Non-coding RNAs in pancreatic cancer: challenges and opportunities for clinical application

Springer Science and Business Media LLC - Tập 39 Số 4 - Trang 295-318 - 2016
Taucher1, Harald Mangge2, Johannes Haybaeck1
1Institute of Pathology, Medical University Graz, Auenbruggerplatz 25, A-8036, Graz, Austria
2Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University Graz, Auenbruggerplatz 25, A-8036, Graz, Austria

Tóm tắt

Từ khóa


Tài liệu tham khảo

M. Malvezzi, P. Bertuccio, F. Levi, C. La Vecchia, E. Negri, European cancer mortality predictions for the year 2014. Ann. Oncol. 25, 1650–1656 (2014)

D.P. Ryan, T.S. Hong, N. Bardeesy, Pancreatic adenocarcinoma. N. Engl. J. Med. 371, 1039–1049 (2014)

T. Furukawa, R. Fujisaki, Y. Yoshida, N. Kanai, M. Sunamura, T. Abe, K. Takeda, S. Matsuno, A. Horii, Distinct progression pathways involving the dysfunction of DUSP6/MKP-3 in pancreatic intraepithelial neoplasia and intraductal papillary-mucinous neoplasms of the pancreas. Mod. Pathol. 18, 1034–1042 (2005)

S.A. Hahn, A.T. Hoque, C.A. Moskaluk, L.T. da Costa, M. Schutte, E. Rozenblum, A.B. Seymour, C.L. Weinstein, C.J. Yeo, R.H. Hruban, S.E. Kern, Homozygous deletion map at 18q21.1 in pancreatic cancer. Cancer Res. 56, 490–494 (1996)

J.M. Bailey, A.M. Hendley, K.J. Lafaro, M.A. Pruski, N.C. Jones, J. Alsina, M. Younes, A. Maitra, F. McAllister, C.A. Iacobuzio-Donahue, S.D. Leach, p53 mutations cooperate with oncogenic Kras to promote adenocarcinoma from pancreatic ductal cells. Oncogene (2015). doi: 10.1038/onc.2015.441

E.G. Chiorean, A.L. Coveler, Pancreatic cancer: optimizing treatment options, new, and emerging targeted therapies. Drug Des. Devel. Ther. 9, 3529–3545 (2015)

C.P. Christov, T.J. Gardiner, D. Szuts, T. Krude, Functional requirement of noncoding Y RNAs for human chromosomal DNA replication. Mol. Cell. Biol. 26, 6993–7004 (2006)

S. Kishore, S. Stamm, Regulation of alternative splicing by snoRNAs. Cold Spring Harb. Symp. Quant. Biol. 71, 329–334 (2006)

A.T. Zhang, A.R. Langley, C.P. Christov, E. Kheir, T. Shafee, T.J. Gardiner, T. Krude, Dynamic interaction of Y RNAs with chromatin and initiation proteins during human DNA replication. J. Cell Sci. 124, 2058–2069 (2011)

Y. Zhu, V. Stribinskis, K.S. Ramos, Y. Li, Sequence analysis of RNase MRP RNA reveals its origination from eukaryotic RNase P RNA. RNA 12, 699–706 (2006)

A. Huttenhofer, P. Schattner, N. Polacek, Non-coding RNAs: hope or hype? Trends Genet. 21, 289–297 (2005)

P. Kapranov, J. Cheng, S. Dike, D.A. Nix, R. Duttagupta, A.T. Willingham, P.F. Stadler, J. Hertel, J. Hackermuller, I.L. Hofacker, I. Bell, E. Cheung, J. Drenkow, E. Dumais, S. Patel, G. Helt, M. Ganesh, S. Ghosh, A. Piccolboni, V. Sementchenko, H. Tammana, T.R. Gingeras, RNA maps reveal new RNA classes and a possible function for pervasive transcription. Science 316, 1484–1488 (2007)

R.J. Taft, K.C. Pang, T.R. Mercer, M. Dinger, J.S. Mattick, Non-coding RNAs: regulators of disease. J. Pathol. 220, 126–139 (2010)

R. Tanaka, M. Tomosugi, M. Horinaka, Y. Sowa, T. Sakai, Metformin causes G1-phase arrest via down-regulation of MiR-221 and enhances TRAIL sensitivity through DR5 up-regulation in pancreatic cancer cells. PLoS One 10, e0125779 (2015)

D. Nalls, S.N. Tang, M. Rodova, R.K. Srivastava, S. Shankar, Targeting epigenetic regulation of miR-34a for treatment of pancreatic cancer by inhibition of pancreatic cancer stem cells. PLoS One 6, e24099 (2011)

L. Buscail, B. Bournet, F. Vernejoul, G. Cambois, H. Lulka, N. Hanoun, M. Dufresne, A. Meulle, A. Vignolle-Vidoni, L. Ligat, N. Saint-Laurent, F. Pont, S. Dejean, M. Gayral, F. Martins, J. Torrisani, O. Barbey, F. Gross, R. Guimbaud, P. Otal, F. Lopez, G. Tiraby, P. Cordelier, First-in-man phase I clinical trial of gene therapy for advanced pancreatic cancer: safety, biodistribution and preliminary clinical findings. Mol. Ther. 23, 202–214 (2015)

V. Ambros, The functions of animal microRNAs. Nature 431, 350–355 (2004)

D.P. Bartel, MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297 (2004)

K. Chen, N. Rajewsky, The evolution of gene regulation by transcription factors and microRNAs. Nat. Rev. Genet. 8, 93–103 (2007)

A. Tanzer, P.F. Stadler, Molecular evolution of a microRNA cluster. J. Mol. Biol. 339, 327–335 (2004)

M.J. Axtell, D.P. Bartel, Antiquity of microRNAs and their targets in land plants. Plant Cell 17, 1658–1673 (2005)

R.C. Friedman, K.K. Farh, C.B. Burge, D.P. Bartel, Most mammalian mRNAs are conserved targets of microRNAs. Genome Res. 19, 92–105 (2009)

I. Fkih M’hamed, M. Privat, F. Ponelle, F. Penault-Llorca, A. Kenani, Y.J. Bignon, Identification of miR-10b, miR-26a, miR-146a and miR-153 as potential triple-negative breast cancer biomarkers. Cell. Oncol. 38, 433–442 (2015)

E. Yiannakopoulou, Targeting epigenetic mechanisms and microRNAs by aspirin and other non steroidal anti-inflammatory agents--implications for cancer treatment and chemoprevention. Cell. Oncol. 37, 167–178 (2014)

C. Salazar, R. Nagadia, P. Pandit, J. Cooper-White, N. Banerjee, N. Dimitrova, W.B. Coman, C. Punyadeera, A novel saliva-based microRNA biomarker panel to detect head and neck cancers. Cell. Oncol. 37, 331–338 (2014)

K.J. Peterson, M.R. Dietrich, M.A. McPeek, MicroRNAs and metazoan macroevolution: insights into canalization, complexity, and the Cambrian explosion. Bioessays 31, 736–747 (2009)

Y. Lee, M. Kim, J. Han, K.H. Yeom, S. Lee, S.H. Baek, V.N. Kim, MicroRNA genes are transcribed by RNA polymerase II. EMBO J. 23, 4051–4060 (2004)

R.I. Gregory, T.P. Chendrimada, R. Shiekhattar, MicroRNA biogenesis: isolation and characterization of the microprocessor complex. Methods Mol. Biol. 342, 33–47 (2006)

E. Lund, J.E. Dahlberg, Substrate selectivity of exportin 5 and Dicer in the biogenesis of microRNAs. Cold Spring Harb. Symp. Quant. Biol. 71, 59–66 (2006)

E. Prodromaki, A. Korpetinou, E. Giannopoulou, E. Vlotinou, M. Chatziathanasiadou, N.I. Papachristou, C.D. Scopa, H. Papadaki, H.P. Kalofonos, D.J. Papachristou, Expression of the microRNA regulators Drosha, Dicer and Ago2 in non-small cell lung carcinomas. Cell. Oncol. 38, 307–317 (2015)

X.J. Wang, J.L. Reyes, N.H. Chua, T. Gaasterland, Prediction and identification of Arabidopsis thaliana microRNAs and their mRNA targets. Genome Biol. 5, R65 (2004)

A. Eulalio, E. Huntzinger, T. Nishihara, J. Rehwinkel, M. Fauser, E. Izaurralde, Deadenylation is a widespread effect of miRNA regulation. RNA 15, 21–32 (2009)

A.A. Bazzini, M.T. Lee, A.J. Giraldez, Ribosome profiling shows that miR-430 reduces translation before causing mRNA decay in zebrafish. Science 336, 233–237 (2012)

B.P. Lewis, I.H. Shih, M.W. Jones-Rhoades, D.P. Bartel, C.B. Burge, Prediction of mammalian microRNA targets. Cell 115, 787–798 (2003)

W.G. Zhao, S.N. Yu, Z.H. Lu, Y.H. Ma, Y.M. Gu, J. Chen, The miR-217 microRNA functions as a potential tumor suppressor in pancreatic ductal adenocarcinoma by targeting KRAS. Carcinogenesis 31, 1726–1733 (2010)

M.C. du Rieu, J. Torrisani, J. Selves, T. Al Saati, A. Souque, M. Dufresne, G.J. Tsongalis, A.A. Suriawinata, N. Carrere, L. Buscail, P. Cordelier, MicroRNA-21 is induced early in pancreatic ductal adenocarcinoma precursor lesions. Clin. Chem. 56, 603–612 (2010)

S. Ye, L. Yang, X. Zhao, W. Song, W. Wang, S. Zheng, Bioinformatics method to predict two regulation mechanism: TF-miRNA-mRNA and lncRNA-miRNA-mRNA in pancreatic cancer. Cell Biochem. Biophys. 70, 1849–1858 (2014)

N. Habbe, J.B. Koorstra, J.T. Mendell, G.J. Offerhaus, J.K. Ryu, G. Feldmann, M.E. Mullendore, M.G. Goggins, S.M. Hong, A. Maitra, MicroRNA miR-155 is a biomarker of early pancreatic neoplasia. Cancer Biol. Ther. 8, 340–346 (2009)

J.K. Ryu, S.M. Hong, C.A. Karikari, R.H. Hruban, M.G. Goggins, A. Maitra, Aberrant MicroRNA-155 expression is an early event in the multistep progression of pancreatic adenocarcinoma. Pancreatology 10, 66–73 (2010)

C. Yu, M. Wang, Z. Li, J. Xiao, F. Peng, X. Guo, Y. Deng, J. Jiang, C. Sun, MicroRNA-138-5p regulates pancreatic cancer cell growth through targeting FOXC1. Cell. Oncol. 38, 173–181 (2015)

J.A. Goodrich, J.F. Kugel, Non-coding-RNA regulators of RNA polymerase II transcription. Nat. Rev. Mol. Cell Biol. 7, 612–616 (2006)

M. Beltran, I. Puig, C. Pena, J.M. Garcia, A.B. Alvarez, R. Pena, F. Bonilla, A.G. de Herreros, A natural antisense transcript regulates Zeb2/Sip1 gene expression during Snail1-induced epithelial-mesenchymal transition. Genes Dev. 22, 756–769 (2008)

A. Mazo, J.W. Hodgson, S. Petruk, Y. Sedkov, H.W. Brock, Transcriptional interference: an unexpected layer of complexity in gene regulation. J. Cell Sci. 120, 2755–2761 (2007)

