2009, 15:1126-1132.
46. Keklikoglou I., Hosaka K., Bender C., Bott A., Koerner C., Mitra D., Will R., Woerner A., Muenstermann E., Wilhelm H., Cao Y., Wiemann S. MicroRNA-206 functions as a pleiotropic modulator of cell proliferation, invasion and lymphangiogenesis in pancreatic adenocarcinoma by targeting ANXA2 and KRAS genes. Oncogene 2014, 1-12.
47. Kent O.A., Chivukula R.R., Mullendore M., Wentzel E.A., Feldmann G., Lee K.H., Liu S., Leach S.D., Maitra A., Mendell J.T. Repression of the miR-143/145 cluster by oncogenic Ras initiates a tumor-promoting feed-forward pathway. Genes Dev. 2010, 24:2754-2759.
48. Kong X., Li L., Li Z., Le X., Huang C., Jia Z., Cui J., Huang S., Wang L., Xie K. Dysregulated expression of FOXM1 isoforms drives progression of pancreatic cancer. Cancer Res. 2013, 73:3987-3996.
49. Lahdaoui F., Delpu Y., Vincent A., Renaud F., Messager M., Duchêne B., Leteurtre E., Mariette C., Torrisani J., Jonckheere N., Van Seuningen I. miR-219-1-3p is a negative regulator of the mucin MUC4 expression and is a tumor suppressor in pancreatic cancer. Oncogene 2015, 34:780-788.
50. Lee K.H., Lotterman C., Karikari C., Omura N., Feldmann G., Habbe N., Goggins M.G., Mendell J.T., Maitra A. Epigenetic silencing of MicroRNA miR-107 regulates cyclin-dependent kinase 6 expression in pancreatic cancer. Pancreatology 2009, 9:293-301.
51. Li C., Heidt D.G., Dalerba P., Burant C.F., Zhang L., Adsay V., Wicha M., Clarke M.F., Simeone D.M. Identification of pancreatic cancer stem cells. Cancer Res. 2007, 67:1030-1037.
52. Li L., Li Z., Kong X., Xie D., Jia Z., Jiang W., Cui J., Du Y., Wei D., Huang S., Xie K. Down-regulation of microRNA-494 via loss of SMAD4 increases FOXM1 and β-catenin signaling in pancreatic ductal adenocarcinoma cells. Gastroenterology 2014, 147:485-497.
53. Li Y., Zhang D., Chen C., Ruan Z., Li Y., Huang Y. MicroRNA-212 displays tumor-promoting properties in non-small cell lung cancer cells and targets the hedgehog pathway receptor PTCH1. Mol. Biol. Cell 2012, 23:1423-1434.
54. Liang X., Zeng J., Wang L., Fang M., Wang Q., Zhao M., Xu X., Liu Z., Li W., Liu S., Yu H., Jia J., Chen C. Histone demethylase retinoblastoma binding protein 2 is overexpressed in hepatocellular carcinoma and negatively regulated by hsa-miR-212. PLoS One 2013, 8:e69784.
55. Liffers S.T., Munding J.B., Vogt M., Kuhlmann J.D., Verdoodt B., Nambiar S., Maghnouj A., Mirmohammadsadegh A., Hahn S.A., Tannapfel A. MicroRNA-148a is down-regulated in human pancreatic ductal adenocarcinomas and regulates cell survival by targeting CDC25B. Lab. Invest. 2011, 91:1472-1479.
56. Listing H., Mardin W.A., Wohlfromm S., Mees S.T., Haier J. MiR-23a/-24-induced gene silencing results in mesothelial cell integration of pancreatic cancer. Br. J. Cancer 2015, 112:131-139.
57. Liu M., Du Y., Gao J., Liu J., Kong X., Gong Y., Li Z., Wu H., Chen H. Aberrant expression miR-196a is associated with abnormal apoptosis, invasion, and proliferation of pancreatic cancer cells. Pancreas 2013, 42:1169-1181.