J.H. Yoon, J. Kim, M. Gorospe, Long noncoding RNA turnover. Biochimie 1859, 209–221 (2015)

K.C. Wang, H.Y. Chang, Molecular mechanisms of long noncoding RNAs. Mol. Cell 43, 904–914 (2011)

D.B. Pontier, J. Gribnau, Xist regulation and function explored. Hum. Genet. 130, 223–236 (2011)

A. Wutz, T.P. Rasmussen, R. Jaenisch, Chromosomal silencing and localization are mediated by different domains of Xist RNA. Nat. Genet. 30, 167–174 (2002)

M. Mourtada-Maarabouni, A.M. Hasan, F. Farzaneh, G.T. Williams, Inhibition of human T-cell proliferation by mammalian target of rapamycin (mTOR) antagonists requires noncoding RNA growth-arrest-specific transcript 5 (GAS5). Mol. Pharmacol. 78, 19–28 (2010)

K. Kim, I. Jutooru, G. Chadalapaka, G. Johnson, J. Frank, R. Burghardt, S. Kim, S. Safe, HOTAIR is a negative prognostic factor and exhibits pro-oncogenic activity in pancreatic cancer. Oncogene 32, 1616–1625 (2013)

R. Bonasio, R. Shiekhattar, Regulation of transcription by long noncoding RNAs. Annu. Rev. Genet. 48, 433–455 (2014)

S. Uchida, S. Dimmeler, Long noncoding RNAs in cardiovascular diseases. Circ. Res. 116, 737–750 (2015)

M. Knoll, H.F. Lodish, L. Sun, Long non-coding RNAs as regulators of the endocrine system. Nat. Rev. Endocrinol. 11, 151–160 (2015)

K. Tano, N. Akimitsu, Long non-coding RNAs in cancer progression. Front. Genet. 3, 219 (2012)

A.G. Bader, D. Brown, J. Stoudemire, P. Lammers, Developing therapeutic microRNAs for cancer. Gene Ther. 18, 1121–1126 (2011)

J. Torrisani, B. Bournet, M.C. du Rieu, M. Bouisson, A. Souque, J. Escourrou, L. Buscail, P. Cordelier, let-7 MicroRNA transfer in pancreatic cancer-derived cells inhibits in vitro cell proliferation but fails to alter tumor progression. Hum.Gene Ther. 20, 831–844 (2009)

P.J. White, F. Anastasopoulos, C.W. Pouton, B.J. Boyd, Overcoming biological barriers to in vivo efficacy of antisense oligonucleotides. Expert Rev. Mol. Med. 11, e10 (2009)

X. Zong, L. Huang, V. Tripathi, R. Peralta, S.M. Freier, S. Guo, K.V. Prasanth, Knockdown of nuclear-retained long noncoding RNAs using modified DNA antisense oligonucleotides. Methods Mol. Biol. 1262, 321–331 (2015)

N. Hanna, P. Ohana, F.M. Konikoff, G. Leichtmann, A. Hubert, L. Appelbaum, Y. Kopelman, A. Czerniak, A. Hochberg, Phase 1/2a, dose-escalation, safety, pharmacokinetic and preliminary efficacy study of intratumoral administration of BC-819 in patients with unresectable pancreatic cancer. Cancer Gene Ther. 19, 374–381 (2012)

M. Lohr, P. Maisonneuve, A.B. Lowenfels, K-Ras mutations and benign pancreatic disease. Int. J. Pancreatol. 27, 93–103 (2000)

M. Wang, X. Lu, X. Dong, F. Hao, Z. Liu, G. Ni, D. Chen, pERK1/2 silencing sensitizes pancreatic cancer BXPC-3 cell to gemcitabine-induced apoptosis via regulating Bax and Bcl-2 expression. World J.Surg.Oncol. 13, 66 (2015). doi: 10.1186/s12957-015-0451-7

O.A. Kent, R.R. Chivukula, M. Mullendore, E.A. Wentzel, G. Feldmann, K.H. Lee, S. Liu, S.D. Leach, A. Maitra, J.T. Mendell, Repression of the miR-143/145 cluster by oncogenic Ras initiates a tumor-promoting feed-forward pathway. Genes Dev. 24, 2754–2759 (2010)

I. Keklikoglou, K. Hosaka, C. Bender, A. Bott, C. Koerner, D. Mitra, R. Will, A. Woerner, E. Muenstermann, H. Wilhelm, Y. Cao, S. Wiemann, MicroRNA-206 functions as a pleiotropic modulator of cell proliferation, invasion and lymphangiogenesis in pancreatic adenocarcinoma by targeting ANXA2 and KRAS genes. Oncogene 34, 4867–4878 (2014)

X. Yan, X. Chen, H. Liang, T. Deng, W. Chen, S. Zhang, M. Liu, X. Gao, Y. Liu, C. Zhao, X. Wang, N. Wang, J. Li, R. Liu, K. Zen, C.Y. Zhang, B. Liu, Y. Ba, miR-143 and miR-145 synergistically regulate ERBB3 to suppress cell proliferation and invasion in breast cancer. Mol. Cancer. 13, 220 (2014). doi: 10.1186/1476-4598-13-220

O.A. Kent, J.T. Mendell, R. Rottapel, Transcriptional regulation of miR-31 by oncogenic KRAS mediates metastatic phenotypes by repressing RASA1. Mol. Cancer. Res. (2016). doi: 10.1158/1541-7786.MCR-15-0456

J. Su, H. Liang, W. Yao, N. Wang, S. Zhang, X. Yan, H. Feng, W. Pang, Y. Wang, X. Wang, Z. Fu, Y. Liu, C. Zhao, J. Zhang, C.Y. Zhang, K. Zen, X. Chen, Y. Wang, MiR-143 and MiR-145 regulate IGF1R to suppress cell proliferation in colorectal cancer. PLoS One 9, e114420 (2014)

X. Chen, X. Guo, H. Zhang, Y. Xiang, J. Chen, Y. Yin, X. Cai, K. Wang, G. Wang, Y. Ba, L. Zhu, J. Wang, R. Yang, Y. Zhang, Z. Ren, K. Zen, J. Zhang, C.Y. Zhang, Role of miR-143 targeting KRAS in colorectal tumorigenesis. Oncogene 28, 1385–1392 (2009)

C. Clape, V. Fritz, C. Henriquet, F. Apparailly, P.L. Fernandez, F. Iborra, C. Avances, M. Villalba, S. Culine, L. Fajas, miR-143 interferes with ERK5 signaling, and abrogates prostate cancer progression in mice. PLoS One 4, e7542 (2009)

M. Sachdeva, S. Zhu, F. Wu, H. Wu, V. Walia, S. Kumar, R. Elble, K. Watabe, Y.Y. Mo, p53 represses c-Myc through induction of the tumor suppressor miR-145. Proc. Natl. Acad. Sci. U. S. A. 106, 3207–3212 (2009)

P. Wang, C.F. Zhu, M.Z. Ma, G. Chen, M. Song, Z.L. Zeng, W.H. Lu, J. Yang, S. Wen, P.J. Chiao, Y. Hu, P. Huang, Micro-RNA-155 is induced by K-Ras oncogenic signal and promotes ROS stress in pancreatic cancer. Oncotarget 6, 21148–21158 (2015)

T. Greither, L.F. Grochola, A. Udelnow, C. Lautenschlager, P. Wurl, H. Taubert, Elevated expression of microRNAs 155, 203, 210 and 222 in pancreatic tumors is associated with poorer survival. Int. J. Cancer 126, 73–80 (2010)

M. Gironella, M. Seux, M.J. Xie, C. Cano, R. Tomasini, J. Gommeaux, S. Garcia, J. Nowak, M.L. Yeung, K.T. Jeang, A. Chaix, L. Fazli, Y. Motoo, Q. Wang, P. Rocchi, A. Russo, M. Gleave, J.C. Dagorn, J.L. Iovanna, A. Carrier, M.J. Pebusque, N.J. Dusetti, Tumor protein 53-induced nuclear protein 1 expression is repressed by miR-155, and its restoration inhibits pancreatic tumor development. Proc. Natl. Acad. Sci. U. S. A. 104, 16170–16175 (2007)

W. Pang, J. Su, Y. Wang, H. Feng, X. Dai, Y. Yuan, X. Chen, W. Yao, Pancreatic cancer-secreted miR-155 implicates in the Conversion from Normal Fibroblasts to Cancer-Associated Fibroblasts. Cancer. Sci. 106, 1362–1369 (2015)

C. Huang, H. Li, W. Wu, T. Jiang, Z. Qiu, Regulation of miR-155 affects pancreatic cancer cell invasiveness and migration by modulating the STAT3 signaling pathway through SOCS1. Oncol. Rep. 30, 1223–1230 (2013)

C. Huang, G. Yang, T. Jiang, G. Zhu, H. Li, Z. Qiu, The effects and mechanisms of blockage of STAT3 signaling pathway on IL-6 inducing EMT in human pancreatic cancer cells in vitro. Neoplasma 58, 396–405 (2011)

I.A. Asangani, S.A. Rasheed, D.A. Nikolova, J.H. Leupold, N.H. Colburn, S. Post, H. Allgayer, MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer. Oncogene 27, 2128–2136 (2008)

J.A. Chan, A.M. Krichevsky, K.S. Kosik, MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res. 65, 6029–6033 (2005)

D.L. Vaux, S. Cory, J.M. Adams, Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature 335, 440–442 (1988)

M. Dillhoff, J. Liu, W. Frankel, C. Croce, M. Bloomston, MicroRNA-21 is overexpressed in pancreatic cancer and a potential predictor of survival. J. Gastrointest. Surg. 12, 2171–2176 (2008)

W.F. Song, L. Wang, W.Y. Huang, X. Cai, J.J. Cui, L.W. Wang, MiR-21 upregulation induced by promoter zone histone acetylation is associated with chemoresistance to gemcitabine and enhanced malignancy of pancreatic cancer cells. Asian Pac. J. Cancer Prev. 14, 7529–7536 (2013)

P. Wang, L. Zhuang, J. Zhang, J. Fan, J. Luo, H. Chen, K. Wang, L. Liu, Z. Chen, Z. Meng, The serum miR-21 level serves as a predictor for the chemosensitivity of advanced pancreatic cancer, and miR-21 expression confers chemoresistance by targeting FasL. Mol. Oncol. 7, 334–345 (2013)

J.H. Hwang, J. Voortman, E. Giovannetti, S.M. Steinberg, L.G. Leon, Y.T. Kim, N. Funel, J.K. Park, M.A. Kim, G.H. Kang, S.W. Kim, M. Del Chiaro, G.J. Peters, G. Giaccone, Identification of microRNA-21 as a biomarker for chemoresistance and clinical outcome following adjuvant therapy in resectable pancreatic cancer. PLoS One 5, e10630 (2010)

P. Liu, H. Liang, Q. Xia, P. Li, H. Kong, P. Lei, S. Wang, Z. Tu, Resveratrol induces apoptosis of pancreatic cancers cells by inhibiting miR-21 regulation of BCL-2 expression. Clin. Transl. Oncol. 15, 741–746 (2013)

J.K. Park, E.J. Lee, C. Esau, T.D. Schmittgen, Antisense inhibition of microRNA-21 or -221 arrests cell cycle, induces apoptosis, and sensitizes the effects of gemcitabine in pancreatic adenocarcinoma. Pancreas 38, e190–e199 (2009)

P.A. Toste, L. Li, B.E. Kadera, A.H. Nguyen, L.M. Tran, N. Wu, D.L. Madnick, S.G. Patel, D.W. Dawson, T.R. Donahue, p85alpha is a microRNA target and affects chemosensitivity in pancreatic cancer. J. Surg. Res. 196, 285–293 (2015)

W.H. Paik, H.R. Kim, J.K. Park, B.J. Song, S.H. Lee, J.H. Hwang, Chemosensitivity induced by down-regulation of microRNA-21 in gemcitabine-resistant pancreatic cancer cells by indole-3-carbinol. Anticancer Res. 33, 1473–1481 (2013)

T.A. Mace, A.L. Collins, S.E. Wojcik, C.M. Croce, G.B. Lesinski, M. Bloomston, Hypoxia induces the overexpression of microRNA-21 in pancreatic cancer cells. J. Surg. Res. 184, 855–860 (2013)

H. Ying, K.G. Elpek, A. Vinjamoori, S.M. Zimmerman, G.C. Chu, H. Yan, E. Fletcher-Sananikone, H. Zhang, Y. Liu, W. Wang, X. Ren, H. Zheng, A.C. Kimmelman, J.H. Paik, C. Lim, S.R. Perry, S. Jiang, B. Malinn, A. Protopopov, S. Colla, Y. Xiao, A.F. Hezel, N. Bardeesy, S.J. Turley, Y.A. Wang, L. Chin, S.P. Thayer, R.A. DePinho, PTEN is a major tumor suppressor in pancreatic ductal adenocarcinoma and regulates an NF-kappaB-cytokine network. Cancer Discov. 1, 158–169 (2011)

B.E. Kadera, L. Li, P.A. Toste, N. Wu, C. Adams, D.W. Dawson, T.R. Donahue, MicroRNA-21 in pancreatic ductal adenocarcinoma tumor-associated fibroblasts promotes metastasis. PLoS One 8, e71978 (2013)

F. Sicard, M. Gayral, H. Lulka, L. Buscail, P. Cordelier, Targeting miR-21 for the therapy of pancreatic cancer. Mol. Ther. 21, 986–994 (2013)

M. Passadouro, M.C. Pedroso de Lima, H. Faneca, MicroRNA modulation combined with sunitinib as a novel therapeutic strategy for pancreatic cancer. Int. J. Nanomedicine 9, 3203–3217 (2014)

Y. Zhang, M. Li, H. Wang, W.E. Fisher, P.H. Lin, Q. Yao, C. Chen, Profiling of 95 microRNAs in pancreatic cancer cell lines and surgical specimens by real-time PCR analysis. World J. Surg. 33, 698–709 (2009)

H. Hermeking, The miR-34 family in cancer and apoptosis. Cell Death Differ. 17, 193–199 (2010)

J. Xia, Q. Duan, A. Ahmad, B. Bao, S. Banerjee, Y. Shi, J. Ma, J. Geng, Z. Chen, K. Rahman, L. Miele, F. Sarkar, Z. Wang, Genistein inhibits cell growth and induces apoptosis through up-regulation of miR-34a in pancreatic cancer cells. 13, 1750–1756 (2012)

Q. Ji, X. Hao, M. Zhang, W. Tang, M. Yang, L. Li, D. Xiang, J.T. Desano, G.T. Bommer, D. Fan, E.R. Fearon, T.S. Lawrence, L. Xu, MicroRNA miR-34 inhibits human pancreatic cancer tumor-initiating cells. PLoS One 4, e6816 (2009)

C. Liu, H. Cheng, S. Shi, X. Cui, J. Yang, L. Chen, P. Cen, X. Cai, Y. Lu, C. Wu, W. Yao, Y. Qin, L. Liu, J. Long, J. Xu, M. Li, X. Yu, MicroRNA-34b inhibits pancreatic cancer metastasis through repressing Smad3. Curr. Mol. Med. 13, 467–478 (2013)

T.C. Chang, E.A. Wentzel, O.A. Kent, K. Ramachandran, M. Mullendore, K.H. Lee, G. Feldmann, M. Yamakuchi, M. Ferlito, C.J. Lowenstein, D.E. Arking, M.A. Beer, A. Maitra, J.T. Mendell, Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. Mol. Cell 26, 745–752 (2007)

A.K. Bubna, Vorinostat-An overview. Indian J. Dermatol. 60, 419 (2015). doi: 10.4103/0019-5154.160511

D.A. Deming, J. Ninan, H.H. Bailey, J.M. Kolesar, J. Eickhoff, J.M. Reid, M.M. Ames, R.M. McGovern, D. Alberti, R. Marnocha, I. Espinoza-Delgado, J. Wright, G. Wilding, W.R. Schelman, A Phase I study of intermittently dosed vorinostat in combination with bortezomib in patients with advanced solid tumors. Invest. New Drugs 32, 323–329 (2014)

J.H. Mitchell, E. Cawood, D. Kinniburgh, A. Provan, A.R. Collins, D.S. Irvine, Effect of a phytoestrogen food supplement on reproductive health in normal males. Clin. Sci. (Lond.) 100, 613–618 (2001)

S. Babashah, M. Sadeghizadeh, M.R. Tavirani, S. Farivar, M. Soleimani, Aberrant microRNA expression and its implications in the pathogenesis of leukemias. Cell. Oncol. 35, 317–334 (2012)

J. Haybaeck, N. Zeller, M. Heikenwalder, The parallel universe: microRNAs and their role in chronic hepatitis, liver tissue damage and hepatocarcinogenesis. Swiss Med. Wkly. 141, w13287 (2011)

ClinicalTrials.gov [Internet] Identifier: NCT01829971, A multicenter phase I study of MRX34, MicroRNA miR-RX34 liposomal injection, 2016 (2015)

R. Zhang, M. Li, W. Zang, X. Chen, Y. Wang, P. Li, Y. Du, G. Zhao, L. Li, MiR-148a regulates the growth and apoptosis in pancreatic cancer by targeting CCKBR and Bcl-2. Tumour Biol. 35, 837–844 (2014)

S.K. Srivastava, A. Bhardwaj, S. Arora, N. Tyagi, S. Singh, J. Andrews, S. McClellan, B. Wang, A.P. Singh, MicroRNA-345 induces apoptosis in pancreatic cancer cells through potentiation of caspase-dependent and -independent pathways. Br. J. Cancer 113, 660–668 (2015)

J. Hao, S. Zhang, Y. Zhou, X. Hu, C. Shao, MicroRNA 483-3p suppresses the expression of DPC4/Smad4 in pancreatic cancer. FEBS Lett. 585, 207–213 (2011)

P. Singh, J.D. Wig, R. Srinivasan, B.D. Radotra, A comprehensive examination of Smad4, Smad6 and Smad7 mRNA expression in pancreatic ductal adenocarcinoma. Indian J. Cancer 48, 170–174 (2011)

Z. Zhu, Y. Xu, J. Zhao, Q. Liu, W. Feng, J. Fan, P. Wang, miR-367 promotes epithelial-to-mesenchymal transition and invasion of pancreatic ductal adenocarcinoma cells by targeting the Smad7-TGF-beta signalling pathway. Br. J. Cancer 112, 1367–1375 (2015)

X. Zhi, J. Tao, K. Xie, Y. Zhu, Z. Li, J. Tang, W. Wang, H. Xu, J. Zhang, Z. Xu, MUC4-induced nuclear translocation of beta-catenin: a novel mechanism for growth, metastasis and angiogenesis in pancreatic cancer. Cancer Lett. 346, 104–113 (2014)

Y. Zhu, J.J. Zhang, W.B. Liang, R. Zhu, B. Wang, Y. Miao, Z.K. Xu, Pancreatic cancer counterattack: MUC4 mediates Fas-independent apoptosis of antigen-specific cytotoxic T lymphocyte. Oncol. Rep. 31, 1768–1776 (2014)

D. Ansari, C. Urey, K.S. Hilmersson, M.P. Bauden, F. Ek, R. Olsson, R. Andersson, Apicidin sensitizes pancreatic cancer cells to gemcitabine by epigenetically regulating MUC4 expression. Anticancer Res. 34, 5269–5276 (2014)

S.K. Srivastava, A. Bhardwaj, S. Singh, S. Arora, B. Wang, W.E. Grizzle, A.P. Singh, MicroRNA-150 directly targets MUC4 and suppresses growth and malignant behavior of pancreatic cancer cells. Carcinogenesis 32, 1832–1839 (2011)

P. Chaturvedi, A.P. Singh, S. Chakraborty, S.C. Chauhan, S. Bafna, J.L. Meza, P.K. Singh, M.A. Hollingsworth, P.P. Mehta, S.K. Batra, MUC4 mucin interacts with and stabilizes the HER2 oncoprotein in human pancreatic cancer cells. Cancer Res. 68, 2065–2070 (2008)

F. Lahdaoui, Y. Delpu, A. Vincent, F. Renaud, M. Messager, B. Duchene, E. Leteurtre, C. Mariette, J. Torrisani, N. Jonckheere, I. Van, Seuningen, miR-219-1-3p is a negative regulator of the mucin MUC4 expression and is a tumor suppressor in pancreatic cancer. Oncogene 34, 780–788 (2015)

D. Chen, Y. Zhang, J. Wang, J. Chen, C. Yang, K. Cai, X. Wang, F. Shi, J. Dou, MicroRNA-200c overexpression inhibits tumorigenicity and metastasis of CD117+CD44+ ovarian cancer stem cells by regulating epithelial-mesenchymal transition. J. Ovarian Res. 6, 50 (2013). doi: 10.1186/1757-2215-6-50

J. Dou, X.F. He, W.H. Cao, F.S. Zhao, X.Y. Wang, Y.R. Liu, J. Wang, Overexpression of microRna-200c in CD44+CD133+ CSCS inhibits the cellular migratory and invasion as well as tumorigenicity in mice. Cell. Mol. Biol. Suppl 59, OL1861-8 (2013)

F.F. Ibrahim, R. Jamal, S.E. Syafruddin, N.S. Ab Mutalib, S. Saidin, R.R. MdZin, M.M. Hossain Mollah, N.M. Mokhtar, MicroRNA-200c and microRNA-31 regulate proliferation, colony formation, migration and invasion in serous ovarian cancer. J. Ovarian Res. 8, 56 (2015). doi: 10.1186/s13048-015-0186-7

J. Lu, G. Getz, E.A. Miska, E. Alvarez-Saavedra, J. Lamb, D. Peck, A. Sweet-Cordero, B.L. Ebert, R.H. Mak, A.A. Ferrando, J.R. Downing, T. Jacks, H.R. Horvitz, T.R. Golub, MicroRNA expression profiles classify human cancers. Nature 435, 834–838 (2005)

D.M. Dykxhoorn, MicroRNAs and metastasis: little RNAs go a long way. Cancer Res. 70, 6401–6406 (2010)

Y. Lu, J. Lu, X. Li, H. Zhu, X. Fan, S. Zhu, Y. Wang, Q. Guo, L. Wang, Y. Huang, M. Zhu, Z. Wang, MiR-200a inhibits epithelial-mesenchymal transition of pancreatic cancer stem cell. BMC Cancer 14, 85 (2014). doi: 10.1186/1471-2407-14-85