58. Liu M., Zhang X., Hu C.F., Xu Q., Zhu H.X., Xu N.Z. MicroRNA-mRNA functional pairs for cisplatin resistance in ovarian cancer cells. Chin. J. Cancer 2014, 33:285-294.
59. Lodygin D., Tarasov V., Epanchintsev A., Berking C., Knyazeva T., Körner H., Knyazev P., Diebold J., Hermeking H. Inactivation of miR-34a by aberrant CpG methylation in multiple types of cancer. Cell Cycle 2008, 7:2591-2600.
60. Lu Z., Li Y., Takwi A., Li B., Zhang J., Conklin D.J., Young K.H., Martin R., Li Y. miR-301a as an NF-κB activator in pancreatic cancer cells. EMBO J. 2011, 30:57-67.
61. di Magliano M.P., Logsdon C.D. Roles for KRAS in pancreatic tumor development and progression. Gastroenterology 2013, 144:1220-1229.
62. Ma C., Nong K., Wu B., Dong B., Bai Y., Zhu H., Wang W., Huang X., Yuan Z., Ai K. miR-212 promotes pancreatic cancer cell growth and invasion by targeting the hedgehog signaling pathway receptor patched-1. J. Exp. Clin. Cancer Res. 2014, 33:54.
63. Malumbres M., Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nat. Rev. Cancer 2009, 9:153-166.
64. Meng X., Wu J., Pan C., Wang H., Ying X., Zhou Y., Yu H., Zuo Y., Pan Z., Liu R.Y., Huang W. Genetic and epigenetic down-regulation of microRNA-212 promotes colorectal tumor metastasis via dysregulation of MnSOD. Gastroenterology 2013, 145:426-436.
65. Moon R.T., Bowerman B., Boutros M., Perrimon N. The promise and perils of Wnt signaling through beta-catenin. Science 2002, 296:1644-1646.
66. Morris J.P., Cano D.A., Sekine S., Wang S.C., Hebrok M. Beta-catenin blocks Kras- dependent reprogramming of acini into pancreatic cancer precursor lesions in mice. J. Clin. Invest. 2010, 120:508-520.
67. Morris J.,P., Wang S.C., Hebrok M. KRAS, Hedgehog, Wnt and the twisted developmental biology of pancreatic ductal adenocarcinoma. Nat. Rev. Cancer 2010, 10:683-695.
68. Morton J.P., Timpson P., Karim S.A., Ridgway R.A., Athineos D., Doyle B., Jamieson N.B., Oien K.A., Lowy A.M., Brunton V.G., Frame M.C., Evans T.R., Sansom O.J. Mutant p53 drives metastasis and overcomes growth arrest/senescence in pancreatic cancer. Proc. Natl. Acad. Sci. USA 2010, 107:246-251.
69. Mu Y., Gudey S.K., Landström M. Non-Smad signaling pathways. Cell Tissue Res. 2012, 347:11-20.
70. Mueller M.T., Hermann P.C., Witthauer J., Rubio-Viqueira B., Leicht S.F., Huber S., Ellwart J.W., Mustafa M., Bartenstein P., D'Haese J.G., Schoenberg M.H., Berger F., Jauch K.W., Hidalgo M., Heeschen C. Combined targeted treatment to eliminate tumorigenic cancer stem cells in human pancreatic cancer. Gastroenterology 2009, 137:1102-1113.
71. Musgrove E.A., Caldon C.E., Barraclough J., Stone A., Sutherland R.L. Cyclin D as a therapeutic target in cancer. Nat. Rev. Cancer 2011, 11:558-572.
72. Nagano H., Tomimaru Y., Eguchi H., Hama N., Wada H., Kawamoto K., Kobayashi S., Mori M., Doki Y. MicroRNA-29a induces resistance to gemcitabine through the Wnt/β-catenin signaling pathway in pancreatic cancer cells. Int. J. Oncol. 2013, 43:1066-1072.