C. Ma, T. Huang, Y.C. Ding, W. Yu, Q. Wang, B. Meng, S.X. Luo, microRNA-200c overexpression inhibits chemoresistance, invasion and colony formation of human pancreatic cancer stem cells. Int. J. Clin. Exp. Pathol. 8, 6533–6539 (2015)

Y. Imanaka, S. Tsuchiya, F. Sato, Y. Shimada, K. Shimizu, G. Tsujimoto, MicroRNA-141 confers resistance to cisplatin-induced apoptosis by targeting YAP1 in human esophageal squamous cell carcinoma. J. Hum. Genet. 56, 270–276 (2011)

L. Xu, Q. Li, D. Xu, Q. Wang, Y. An, Q. Du, J. Zhang, Y. Zhu, Y. Miao, hsa-miR-141 downregulates TM4SF1 to inhibit pancreatic cancer cell invasion and migration. Int. J. Oncol. 44, 459–466 (2014)

G. Zhao, B. Wang, Y. Liu, J.G. Zhang, S.C. Deng, Q. Qin, K. Tian, X. Li, S. Zhu, Y. Niu, Q. Gong, C.Y. Wang, miRNA-141, downregulated in pancreatic cancer, inhibits cell proliferation and invasion by directly targeting MAP4K4. Mol. Cancer. Ther. 12, 2569–2580 (2013)

Z.M. Zhu, Y.F. Xu, Q.J. Su, J.D. Du, X.L. Tan, Y.L. Tu, J.W. Tan, H.B. Jiao, Prognostic significance of microRNA-141 expression and its tumor suppressor function in human pancreatic ductal adenocarcinoma. Mol. Cell. Biochem. 388, 39–49 (2014)

T. Avnit-Sagi, L. Kantorovich, S. Kredo-Russo, E. Hornstein, M.D. Walker, The promoter of the pri-miR-375 gene directs expression selectively to the endocrine pancreas. PLoS One 4, e5033 (2009)

M.N. Poy, L. Eliasson, J. Krutzfeldt, S. Kuwajima, X. Ma, P.E. Macdonald, S. Pfeffer, T. Tuschl, N. Rajewsky, P. Rorsman, M. Stoffel, A pancreatic islet-specific microRNA regulates insulin secretion. Nature 432, 226–230 (2004)

A. Basu, H. Alder, A. Khiyami, P. Leahy, C.M. Croce, S. Haldar, MicroRNA-375 and MicroRNA-221: potential noncoding RNAs associated with antiproliferative activity of benzyl isothiocyanate in pancreatic cancer. Genes Cancer 2, 108–119 (2011)

J. Zhou, S. Song, S. He, X. Zhu, Y. Zhang, B. Yi, B. Zhang, G. Qin, D. Li, MicroRNA-375 targets PDK1 in pancreatic carcinoma and suppresses cell growth through the Akt signaling pathway. Int. J. Mol. Med. 33, 950–956 (2014)

J. Zhou, S. Song, J. Cen, D. Zhu, D. Li, Z. Zhang, MicroRNA-375 is downregulated in pancreatic cancer and inhibits cell proliferation in vitro. Oncol. Res. 20, 197–203 (2012)

S.D. Song, J. Zhou, J. Zhou, H. Zhao, J.N. Cen, D.C. Li, MicroRNA-375 targets the 3-phosphoinositide-dependent protein kinase-1 gene in pancreatic carcinoma. Oncol. Lett. 6, 953–959 (2013)

J. Li, Y. Wang, W. Yu, J. Chen, J. Luo, Expression of serum miR-221 in human hepatocellular carcinoma and its prognostic significance. Biochem. Biophys. Res. Commun. 406, 70–73 (2011)

M. Bloomston, W.L. Frankel, F. Petrocca, S. Volinia, H. Alder, J.P. Hagan, C.G. Liu, D. Bhatt, C. Taccioli, C.M. Croce, MicroRNA expression patterns to differentiate pancreatic adenocarcinoma from normal pancreas and chronic pancreatitis. JAMA 297, 1901–1908 (2007)

Q. Xu, P. Li, X. Chen, L. Zong, Z. Jiang, L. Nan, J. Lei, W. Duan, D. Zhang, X. Li, H. Sha, Z. Wu, Q. Ma, Z. Wang, miR-221/222 induces pancreatic cancer progression through the regulation of matrix metalloproteinases. Oncotarget 6, 14153–14164 (2015)

S. Sarkar, H. Dubaybo, S. Ali, P. Goncalves, S.L. Kollepara, S. Sethi, P.A. Philip, Y. Li, Down-regulation of miR-221 inhibits proliferation of pancreatic cancer cells through up-regulation of PTEN, p27(kip1), p57(kip2), and PUMA. Am. J. Cancer. Res. 3, 465–477 (2013)

Y. Li, T.G. VandenBoom 2nd, D. Kong, Z. Wang, S. Ali, P.A. Philip, F.H. Sarkar, Up-regulation of miR-200 and let-7 by natural agents leads to the reversal of epithelial-to-mesenchymal transition in gemcitabine-resistant pancreatic cancer cells. Cancer Res. 69, 6704–6712 (2009)

K. Patel, A. Kollory, A. Takashima, S. Sarkar, D.V. Faller, S.K. Ghosh, MicroRNA let-7 downregulates STAT3 phosphorylation in pancreatic cancer cells by increasing SOCS3 expression. Cancer Lett. 347, 54–64 (2014)

Y.D. Bhutia, S.W. Hung, M. Krentz, D. Patel, D. Lovin, R. Manoharan, J.M. Thomson, R. Govindarajan, Differential processing of let-7a precursors influences RRM2 expression and chemosensitivity in pancreatic cancer: role of LIN-28 and SET oncoprotein. PLoS One 8, e53436 (2013)

S. Watanabe, Y. Ueda, S. Akaboshi, Y. Hino, Y. Sekita, M. Nakao, HMGA2 maintains oncogenic RAS-induced epithelial-mesenchymal transition in human pancreatic cancer cells. Am. J. Pathol. 174, 854–868 (2009)

A. Druz, Y.C. Chen, R. Guha, M. Betenbaugh, S.E. Martin, J. Shiloach, Large-scale screening identifies a novel microRNA, miR-15a-3p, which induces apoptosis in human cancer cell lines. RNA Biol. 10, 287–300 (2013)

S. Guo, X. Xu, Y. Tang, C. Zhang, J. Li, Y. Ouyang, J. Ju, P. Bie, H. Wang, miR-15a inhibits cell proliferation and epithelial to mesenchymal transition in pancreatic ductal adenocarcinoma by down-regulating Bmi-1 expression. Cancer Lett. 344, 40–46 (2014)

F. Wang, X. Xue, J. Wei, Y. An, J. Yao, H. Cai, J. Wu, C. Dai, Z. Qian, Z. Xu, Y. Miao, hsa-miR-520h downregulates ABCG2 in pancreatic cancer cells to inhibit migration, invasion, and side populations. Br. J. Cancer 103, 567–574 (2010)

J. Jiang, C. Yu, M. Chen, H. Zhang, S. Tian, C. Sun, Reduction of miR-29c enhances pancreatic cancer cell migration and stem cell-like phenotype. Oncotarget 6, 2767–2778 (2015)

M.K. Muniyappa, P. Dowling, M. Henry, P. Meleady, P. Doolan, P. Gammell, M. Clynes, N. Barron, MiRNA-29a regulates the expression of numerous proteins and reduces the invasiveness and proliferation of human carcinoma cell lines. Eur. J. Cancer 45, 3104–3118 (2009)

S. Yu, Z. Lu, C. Liu, Y. Meng, Y. Ma, W. Zhao, J. Liu, J. Yu, J. Chen, miRNA-96 suppresses KRAS and functions as a tumor suppressor gene in pancreatic cancer. Cancer Res. 70, 6015–6025 (2010)

J. Feng, J. Yu, X. Pan, Z. Li, Z. Chen, W. Zhang, B. Wang, L. Yang, H. Xu, G. Zhang, Z. Xu, HERG1 functions as an oncogene in pancreatic cancer and is downregulated by miR-96. Oncotarget 5, 5832–5844 (2014)

C. Li, X. Du, S. Tai, X. Zhong, Z. Wang, Z. Hu, L. Zhang, P. Kang, D. Ji, X. Jiang, Q. Zhou, M. Wan, G. Jiang, Y. Cui, GPC1 regulated by miR-96-5p, rather than miR-182-5p, in inhibition of pancreatic carcinoma cell proliferation. Int. J. Mol. Sci. 15, 6314–6327 (2014)

X. Huang, W. Lv, J.H. Zhang, D.L. Lu, miR96 functions as a tumor suppressor gene by targeting NUAK1 in pancreatic cancer. Int. J. Mol. Med. 34, 1599–1605 (2014)

D. Li, X. Li, W. Cao, Y. Qi, X. Yang, Antagonism of microRNA-99a promotes cell invasion and down-regulates E-cadherin expression in pancreatic cancer cells by regulating mammalian target of rapamycin. Acta Histochem. 116, 723–729 (2014)

Z. Li, X. Li, C. Yu, M. Wang, F. Peng, J. Xiao, R. Tian, J. Jiang, C. Sun, MicroRNA-100 regulates pancreatic cancer cells growth and sensitivity to chemotherapy through targeting FGFR3. Tumour Biol. 35, 11751–11759 (2014)

W. Jiang, W. Gu, R. Qiu, C. Shen, E.Y. YaohaoWu, J. Zhang, J. Zhou, Y. Guo, Z. Li, J. Deng, L. Zeng, J. Tang, Q. Zhi, X. Deng, miRNA-101 suppresses epithelial-to-mesenchymal transition by targeting HMGA2 in pancreatic cancer cells. Anticancer Agents Med. Chem. (2015). doi: 10.2174/1871520615666150507122142

A.M. Qazi, O. Gruzdyn, A. Semaan, S. Seward, S. Chamala, V. Dhulipala, S. Sethi, R. Ali-Fehmi, P.A. Philip, D.L. Bouwman, D.W. Weaver, S.A. Gruber, R.B. Batchu, Restoration of E-cadherin expression in pancreatic ductal adenocarcinoma treated with microRNA-101. Surgery 152, 704–711 (2012)

K.H. Lee, C. Lotterman, C. Karikari, N. Omura, G. Feldmann, N. Habbe, M.G. Goggins, J.T. Mendell, A. Maitra, Epigenetic silencing of MicroRNA miR-107 regulates cyclin-dependent kinase 6 expression in pancreatic cancer. Pancreatology 9, 293–301 (2009)

P. Wang, L. Chen, J. Zhang, H. Chen, J. Fan, K. Wang, J. Luo, Z. Chen, Z. Meng, L. Liu, Methylation-mediated silencing of the miR-124 genes facilitates pancreatic cancer progression and metastasis by targeting Rac1. Oncogene 33, 514–524 (2014)

S. Hamada, K. Satoh, W. Fujibuchi, M. Hirota, A. Kanno, J. Unno, A. Masamune, K. Kikuta, K. Kume, T. Shimosegawa, MiR-126 acts as a tumor suppressor in pancreatic cancer cells via the regulation of ADAM9. Mol. Cancer Res. 10, 3–10 (2012)

G. Zhao, J.G. Zhang, Y. Shi, Q. Qin, Y. Liu, B. Wang, K. Tian, S.C. Deng, X. Li, S. Zhu, Q. Gong, Y. Niu, C.Y. Wang, MiR-130b is a prognostic marker and inhibits cell proliferation and invasion in pancreatic cancer through targeting STAT3. PLoS One 8, e73803 (2013)