73. Oettle H., Post S., Neuhaus P., Gellert K., Langrehr J., Ridwelski K., Schramm H., Fahlke J., Zuelke C., Burkart C., Gutberlet K., Kettner E., Schmalenberg H., Weigang-Koehler K., Bechstein W.O., Niedergethmann M., Schmidt-Wolf I., Roll L., Doerken B., Riess H. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA 2007, 297:267-277.
74. Olive K.P., Jacobetz M.A., Davidson C.J., Gopinathan A., McIntyre D., Honess D., Madhu B., Goldgraben M.A., Caldwell M.E., Allard D., Frese K.K., Denicola G., Feig C., Combs C., Winter S.P., Ireland-Zecchini H., Reichelt S., Howat W.J., Chang A., Dhara M., Wang L., Rückert F., Grützmann R., Pilarsky C., Izeradjene K., Hingorani S.R., Huang P., Davies S.E., Plunkett W., Egorin M., Hruban R.H., Whitebread N., McGovern K., Adams J., Iacobuzio-Donahue C., Griffiths J., Tuveson D.A. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 2009, 324:1457-1461.
75. Ozdamar B., Bose R., Barrios-Rodiles M., Wang H.R., Zhang Y., Wrana J.L. Regulation of the polarity protein Par6 by TGFbeta receptors controls epithelial cell plasticity. Science 2005, 307:1603-1609.
76. Padua D., Massagué J. Roles of TGFbeta in metastasis. Cell Res. 2009, 19:89-102.
77. Pan Y., Bai C.B., Joyner A.L., Wang B. Sonic hedgehog signaling regulates Gli2 transcriptional activity by suppressing its processing and degradation. Mol. Cell. Biol. 2006, 26:3365-3377.
78. Park J.K., Henry J.C., Jiang J., Esau C., Gusev Y., Lerner M.R., Postier R.G., Brackett D.J., Schmittgen T.D. miR-132 and miR-212 are increased in pancreatic cancer and target the retinoblastoma tumor suppressor. Biochem. Biophys. Res. Commun. 2011, 406:518-523.
79. Peifer M., Polakis P. Wnt signaling in oncogenesis and embryogenesis-a look outside the nucleus. Science 2000, 287:1606-1609.
80. Prakash N., Wurst W. A Wnt signal regulates stem cell fate and differentiation in vivo. Neurodegener. Dis. 2007, 4:333-338.
81. Pylayeva-Gupta Y., Grabocka E., Bar-Sagi D. RAS oncogenes: weaving a tumorigenic web. Nat. Rev. Cancer 2011, 11:761-774.
82. Reya T., Clevers H. Wnt signalling in stem cells and cancer. Nature 2005, 434:843-850.
83. Ristorcelli E., Beraud E., Verrando P., Villard C., Lafitte D., Sbarra V., Lombardo D., Verine A. Human tumor nanoparticles induce apoptosis of pancreatic cancer cells. FASEB J. 2008, 22:3358-3369.
84. Rivera F., López-Tarruella S., Vega-Villegas M.E., Salcedo M. Treatment of advanced pancreatic cancer: from gemcitabine single agent to combinations and targeted therapy. Cancer Treat. Rev. 2009, 35:335-339.
85. Rosty C., Goggins M. Early detection of pancreatic carcinoma. Hematol. Oncol. Clin. North Am. 2002, 16:37-52.
86. Rubin L.L., de Sauvage F.J. Targeting the Hedgehog pathway in cancer. Nat. Rev. Drug Discov. 2006, 5:1026-1033.
87. Samavarchi-Tehrani P., Golipour A., David L., Sung H.K., Beyer T.A., Datti A., Woltjen K., Nagy A., Wrana J.L. Functional genomics reveals a BMP-driven mesenchymal-toepithelial transition in the initiation of somatic cell reprogramming. Cell Stem Cell 2010, 7:64-77.
88. Scapoli L., Palmieri A., Lo M.L., Pezzetti F., Rubini C., Girardi A., Farinella F., Mazzotta M., Carinci F. MicroRNA expression profiling of oral carcinoma identifies new markers of tumor progression. Int. J. Immunopathol. Pharmacol. 2010, 23:1229-1234.
89. Shen J., Wan R., Hu G., Yang L., Xiong J., Wang F., Shen J., He S., Guo X., Ni J., Guo C., Wang X. miR-15b and miR-16 induce the apoptosis of rat activated pancreatic stellate cells by targeting Bcl-2 in vitro. Pancreatology 2012, 12:91-99.
90. Shi W., Sun C., He B., Xiong W., Shi X., Yao D., Cao X. GADD34-PP1c recruited by Smad7 dephosphorylates TGFbeta type I receptor. J. Cell Biol. 2004, 164:291-300.
91. Siegel R., Ma J., Zou Z., Jemal A. Cancer statistics, 2014. CA Cancer J. Clin. 2014, 64:9-29.
92. Singh P., Srinivasan R., Wig J.D. Major molecular markers in pancreatic ductal adenocarcinoma and their roles in screening, diagnosis, prognosis, and treatment. Pancreas 2011, 40:644-652.
93. Singh P., Srinivasan R., Wig J.D., Radotra B.D. A study of Smad4, Smad6 and Smad7 in surgically resected samples of pancreatic ductal adenocarcinoma and their correlation with clinicopathological parameters and patient survival. BMC. Res. Notes 2011, 4:560-564.
94. Slack F.J., Weidhaas J.B. MicroRNA in cancer prognosis. N. Engl. J. Med. 2008, 359:2720-2722.
95. Song S.D., Zhou J., Zhou J., Zhao H., Cen J.N., Li D.C. MicroRNA-375 targets the 3-phosphoinositide-dependent protein kinase-1 gene in pancreatic carcinoma. Oncol. Lett. 2013, 6:953-959.
96. Spaderna S., Schmalhofer O., Hlubek F., Berx G., Eger A., Merkel S., Jung A., Kirchner T., Brabletz T. A transient, EMT-linked loss of basement membranes indicates metastasis and poor survival in colorectal cancer. Gastroenterology 2006, 131:830-840.
97. Spaderna S., Schmalhofer O., Wahlbuhl M., Dimmler A., Bauer K., Sultan A., Hlubek F., Jung A., Strand D., Eger A., Kirchner T., Behrens J., Brabletz T. The transcriptional repressor ZEB1 promotes metastasis and loss of cell polarity in cancer. Cancer Res. 2008, 68:537-544.
98. Sun A., Bagella L., Tutton S., Romano G., Giordano A. From G0 to S phase: a view of the roles played by the retinoblastoma (Rb) family members in the Rb-E2F pathway. J. Cell. Biochem. 2007, 102:1400-1404.
99. Sun Y., Guo F., Bagnoli M., Xue F.X., Sun B.C., Shmulevich I., Mezzanzanica D., Chen K.X., Sood A.K., Yang D., Zhang W. Key nodes of a microRNA network associated with the integrated mesenchymal subtype of high-grade serous ovarian cancer. Chin. J. Cancer 2015, 34:28-40.
100. Sun Y., Zhang T., Wang C., Jin X., Jia C., Yu S., Chen J. MiRNA-615-5p functions as a tumor suppressor in pancreatic ductal adenocarcinoma by targeting AKT2. PLoS One 2015, 10:e0119783.
101. Takiuchi D., Eguchi H., Nagano H., Iwagami Y., Tomimaru Y., Wada H., Kawamoto K., Kobayashi S., Marubashi S., Tanemura M., Mori M., Doki Y. Involvement of microRNA-181b in the gemcitabine resistance of pancreatic cancer cells. Pancreatology 2013, 13:517-523.