S. Zhang, J. Hao, F. Xie, X. Hu, C. Liu, J. Tong, J. Zhou, J. Wu, C. Shao, Downregulation of miR-132 by promoter methylation contributes to pancreatic cancer development. Carcinogenesis 32, 1183–1189 (2011)

Z. Dang, W.H. Xu, P. Lu, N. Wu, J. Liu, B. Ruan, L. Zhou, W.J. Song, K.F. Dou, MicroRNA-135a inhibits cell proliferation by targeting Bmi1 in pancreatic ductal adenocarcinoma. Int. J. Biol. Sci. 10, 733–745 (2014)

C. Yu, M. Wang, M. Chen, Y. Huang, J. Jiang, Upregulation of microRNA1385p inhibits pancreatic cancer cell migration and increases chemotherapy sensitivity. Mol. Med. Rep. 12, 5135–5140 (2015)

S. Liang, X. Gong, G. Zhang, G. Huang, Y. Lu, Y. Li, MicroRNA-140 regulates cell growth and invasion in pancreatic duct adenocarcinoma by targeting iASPP. Acta Biochim. Biophys. Sin. (Shanghai) 48, 174–181 (2016)

T.N. MacKenzie, N. Mujumdar, S. Banerjee, V. Sangwan, A. Sarver, S. Vickers, S. Subramanian, A.K. Saluja, 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, 1266–1275 (2013)

Y. Hu, Y. Ou, K. Wu, Y. Chen, W. Sun, miR-143 inhibits the metastasis of pancreatic cancer and an associated signaling pathway. Tumour Biol. 33, 1863–1870 (2012)

H. Pham, C.E. Rodriguez, G.W. Donald, K.M. Hertzer, X.S. Jung, H.H. Chang, A. Moro, H.A. Reber, O.J. Hines, G. Eibl, miR-143 decreases COX-2 mRNA stability and expression in pancreatic cancer cells. Biochem. Biophys. Res. Commun. 439, 6–11 (2013)

T. Han, X.P. Yi, B. Liu, M.J. Ke, Y.X. Li, MicroRNA-145 suppresses cell proliferation, invasion and migration in pancreatic cancer cells by targeting NEDD9. Mol. Med. Rep. 11, 4115–4120 (2015)

S. Khan, M.C. Ebeling, M.S. Zaman, M. Sikander, M.M. Yallapu, N. Chauhan, A.M. Yacoubian, S.W. Behrman, N. Zafar, D. Kumar, P.A. Thompson, M. Jaggi, S.C. Chauhan, MicroRNA-145 targets MUC13 and suppresses growth and invasion of pancreatic cancer. Oncotarget 5, 7599–7609 (2014)

S. Ali, A. Ahmad, A. Aboukameel, A. Ahmed, B. Bao, S. Banerjee, P.A. Philip, F.H. Sarkar, Deregulation of miR-146a expression in a mouse model of pancreatic cancer affecting EGFR signaling. Cancer Lett. 351, 134–142 (2014)

Y. Li, T.G. VandenBoom 2nd, Z. Wang, D. Kong, S. Ali, P.A. Philip, F.H. Sarkar, Up-regulation of miR-146a contributes to the inhibition of invasion of pancreatic cancer cells. Cancer Res. 70, 5703 (2010)

F. Lin, X. Wang, Z. Jie, X. Hong, X. Li, M. Wang, Y. Yu, Inhibitory effects of miR-146b-5p on cell migration and invasion of pancreatic cancer by targeting MMP16. J. Huazhong Univ. Sci. Technolog. Med. Sci. 31, 509–514 (2011)

M. Azizi, L. Teimoori-Toolabi, M.K. Arzanani, K. Azadmanesh, P. Fard-Esfahani, S. Zeinali, MicroRNA-148b and microRNA-152 reactivate tumor suppressor genes through suppression of DNA methyltransferase-1 gene in pancreatic cancer cell lines. Cancer Biol. Ther. 15, 419–427 (2014)

X. Bofill-De Ros, M. Gironella, C. Fillat, miR-148a- and miR-216a-regulated oncolytic adenoviruses targeting pancreatic tumors attenuate tissue damage without perturbation of miRNA activity. Mol. Ther. 22, 1665–1677 (2014)

S.T. Liffers, J.B. Munding, M. Vogt, J.D. Kuhlmann, B. Verdoodt, S. Nambiar, A. Maghnouj, A. Mirmohammadsadegh, S.A. Hahn, A. Tannapfel, MicroRNA-148a is down-regulated in human pancreatic ductal adenocarcinomas and regulates cell survival by targeting CDC25B. Lab. Invest. 91, 1472–1479 (2011)

G. Zhao, J.G. Zhang, Y. Liu, Q. Qin, B. Wang, K. Tian, L. Liu, X. Li, Y. Niu, S.C. Deng, C.Y. Wang, miR-148b functions as a tumor suppressor in pancreatic cancer by targeting AMPKalpha1. Mol. Cancer. Ther. 12, 83–93 (2013)

L. Farhana, M.I. Dawson, F. Murshed, J.K. Das, A.K. Rishi, J.A. Fontana, Upregulation of miR-150* and miR-630 induces apoptosis in pancreatic cancer cells by targeting IGF-1R. PLoS One 8, e61015 (2013)

Y. Sun, X.L. Jin, T.T. Zhang, C.W. Jia, J. Chen, MiR-150-5p inhibits the proliferation and promoted apoptosis of pancreatic cancer cells. Zhonghua Bing Li Xue Za Zhi 42, 460–464 (2013)

L. Zhou, W.G. Zhang, D.S. Wang, K.S. Tao, W.J. Song, K.F. Dou, MicroRNA-183 is involved in cell proliferation, survival and poor prognosis in pancreatic ductal adenocarcinoma by regulating Bmi-1. Oncol. Rep. 32, 1734–1740 (2014)

H. Liu, X.F. Xu, Y. Zhao, M.C. Tang, Y.Q. Zhou, J. Lu, F.H. Gao, MicroRNA-191 promotes pancreatic cancer progression by targeting USP10. Tumour Biol. 35, 12157–12163 (2014)

J. Li, F. Kong, K. Wu, K. Song, J. He, W. Sun, miR-193b directly targets STMN1 and uPA genes and suppresses tumor growth and metastasis in pancreatic cancer. Mol. Med. Rep. 10, 2613–2620 (2014)

C. Marin-Muller, D. Li, U. Bharadwaj, M. Li, C. Chen, S.E. Hodges, W.E. Fisher, Q. Mo, M.C. Hung, Q. Yao, A tumorigenic factor interactome connected through tumor suppressor microRNA-198 in human pancreatic cancer. Clin. Cancer Res. 19, 5901–5913 (2013)

P. Radhakrishnan, A.M. Mohr, P.M. Grandgenett, M.M. Steele, S.K. Batra, M.A. Hollingsworth, MicroRNA-200c modulates the expression of MUC4 and MUC16 by directly targeting their coding sequences in human pancreatic cancer. PLoS One 8, e73356 (2013)

J. Yu, K. Ohuchida, K. Mizumoto, N. Sato, T. Kayashima, H. Fujita, K. Nakata, M. Tanaka, MicroRNA, hsa-miR-200c, is an independent prognostic factor in pancreatic cancer and its upregulation inhibits pancreatic cancer invasion but increases cell proliferation. Mol. Cancer. 9, 169 (2010). doi: 10.1186/1476-4598-9-169

O. Soubani, A.S. Ali, F. Logna, S. Ali, P.A. Philip, F.H. Sarkar, Re-expression of miR-200 by novel approaches regulates the expression of PTEN and MT1-MMP in pancreatic cancer. Carcinogenesis 33, 1563–1571 (2012)

L. Miao, X. Xiong, Y. Lin, Y. Cheng, J. Lu, J. Zhang, N. Cheng, miR-203 inhibits tumor cell migration and invasion via caveolin-1 in pancreatic cancer cells. Oncol. Lett. 7, 658–662 (2014)

D. Xu, Q. Wang, Y. An, L. Xu, MiR203 regulates the proliferation, apoptosis and cell cycle progression of pancreatic cancer cells by targeting survivin. Mol. Med. Rep. 8, 379–384 (2013)

N. Ikenaga, K. Ohuchida, K. Mizumoto, J. Yu, T. Kayashima, H. Sakai, H. Fujita, K. Nakata, M. Tanaka, MicroRNA-203 expression as a new prognostic marker of pancreatic adenocarcinoma. Ann. Surg. Oncol. 17, 3120–3128 (2010)

A. Mittal, D. Chitkara, S.W. Behrman, R.I. Mahato, Efficacy of gemcitabine conjugated and miRNA-205 complexed micelles for treatment of advanced pancreatic cancer. Biomaterials 35, 7077–7087 (2014)

C. Stahlhut, Y. Suarez, J. Lu, Y. Mishima, A.J. Giraldez, miR-1 and miR-206 regulate angiogenesis by modulating VegfA expression in zebrafish. Development 139, 4356–4364 (2012)

I. Keklikoglou, K. Hosaka, C. Bender, A. Bott, C. Koerner, D. Mitra, R. Will, A. Woerner, E. Muenstermann, H. Wilhelm, Y. Cao, S. Wiemann, MicroRNA-206 functions as a pleiotropic modulator of cell proliferation, invasion and lymphangiogenesis in pancreatic adenocarcinoma by targeting ANXA2 and KRAS genes. Oncogene 34, 4867–4878 (2015)

M. Maftouh, A. Avan, N. Funel, A.E. Frampton, H. Fiuji, S. Pelliccioni, L. Castellano, V. Galla, G.J. Peters, E. Giovannetti, miR-211 modulates gemcitabine activity through downregulation of ribonucleotide reductase and inhibits the invasive behavior of pancreatic cancer cells. Nucleosides Nucleotides Nucleic Acids 33, 384–393 (2014)

S. Wang, X. Chen, M. Tang, MicroRNA-216a inhibits pancreatic cancer by directly targeting Janus kinase 2. Oncol. Rep. 32, 2824–2830 (2014)

X. Zhang, H. Shi, S. Lin, M. Ba, S. Cui, MicroRNA-216a enhances the radiosensitivity of pancreatic cancer cells by inhibiting beclin-1-mediated autophagy. Oncol. Rep. 34, 1557–1564 (2015)

H. He, S.J. Hao, L. Yao, F. Yang, Y. Di, J. Li, Y.J. Jiang, C. Jin, D.L. Fu, MicroRNA-218 inhibits cell invasion and migration of pancreatic cancer via regulating ROBO1. Cancer Biol. Ther. 15, 1333–1339 (2014)

C.H. Li, K.F. To, J.H. Tong, Z. Xiao, T. Xia, P.B. Lai, S.C. Chow, Y.X. Zhu, S.L. Chan, V.E. Marquez, Y. Chen, Enhancer of zeste homolog 2 silences microRNA-218 in human pancreatic ductal adenocarcinoma cells by inducing formation of heterochromatin. Gastroenterology 144, 1086–1097.e9 (2013)

Z.L. Zhang, Z.H. Bai, X.B. Wang, L. Bai, F. Miao, H.H. Pei, miR-186 and 326 predict the prognosis of pancreatic ductal adenocarcinoma and affect the proliferation and migration of cancer cells. PLoS One 10, e0118814 (2015)

L. Gao, Y. Yang, H. Xu, R. Liu, D. Li, H. Hong, M. Qin, Y. Wang, MiR-335 functions as a tumor suppressor in pancreatic cancer by targeting OCT4. Tumour Biol. 35, 8309–8318 (2014)

R. Guo, J. Gu, Z. Zhang, Y. Wang, C. Gu, MicroRNA-410 functions as a tumor suppressor by targeting angiotensin II type 1 receptor in pancreatic cancer. IUBMB Life 67, 42–53 (2015)

R. Guo, Y. Wang, W.Y. Shi, B. Liu, S.Q. Hou, L. Liu, MicroRNA miR-491-5p targeting both TP53 and Bcl-XL induces cell apoptosis in SW1990 pancreatic cancer cells through mitochondria mediated pathway. Molecules 17, 14733–14747 (2012)

Y. Liu, X. Li, S. Zhu, J.G. Zhang, M. Yang, Q. Qin, S.C. Deng, B. Wang, K. Tian, L. Liu, Y. Niu, C.Y. Wang, G. Zhao, Ectopic expression of miR-494 inhibited the proliferation, invasion and chemoresistance of pancreatic cancer by regulating SIRT1 and c-Myc. Gene Ther. 22, 729–738 (2015)

L. Li, Z. Li, X. Kong, D. Xie, Z. Jia, W. Jiang, J. Cui, Y. Du, D. Wei, S. Huang, K. Xie, Down-regulation of MicroRNA 494 via loss of SMAD4 increases FOXM1 and beta-catenin signaling in pancreatic ductal adenocarcinoma cells. Gastroenterology 147, 485–497 (2014)

J.W. Xu, T.X. Wang, L. You, L.F. Zheng, H. Shu, T.P. Zhang, Y.P. Zhao, 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 9, e92847 (2014)

J. Xu, T. Wang, Z. Cao, H. Huang, J. Li, W. Liu, S. Liu, L. You, L. Zhou, T. Zhang, Y. Zhao, MiR-497 downregulation contributes to the malignancy of pancreatic cancer and associates with a poor prognosis. Oncotarget 5, 6983–6993 (2014)

J. Du, X. Zheng, S. Cai, Z. Zhu, J. Tan, B. Hu, Z. Huang, H. Jiao, MicroRNA506 participates in pancreatic cancer pathogenesis by targeting PIM3. Mol. Med. Rep. 12, 5121–5126 (2015)

B. Song, W. Ji, S. Guo, A. Liu, W. Jing, C. Shao, G. Li, G. Jin, miR-545 inhibited pancreatic ductal adenocarcinoma growth by targeting RIG-I. FEBS Lett. 588, 4375–4381 (2014)

H. Heyn, S. Schreek, R. Buurman, T. Focken, B. Schlegelberger, C. Beger, MicroRNA miR-548d is a superior regulator in pancreatic cancer. Pancreas 41, 218–221 (2012)

Y. Sun, T. Zhang, C. Wang, X. Jin, C. Jia, S. Yu, J. Chen, MiRNA-615-5p Functions as a Tumor Suppressor in Pancreatic Ductal Adenocarcinoma by Targeting AKT2. PLoS One 10, e0119783 (2015)

Y. Harazono, T. Muramatsu, H. Endo, N. Uzawa, T. Kawano, K. Harada, J. Inazawa, K. Kozaki, miR-655 Is an EMT-suppressive microRNA targeting ZEB1 and TGFBR2. PLoS One 8, e62757 (2013)

S. Muller, S. Raulefs, P. Bruns, F. Afonso-Grunz, A. Plotner, R. Thermann, C. Jager, A.M. Schlitter, B. Kong, I. Regel, W.K. Roth, B. Rotter, K. Hoffmeier, G. Kahl, I. Koch, F.J. Theis, J. Kleeff, P. Winter, C.W. Michalski, Next-generation sequencing reveals novel differentially regulated mRNAs, lncRNAs, miRNAs, sdRNAs and a piRNA in pancreatic cancer. Mol. Cancer. 14, 94 (2015). doi: 10.1186/s12943-015-0358-5

J. Jiang, Z. Li, C. Yu, M. Chen, S. Tian, C. Sun, MiR-1181 inhibits stem cell-like phenotypes and suppresses SOX2 and STAT3 in human pancreatic cancer. Cancer Lett. 356, 962–970 (2015)

S. Shi, Y. Lu, Y. Qin, W. Li, H. Cheng, Y. Xu, J. Xu, J. Long, L. Liu, C. Liu, X. Yu, miR-1247 is correlated with prognosis of pancreatic cancer and inhibits cell proliferation by targeting neuropilins. Curr. Mol. Med. 14, 316–327 (2014)

K. Ohuchida, K. Mizumoto, C. Lin, H. Yamaguchi, T. Ohtsuka, N. Sato, H. Toma, M. Nakamura, E. Nagai, M. Hashizume, M. Tanaka, MicroRNA-10a is overexpressed in human pancreatic cancer and involved in its invasiveness partially via suppression of the HOXA1 gene. Ann. Surg. Oncol. 19, 2394–2402 (2012)

F.U. Weiss, I.J. Marques, J.M. Woltering, D.H. Vlecken, A. Aghdassi, L.I. Partecke, C.D. Heidecke, M.M. Lerch, C.P. Bagowski, Retinoic acid receptor antagonists inhibit miR-10a expression and block metastatic behavior of pancreatic cancer. Gastroenterology 137, 2136–45.e1-7 (2009)

H. Ouyang, J. Gore, S. Deitz, M. Korc, microRNA-10b enhances pancreatic cancer cell invasion by suppressing TIP30 expression and promoting EGF and TGF-beta actions. Oncogene 33, 4664–4674 (2014)

K. Nakata, K. Ohuchida, K. Mizumoto, T. Kayashima, N. Ikenaga, H. Sakai, C. Lin, H. Fujita, T. Otsuka, S. Aishima, E. Nagai, Y. Oda, M. Tanaka, MicroRNA-10b is overexpressed in pancreatic cancer, promotes its invasiveness, and correlates with a poor prognosis. Surgery 150, 916–922 (2011)

J. Yu, K. Ohuchida, K. Mizumoto, H. Fujita, K. Nakata, M. Tanaka, MicroRNA miR-17-5p is overexpressed in pancreatic cancer, associated with a poor prognosis, and involved in cancer cell proliferation and invasion. Cancer Biol. Ther. 10, 748–757 (2010)

H.J. Yan, W.S. Liu, W.H. Sun, J. Wu, M. Ji, Q. Wang, X. Zheng, J.T. Jiang, C.P. Wu, miR-17-5p inhibitor enhances chemosensitivity to gemcitabine via upregulating Bim expression in pancreatic cancer cells. Dig. Dis. Sci. 57, 3160–3167 (2012)

Y. Nagao, M. Hisaoka, A. Matsuyama, S. Kanemitsu, T. Hamada, T. Fukuyama, R. Nakano, A. Uchiyama, M. Kawamoto, K. Yamaguchi, H. Hashimoto, Association of microRNA-21 expression with its targets, PDCD4 and TIMP3, in pancreatic ductal adenocarcinoma. Mod. Pathol. 25, 112–121 (2012)

J. Dong, Y.P. Zhao, L. Zhou, T.P. Zhang, G. Chen, 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. 42, 8–14 (2011)

T. Moriyama, K. Ohuchida, K. Mizumoto, J. Yu, N. Sato, T. Nabae, S. Takahata, H. Toma, E. Nagai, M. Tanaka, MicroRNA-21 modulates biological functions of pancreatic cancer cells including their proliferation, invasion, and chemoresistance. Mol. Cancer Ther. 8, 1067–1074 (2009)

Y. Ma, S. Yu, W. Zhao, Z. Lu, J. Chen, miR-27a regulates the growth, colony formation and migration of pancreatic cancer cells by targeting Sprouty2. Cancer Lett. 298, 150–158 (2010)

G. He, L. Zhang, Q. Li, L. Yang, miR-92a/DUSP10/JNK signalling axis promotes human pancreatic cancer cells proliferation. Biomed. Pharmacother. 68, 25–30 (2014)

W.G. Li, Y.Z. Yuan, M.M. Qiao, Y.P. Zhang, High dose glargine alters the expression profiles of microRNAs in pancreatic cancer cells. World J. Gastroenterol. 18, 2630–2639 (2012)

P. Li, Q. Xu, D. Zhang, X. Li, L. Han, J. Lei, W. Duan, Q. Ma, Z. Wu, Z. Wang, Upregulated miR-106a plays an oncogenic role in pancreatic cancer. FEBS Lett. 588, 705–712 (2014)

Z. Bai, J. Sun, X. Wang, H. Wang, H. Pei, Z. Zhang, MicroRNA-153 is a prognostic marker and inhibits cell migration and invasion by targeting SNAI1 in human pancreatic ductal adenocarcinoma. Oncol. Rep. 34, 595–602 (2015)

D. Takiuchi, H. Eguchi, H. Nagano, Y. Iwagami, Y. Tomimaru, H. Wada, K. Kawamoto, S. Kobayashi, S. Marubashi, M. Tanemura, M. Mori, Y. Doki, Involvement of microRNA-181b in the gemcitabine resistance of pancreatic cancer cells. Pancreatology 13, 517–523 (2013)

Z. Song, H. Ren, S. Gao, X. Zhao, H. Zhang, J. Hao, The clinical significance and regulation mechanism of hypoxia-inducible factor-1 and miR-191 expression in pancreatic cancer. Tumour Biol. 35, 11319–11328 (2014)

C. Zhao, J. Zhang, S. Zhang, D. Yu, Y. Chen, Q. Liu, M. Shi, C. Ni, M. Zhu, Diagnostic and biological significance of microRNA-192 in pancreatic ductal adenocarcinoma. Oncol. Rep. 30, 276–284 (2013)

J. Zhang, C.Y. Zhao, S.H. Zhang, D.H. Yu, Y. Chen, Q.H. Liu, M. Shi, C.R. Ni, M.H. Zhu, Upregulation of miR-194 contributes to tumor growth and progression in pancreatic ductal adenocarcinoma. Oncol. Rep. 31, 1157–1164 (2014)

M. Liu, Y. Du, J. Gao, J. Liu, X. Kong, Y. Gong, Z. Li, H. Wu, H. Chen, Aberrant expression miR-196a is associated with abnormal apoptosis, invasion, and proliferation of pancreatic cancer cells. Pancreas 42, 1169–1181 (2013)

F. Huang, J. Tang, X. Zhuang, Y. Zhuang, W. Cheng, W. Chen, H. Yao, S. Zhang, MiR-196a promotes pancreatic cancer progression by targeting nuclear factor kappa-B-inhibitor alpha. PLoS One 9, e87897 (2014)

S. Hamada, K. Satoh, S. Miura, M. Hirota, A. Kanno, A. Masamune, K. Kikuta, K. Kume, J. Unno, S. Egawa, F. Motoi, M. Unno, T. Shimosegawa, miR-197 induces epithelial-mesenchymal transition in pancreatic cancer cells by targeting p120 catenin. J. Cell. Physiol. 228, 1255–1263 (2013)

A. Liu, C. Shao, G. Jin, R. Liu, J. Hao, B. Song, L. Ouyang, X. Hu, miR-208-induced epithelial to mesenchymal transition of pancreatic cancer cells promotes cell metastasis and invasion. Cell Biochem. Biophys. 69, 341–346 (2014)