102. Thayer S.P., di Magliano M.P., Heiser P.W., Nielsen C.M., Roberts D.J., Lauwers G.Y., Qi Y.P., Gysin S., Fernández-del Castillo C., Yajnik V., Antoniu B., McMahon M., Warshaw A.L., Hebrok M. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 2003, 425:851-856.
103. Tian M., Neil J.R., Schiemann W.P. Transforming growth factor-β and the hallmarks of cancer. Cell. Signal. 2011, 23:951-962.
104. Torrisani J., Bournet B., du Rieu M.C., Bouisson M., Souque A., Escourrou J., Buscail L., Cordelier P. Let-7 MicroRNA transfer in pancreatic cancer-derived cells inhibits in vitro cell proliferation but fails to alter tumor progression. Hum. Gene Ther. 2009, 20:831-844.
105. Tsuda N., Ishiyama S., Li Y., Ioannides C.G., Abbruzzese J.L., Chang D.Z. Synthetic microRNA designed to target glioma-associated antigen 1 transcription factor inhibits division and induces late apoptosis in pancreatic tumor cells. Clin. Cancer Res. 2006, 12:6557-6564.
106. van den Brink G.R. Hedgehog signaling in development and homeostasis of the gastrointestinal tract. Physiol. Rev. 2007, 87:1343-1375.
107. Vousden K.H., Prives C. Blinded by the light: the growing complexity of p53. Cell 2009, 137:413-431.
108. Walter B.A., Valera V.A., Pinto P.A., Merino M.J. Comprehensive microRNA profiling of prostate cancer. J. Cancer 2013, 4:350-357.
109. Wang P., Fan J., Chen Z., Meng Z.Q., Luo J.M., Lin J.H., Zhou Z.H., Chen H., Wang K., Xu Z.D., Liu L.M. Low-level expression of Smad7 correlates with lymph node metastasis and poor prognosis in patients with pancreatic cancer. Ann. Surg. Oncol. 2009, 16:826-835.
110. Wang R.A., Li Z.S., Yan Q.G., Bian X.W., Ding Y.Q., Du X., Sun B.C., Sun Y.T., Zhang X.H. Resistance to apoptosis should not be taken as a hallmark of cancer. Chin. J. Cancer 2014, 33:47-50.
111. Wang S., Chen X., Tang M. MicroRNA-216a inhibits pancreatic cancer by directly targeting Janus kinase 2. Oncol. Rep. 2014, 32:2824-2830.
112. Watanabe S., Ueda Y., Akaboshi S., Hino Y., Sekita Y., Nakao M. HMGA2 maintains oncogenic RAS-induced epithelial-mesenchymal transition in human pancreatic cancer cells. Am. J. Pathol. 2009, 174:854-868.
113. Wei D., Wang L., Kanai M., Jia Z., Le X., Li Q., Wang H., Xie K. KLF4α up-regulation promotes cell cycle progression and reduces survival time of patients with pancreatic cancer. Gastroenterology 2010, 139:2135-2145.
114. Wong H.H., Lemoine N.R. Pancreatic cancer: molecular pathogenesis and new therapeutic targets. Nat. Rev. Gastroenterol. Hepatol. 2009, 6:412-422.
115. Xu J.W., Wang T.X., You L., Zheng L.F., Shu H., Zhang T.P., Zhao Y.P. Insulin-like growth factor 1 receptor (IGF-1R) as a target of MiR-497 and plasma IGF-1R levels associated with TNM stage of pancreatic cancer. PLoS One 2014, 9:e92847.
116. Yan H.J., Liu W.S., Sun W.H., Wu J., Ji M., Wang Q., Zheng X., Jiang J.T., Wu C.P. miR-17-5p inhibitor enhances chemosensitivity to gemcitabine via upregulating Bim expression in pancreatic cancer cells. Dig. Dis. Sci. 2012, 57:3160-3167.
117. Youle R.J., Strasser A. The BCL-2 protein family: opposing activities that mediate cell death. Nat. Rev. Mol. Cell Biol. 2008, 9:47-59.