J. Jung, C. Yeom, Y.S. Choi, S. Kim, E. Lee, M.J. Park, S.W. Kang, S.B. Kim, S. Chang, Simultaneous inhibition of multiple oncogenic miRNAs by a multi-potent microRNA sponge. Oncotarget 6, 20370–20387 (2015)

J. Ma, B. Fang, F. Zeng, C. Ma, H. Pang, L. Cheng, Y. Shi, H. Wang, B. Yin, J. Xia, Z. Wang, Down-regulation of miR-223 reverses epithelial-mesenchymal transition in gemcitabine-resistant pancreatic cancer cells. Oncotarget 6, 1740–1749 (2015)

J. Ma, L. Cheng, H. Liu, J. Zhang, Y. Shi, F. Zeng, L. Miele, F.H. Sarkar, J. Xia, Z. Wang, Genistein down-regulates miR-223 expression in pancreatic cancer cells. Curr. Drug Targets 14, 1150–1156 (2013)

Z. Chen, L.Y. Chen, H.Y. Dai, P. Wang, S. Gao, K. Wang, miR-301a promotes pancreatic cancer cell proliferation by directly inhibiting Bim expression. J. Cell. Biochem. 113, 3229–3235 (2012)

Z. Lu, Y. Li, A. Takwi, B. Li, J. Zhang, D.J. Conklin, K.H. Young, R. Martin, Y. Li, miR-301a as an NF-kappaB activator in pancreatic cancer cells. EMBO J. 30, 57–67 (2011)

N. Funamizu, C.R. Lacy, S.T. Parpart, A. Takai, Y. Hiyoshi, K. Yanaga, MicroRNA-301b promotes cell invasiveness through targeting TP63 in pancreatic carcinoma cells. Int. J. Oncol. 44, 725–734 (2014)

S. Hamada, A. Masamune, S. Miura, K. Satoh, T. Shimosegawa, MiR-365 induces gemcitabine resistance in pancreatic cancer cells by targeting the adaptor protein SHC1 and pro-apoptotic regulator BAX. Cell. Signal. 26, 179–185 (2014)

D. He, H. Miao, Y. Xu, L. Xiong, Y. Wang, H. Xiang, H. Zhang, Z. Zhang, MiR-371-5p facilitates pancreatic cancer cell proliferation and decreases patient survival. PLoS One 9, e112930 (2014)

K. Wu, G. Hu, X. He, P. Zhou, J. Li, B. He, W. Sun, MicroRNA-424-5p suppresses the expression of SOCS6 in pancreatic cancer. Pathol. Oncol. Res. 19, 739–748 (2013)

S. Hasegawa, H. Eguchi, H. Nagano, M. Konno, Y. Tomimaru, H. Wada, N. Hama, K. Kawamoto, S. Kobayashi, N. Nishida, J. Koseki, T. Nishimura, N. Gotoh, S. Ohno, N. Yabuta, H. Nojima, M. Mori, Y. Doki, H. Ishii, MicroRNA-1246 expression associated with CCNG2-mediated chemoresistance and stemness in pancreatic cancer. Br. J. Cancer 111, 1572–1580 (2014)

Y. Wang, Z. Li, S. Zheng, Y. Zhou, L. Zhao, H. Ye, X. Zhao, W. Gao, Z. Fu, Q. Zhou, Y. Liu, R. Chen, Expression profile of long non-coding RNAs in pancreatic cancer and their clinical significance as biomarkers. Oncotarget 6, 35684–35698 (2015)

Q. Wang, H. Jiang, C. Ping, R. Shen, T. Liu, J. Li, Y. Qian, Y. Tang, S. Cheng, W. Yao, L. Wang, Exploring the Wnt pathway-associated LncRNAs and genes involved in pancreatic carcinogenesis driven by Tp53 mutation. Pharm. Res. 32, 793–805 (2015)

A.C. Tahira, M.S. Kubrusly, M.F. Faria, B. Dazzani, R.S. Fonseca, V. Maracaja-Coutinho, S. Verjovski-Almeida, M.C. Machado, E.M. Reis, Long noncoding intronic RNAs are differentially expressed in primary and metastatic pancreatic cancer. Mol. Cancer. 10, 141 (2011). doi: 10.1186/1476-4598-10-141

S. Cao, W. Liu, F. Li, W. Zhao, C. Qin, Decreased expression of lncRNA GAS5 predicts a poor prognosis in cervical cancer. Int. J. Clin. Exp. Pathol. 7, 6776–6783 (2014)

M. Mourtada-Maarabouni, M.R. Pickard, V.L. Hedge, F. Farzaneh, G.T. Williams, GAS5, a non-protein-coding RNA, controls apoptosis and is downregulated in breast cancer. Oncogene 28, 195–208 (2009)

Y. Nakamura, N. Takahashi, E. Kakegawa, K. Yoshida, Y. Ito, H. Kayano, N. Niitsu, I. Jinnai, M. Bessho, The GAS5 (growth arrest-specific transcript 5) gene fuses to BCL6 as a result of t(1;3)(q25;q27) in a patient with B-cell lymphoma. Cancer Genet. Cytogenet. 182, 144–149 (2008)

K. Yacqub-Usman, M.R. Pickard, G.T. Williams, Reciprocal regulation of GAS5 lncRNA levels and mTOR inhibitor action in prostate cancer cells. Prostate 75, 693–705 (2015)

X. Lu, Y. Fang, Z. Wang, J. Xie, Q. Zhan, X. Deng, H. Chen, J. Jin, C. Peng, H. Li, B. Shen, Downregulation of gas5 increases pancreatic cancer cell proliferation by regulating CDK6. Cell Tissue Res. 354, 891–896 (2013)

P. Ji, S. Diederichs, W. Wang, S. Boing, R. Metzger, P.M. Schneider, N. Tidow, B. Brandt, H. Buerger, E. Bulk, M. Thomas, W.E. Berdel, H. Serve, C. Muller-Tidow, MALAT-1, a novel noncoding RNA, and thymosin beta4 predict metastasis and survival in early-stage non-small cell lung cancer. Oncogene 22, 8031–8041 (2003)

E.J. Pang, R. Yang, X.B. Fu, Y.F. Liu, Overexpression of long non-coding RNA MALAT1 is correlated with clinical progression and unfavorable prognosis in pancreatic cancer. Tumour Biol. 36, 2403–2407 (2015)

F. Jiao, H. Hu, C. Yuan, L. Wang, W. Jiang, Z. Jin, Z. Guo, L. Wang, Elevated expression level of long noncoding RNA MALAT-1 facilitates cell growth, migration and invasion in pancreatic cancer. Oncol. Rep. 32, 2485–2492 (2014)

F. Jiao, H. Hu, T. Han, C. Yuan, L. Wang, Z. Jin, Z. Guo, L. Wang, Long noncoding RNA MALAT-1 enhances stem cell-like phenotypes in pancreatic cancer cells. Int. J. Mol. Sci. 16, 6677–6693 (2015)

K. Panzitt, M.M. Tschernatsch, C. Guelly, T. Moustafa, M. Stradner, H.M. Strohmaier, C.R. Buck, H. Denk, R. Schroeder, M. Trauner, K. Zatloukal, Characterization of HULC, a novel gene with striking up-regulation in hepatocellular carcinoma, as noncoding RNA. Gastroenterology 132, 330–342 (2007)

W. Peng, W. Gao, J. Feng, Long noncoding RNA HULC is a novel biomarker of poor prognosis in patients with pancreatic cancer. Med. Oncol. 31, 346 (2014). doi: 10.1007/s12032-014-0346-4

M. Hajjari, A. Salavaty, HOTAIR: an oncogenic long non-coding RNA in different cancers. Cancer. Biol. Med. 12, 1–9 (2015)

J.K. Stratford, D.J. Bentrem, J.M. Anderson, C. Fan, K.A. Volmar, J.S. Marron, E.D. Routh, L.S. Caskey, J.C. Samuel, C.J. Der, L.B. Thorne, B.F. Calvo, H.J. Kim, M.S. Talamonti, C.A. Iacobuzio-Donahue, M.A. Hollingsworth, C.M. Perou, J.J. Yeh, A six-gene signature predicts survival of patients with localized pancreatic ductal adenocarcinoma. PLoS Med. 7, e1000307 (2010)

M.C. Tsai, O. Manor, Y. Wan, N. Mosammaparast, J.K. Wang, F. Lan, Y. Shi, E. Segal, H.Y. Chang, Long noncoding RNA as modular scaffold of histone modification complexes. Science 329, 689–693 (2010)

R.A. Gupta, N. Shah, K.C. Wang, J. Kim, H.M. Horlings, D.J. Wong, M.C. Tsai, T. Hung, P. Argani, J.L. Rinn, Y. Wang, P. Brzoska, B. Kong, R. Li, R.B. West, M.J. van de Vijver, S. Sukumar, H.Y. Chang, Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature 464, 1071–1076 (2010)

Y. Jiang, Z. Li, S. Zheng, H. Chen, X. Zhao, W. Gao, Z. Bi, K. You, Y. Wang, W. Li, L. Li, Y. Liu, R. Chen, The long non-coding RNA HOTAIR affects the radiosensitivity of pancreatic ductal adenocarcinoma by regulating the expression of Wnt inhibitory factor 1. Tumour Biol. (2015). doi: 10.1007/s13277-015-4234-0

A.E. Teschendorff, S.H. Lee, A. Jones, H. Fiegl, M. Kalwa, W. Wagner, K. Chindera, I. Evans, L. Dubeau, A. Orjalo, H.M. Horlings, L. Niederreiter, A. Kaser, W. Yang, E.L. Goode, B.L. Fridley, R.G. Jenner, E.M. Berns, E. Wik, H.B. Salvesen, G.B. Wisman, A.G. van der Zee, B. Davidson, C.G. Trope, S. Lambrechts, I. Vergote, H. Calvert, I.J. Jacobs, M. Widschwendter, HOTAIR and its surrogate DNA methylation signature indicate carboplatin resistance in ovarian cancer. Genome Med. 7, 108 (2015). doi: 10.1186/s13073-015-0233-4

K.C. Wang, Y.W. Yang, B. Liu, A. Sanyal, R. Corces-Zimmerman, Y. Chen, B.R. Lajoie, A. Protacio, R.A. Flynn, R.A. Gupta, J. Wysocka, M. Lei, J. Dekker, J.A. Helms, H.Y. Chang, A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression. Nature 472, 120–124 (2011)

J.J. Song, R.E. Kingston, WDR5 interacts with mixed lineage leukemia (MLL) protein via the histone H3-binding pocket. J. Biol. Chem. 283, 35258–35264 (2008)

L. Quagliata, M.S. Matter, S. Piscuoglio, L. Arabi, C. Ruiz, A. Procino, M. Kovac, F. Moretti, Z. Makowska, T. Boldanova, J.B. Andersen, M. Hammerle, L. Tornillo, M.H. Heim, S. Diederichs, C. Cillo, L.M. Terracciano, Long noncoding RNA HOTTIP/HOXA13 expression is associated with disease progression and predicts outcome in hepatocellular carcinoma patients. Hepatology 59, 911–923 (2014)

Z. Li, X. Zhao, Y. Zhou, Y. Liu, Q. Zhou, H. Ye, Y. Wang, J. Zeng, Y. Song, W. Gao, S. Zheng, B. Zhuang, H. Chen, W. Li, H. Li, H. Li, Z. Fu, R. Chen, The long non-coding RNA HOTTIP promotes progression and gemcitabine resistance by regulating HOXA13 in pancreatic cancer. J. Transl. Med. 13, 84 (2015). doi: 10.1186/s12967-015-0442-z