118. Yu S., Lu Z., Liu C., Meng Y., Ma Y., Zhao W., Liu J., Yu J., Chen J. miRNA-96 suppresses KRAS and functions as a tumor suppressor gene in pancreatic cancer. Cancer Res. 2010, 70:6015-6025.
119. Zang W., Wang Y., Wang T., Du Y., Chen X., Li M., Zhao G. miR-663 attenuates tumor growth and invasiveness by targeting eEF1A2 in pancreatic cancer. Mol. Cancer 2015, 14:37.
120. Zeng J.P., Fang M., Wang L.X., Liang X.M., Shen Y.Q., Yu H., Liu Z.F., Sun Y.D., Liu S.L., Chen C.Y., Jia J.H. MicroRNA-212 inhibits proliferation of gastric cancer by directly repressing retinoblastoma binding protein 2. J. Cell. Biochem. 2013, 114:2666-2672.
121. Zhang B., Ma J.X. Wnt pathway antagonists and angiogenesis. Protein Cell 2010, 1:898-906.
122. Zhang J., Jia Z., Li Q., Wang L., Rashid A., Zhu Z., Evans D.B., Vauthey J.N., Xie K., Yao J.C. Elevated expression of vascular endothelial growth factor correlates with increased angiogenesis and decreased progression-free survival among patients with low-grade neuroendocrine tumors. Cancer 2007, 109:1478-1486.
123. Zhang R., Li M., Zang W., Chen X., Wang Y., Li P., Du Y., Zhao G., Li L. MiR-148a regulates the growth and apoptosis in pancreatic cancer by targeting CCKBR and Bcl-2. Tumor Biol. 2014, 35:837-844.
124. Zhang X.J., Ye H., Zeng C.W., He B., Zhang H., Chen Y.Q. Dysregulation of miR-15a and miR-214 in human pancreatic cancer. J. Hematol. Oncol. 2010, 3:46.
125. Zhao G., Zhang J.G., Shi Y., Qin Q., Liu Y., Wang B., Tian K., Deng S.C., Li X., Zhu S., Gong Q., Niu Y., Wang C.Y. MiR-130b is a prognostic marker and inhibits cell proliferation and invasion in pancreatic cancer through targeting STAT3. PLoS One 2013, 8:e73803.
126. Zhao G., Zhang J.G., Liu Y., Qin Q., Wang B., Tian K., Liu L., Li X., Niu Y., Deng S.C., Wang C.Y. miR-148b functions as a tumor suppressor in pancreatic cancer by targeting AMPKα1. Mol. Cancer Ther. 2013, 12:83-93.
127. Zhao W.G., Yu S.N., Lu Z.H., Ma Y.H., Gu Y.M., Chen J. The miR-217 microRNA functions as a potential tumor suppressor in pancreatic ductal adenocarcinoma by targeting KRAS. Carcinogenesis 2010, 31:1726-1733.
128. Zhou J., Song S., He S., Zhu X., Zhang Y., Yi B., Zhang B., Qin G., Li D. MicroRNA-375 targets PDK1 in pancreatic carcinoma and suppresses cell growth through the Akt signaling pathway. Int. J. Mol. Med. 2014, 33:950-956.
129. Zhou L., Zhang W.G., Wang D.S., Tao K.S., Song W.J., Dou K.F. MicroRNA-183 is involved in cell proliferation, survival and poor prognosis in pancreatic ductal adenocarcinoma by regulating Bmi-1. Oncol. Rep. 2014, 32:1734-1740.
130. Zhu Z., Xu Y., Zhao J., Liu Q., Feng W., Fan J., Wang P. miR-367 promotes epithelial-to-mesenchymal transition and invasion of pancreatic ductal adenocarcinoma cells by targeting the Smad7-TGF-β signalling pathway. Br. J. Cancer 2015, 112:1367-1375.