Y. Cheng, I. Jutooru, G. Chadalapaka, J.C. Corton, S. Safe, The long non-coding RNA HOTTIP enhances pancreatic cancer cell proliferation, survival and migration. Oncotarget 6, 10840–10852 (2015)

Y.W. Sun, Y.F. Chen, J. Li, Y.M. Huo, D.J. Liu, R. Hua, J.F. Zhang, W. Liu, J.Y. Yang, X.L. Fu, T. Yan, J. Hong, H. Cao, A novel long non-coding RNA ENST00000480739 suppresses tumour cell invasion by regulating OS-9 and HIF-1alpha in pancreatic ductal adenocarcinoma. Br. J. Cancer 111, 2131–2141 (2014)

S. Zheng, H. Chen, Y. Wang, W. Gao, Z. Fu, Q. Zhou, Y. Jiang, Q. Lin, L. Tan, H. Ye, X. Zhao, Y. Luo, G. Li, L. Ye, Y. Liu, W. Li, Z. Li, R. Chen, Long non-coding RNA LOC389641 promotes progression of pancreatic ductal adenocarcinoma and increases cell invasion by regulating E-cadherin in a TNFRSF10A-related manner. Cancer Lett. 37, 354–365 (2016)

A. Ashkenazi, R.C. Pai, S. Fong, S. Leung, D.A. Lawrence, S.A. Marsters, C. Blackie, L. Chang, A.E. McMurtrey, A. Hebert, L. DeForge, I.L. Koumenis, D. Lewis, L. Harris, J. Bussiere, H. Koeppen, Z. Shahrokh, R.H. Schwall, Safety and antitumor activity of recombinant soluble Apo2 ligand. J. Clin. Invest. 104, 155–162 (1999)

I. Ariel, S. Ayesh, E.J. Perlman, G. Pizov, V. Tanos, T. Schneider, V.A. Erdmann, D. Podeh, D. Komitowski, A.S. Quasem, N. de Groot, A. Hochberg, The product of the imprinted H19 gene is an oncofetal RNA. Mol. Pathol. 50, 34–44 (1997)

T. Arima, T. Matsuda, N. Takagi, N. Wake, Association of IGF2 and H19 imprinting with choriocarcinoma development. Cancer Genet. Cytogenet. 93, 39–47 (1997)

G. Banet, O. Bibi, I. Matouk, S. Ayesh, M. Laster, K.M. Kimber, M. Tykocinski, N. de Groot, A. Hochberg, P. Ohana, Characterization of human and mouse H19 regulatory sequences. Mol. Biol. Rep. 27, 157–165 (2000)

I.J. Matouk, N. DeGroot, S. Mezan, S. Ayesh, R. Abu-lail, A. Hochberg, E. Galun, The H19 non-coding RNA is essential for human tumor growth. PLoS One 2, e845 (2007)

C. Ma, K. Nong, H. Zhu, W. Wang, X. Huang, Z. Yuan, K. Ai, H19 promotes pancreatic cancer metastasis by derepressing let-7’s suppression on its target HMGA2-mediated EMT. Tumour Biol. 35, 9163–9169 (2014)

D. Amit, A. Hochberg, Development of targeted therapy for a broad spectrum of cancers (pancreatic cancer, ovarian cancer, glioblastoma and HCC) mediated by a double promoter plasmid expressing diphtheria toxin under the control of H19 and IGF2-P4 regulatory sequences. Int. J. Clin. Exp. Med. 5, 296–305 (2012)

A.A. Sidi, P. Ohana, S. Benjamin, M. Shalev, J.H. Ransom, D. Lamm, A. Hochberg, I. Leibovitch, Phase I/II marker lesion study of intravesical BC-819 DNA plasmid in H19 over expressing superficial bladder cancer refractory to bacillus Calmette-Guerin. J. Urol. 180, 2379–2383 (2008)

A. Mizrahi, A. Czerniak, T. Levy, S. Amiur, J. Gallula, I. Matouk, R. Abu-lail, V. Sorin, T. Birman, N. de Groot, A. Hochberg, P. Ohana, Development of targeted therapy for ovarian cancer mediated by a plasmid expressing diphtheria toxin under the control of H19 regulatory sequences. J.Transl.Med. 7, 69 (2009). doi: 10.1186/1479-5876-7-69

ClinicalTrials.gov [Internet] Identifier: NCT01413087, Efficacy and safety of BC-819 and gemcitabine in patients with locally advanced pancreatic adenocarcinoma (LAPC-BC-819), 2015 (2012)

J.H. Liu, G. Chen, Y.W. Dang, C.J. Li, D.Z. Luo, Expression and prognostic significance of lncRNA MALAT1 in pancreatic cancer tissues. Asian Pac. J. Cancer Prev. 15, 2971–2977 (2014)

E. Heister, V. Neves, C. Lamprecht, S.R.P. Silva, H.M. Coley, J. McFadden, Drug loading, dispersion stability, and therapeutic efficacy in targeted drug delivery with carbon nanotubes. 50, 622–632 (2012)

C.J. Cheng, R. Bahal, I.A. Babar, Z. Pincus, F. Barrera, C. Liu, A. Svoronos, D.T. Braddock, P.M. Glazer, D.M. Engelman, W.M. Saltzman, F.J. Slack, MicroRNA silencing for cancer therapy targeted to the tumour microenvironment. Nature 518, 107–110 (2015)

C.F. Bennett, E.E. Swayze, RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform. Annu. Rev. Pharmacol. Toxicol. 50, 259–293 (2010)

C.M. Sousa, A.C. Kimmelman, The complex landscape of pancreatic cancer metabolism. Carcinogenesis 35, 1441–1450 (2014)

C.W. Kimbrough, A. Khanal, M. Zeiderman, B.R. Khanal, N.C. Burton, K.M. McMasters, S.M. Vickers, W.E. Grizzle, L.R. McNally, Targeting acidity in pancreatic adenocarcinoma: multispectral optoacoustic tomography detects pH-low insertion peptide probes in vivo. Clin. Cancer Res. 21, 4576–4585 (2015)

H. Atkinson, R. Chalmers, Delivering the goods: viral and non-viral gene therapy systems and the inherent limits on cargo DNA and internal sequences. Genetica 138, 485–498 (2010)

B.D. Adams, C. Parsons, F.J. Slack, The tumor-suppressive and potential therapeutic functions of miR-34a in epithelial carcinomas. Expert Opin. Ther. Targets (2015). doi: 10.1517/14728222.2016.1114102

G. Almer, K.L. Summers, B. Scheicher, J. Kellner, I. Stelzer, G. Leitinger, A. Gries, R. Prassl, A. Zimmer, H. Mangge, Interleukin 10-coated nanoparticle systems compared for molecular imaging of atherosclerotic lesions. Int. J. Nanomedicine 9, 4211–4222 (2014)

S. Zalba, A.M. Contreras, A. Haeri, T.L. Ten Hagen, I. Navarro, G. Koning, M.J. Garrido, Cetuximab-oxaliplatin-liposomes for epidermal growth factor receptor targeted chemotherapy of colorectal cancer. J. Control. Release 210, 26–38 (2015)

K. Bates, K. Kostarelos, Carbon nanotubes as vectors for gene therapy: past achievements, present challenges and future goals. Adv. Drug Deliv. Rev. 65, 2023–2033 (2013)

H.L. Janssen, H.W. Reesink, E.J. Lawitz, S. Zeuzem, M. Rodriguez-Torres, K. Patel, A.J. van der Meer, A.K. Patick, A. Chen, Y. Zhou, R. Persson, B.D. King, S. Kauppinen, A.A. Levin, M.R. Hodges, Treatment of HCV infection by targeting microRNA. N. Engl. J. Med. 368, 1685–1694 (2013)

E.C. Verna, V. Dhar, Endoscopic ultrasound-guided fine needle injection for cancer therapy: the evolving role of therapeutic endoscopic ultrasound. Ther. Adv. Gastroenterol. 1, 103–109 (2008)

A. Kambadakone, A. Thabet, D.A. Gervais, P.R. Mueller, R.S. Arellano, CT-guided celiac plexus neurolysis: a review of anatomy, indications, technique, and tips for successful treatment. Radiographics 31, 1599–1621 (2011)

V. Scaiewicz, V. Sorin, Y. Fellig, T. Birman, A. Mizrahi, J. Galula, R. Abu-Lail, T. Shneider, P. Ohana, L. Buscail, A. Hochberg, A. Czerniak, Use of H19 gene regulatory sequences in DNA-based therapy for pancreatic cancer. J. Oncol. 2010, 178174 (2010)

J. Kota, R.R. Chivukula, K.A. O’Donnell, E.A. Wentzel, C.L. Montgomery, H.W. Hwang, T.C. Chang, P. Vivekanandan, M. Torbenson, K.R. Clark, J.R. Mendell, J.T. Mendell, Therapeutic delivery of miR-26a inhibits cancer cell proliferation and induces tumor-specific apoptosis. Cell 137, 1005–1017 (2009)

G.A. Calin, C.D. Dumitru, M. Shimizu, R. Bichi, S. Zupo, E. Noch, H. Aldler, S. Rattan, M. Keating, K. Rai, L. Rassenti, T. Kipps, M. Negrini, F. Bullrich, C.M. Croce, Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc. Natl. Acad. Sci. U. S. A. 99, 15524–15529 (2002)

H.A. Burris 3rd, M.J. Moore, J. Andersen, M.R. Green, M.L. Rothenberg, M.R. Modiano, M.C. Cripps, R.K. Portenoy, A.M. Storniolo, P. Tarassoff, R. Nelson, F.A. Dorr, C.D. Stephens, D.D. Von Hoff, Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J. Clin. Oncol. 15, 2403–2413 (1997)

Y. Ren, J. Gao, J.Q. Liu, X.W. Wang, J.J. Gu, H.J. Huang, Y.F. Gong, Z.S. Li, Differential signature of fecal microRNAs in patients with pancreatic cancer. Mol. Med. Rep. 6, 201–209 (2012)

M. Humeau, A. Vignolle-Vidoni, F. Sicard, F. Martins, B. Bournet, L. Buscail, J. Torrisani, P. Cordelier, Salivary MicroRNA in pancreatic cancer patients. PLoS One 10, e0130996 (2015)

S.A. Dhayat, B. Abdeen, G. Kohler, N. Senninger, J. Haier, W.A. Mardin, MicroRNA-100 and microRNA-21 as markers of survival and chemotherapy response in pancreatic ductal adenocarcinoma UICC stage II. Clin. Epigenetics 7, 132 (2015). doi: 10.1186/s13148-015-0166-1 . eCollection 2015

J. Liu, J. Gao, Y. Du, Z. Li, Y. Ren, J. Gu, X. Wang, Y. Gong, W. Wang, X. Kong, Combination of plasma microRNAs with serum CA19-9 for early detection of pancreatic cancer. Int. J. Cancer 131, 683–691 (2012)

K.H. Lee, J.K. Lee, D.W. Choi, I.G. Do, I. Sohn, K.T. Jang, S.H. Jung, J.S. Heo, S.H. Choi, K.T. Lee, Postoperative prognosis prediction of pancreatic cancer with seven MicroRNAs. Pancreas 44, 764–768 (2015)