Integrated analysis of mRNA and miRNA expression profiles in pancreatic ductal adenocarcinoma

Sun,Hongwei; Zhao,Liang; Pan,Kehua; Zhang,Zhao; Zhou,Mengtao; Cao,Guoquan

doi:10.3892/or.2017.5526

Integrated analysis of mRNA and miRNA expression profiles in pancreatic ductal adenocarcinoma

Authors:
- Hongwei Sun
- Liang Zhao
- Kehua Pan
- Zhao Zhang
- Mengtao Zhou
- Guoquan Cao
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Affiliations: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, P.R. China, Department of Radiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, P.R. China
Published online on: March 24, 2017 https://doi.org/10.3892/or.2017.5526
Pages: 2779-2786

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Abstract

In the present study, to investigate the potential molecular mechanism of pancreatic ductal adenocarcinoma (PDAC), mRNA and miRNA expression profiles were integrated for systematic analysis. Results showed that a total of 76 common differentially expressed genes (DEGs) were identified from 2 mRNA expression profiles that contained 39 tumor and 15 normal samples. Notably, the tumor and normal samples were able to be clearly classified into 4 groups based on the DEGs. mRNA‑miRNA regulation network analysis indicated that 22 out of the 76 DEGs including MUC4, RRM2 and CCL2 are regulated by 5 reported miRNAs. Survival analysis using SurvExpress database demonstrated that the common DEGs were able to significantly differentiate low- and high-risk PDAC groups in 4 datasets. In summary, various biological processes are probably involved in the development and progression of PDAC. Firstly, activation of MUC4 induces nuclear translocation of β-catenin and promotes the process of angiogenesis that provides necessary nutrition or oxygen for cancer cells. Then, RRM2 induces the invasiveness of PDAC via NF-κB. Finally, the formation of an immunosuppressive tumor microenvironment by recruiting regulatory T cells with high expression of CCL2 further promotes cancer cell proliferation and vascularization. Identification of valuable biological processes and genes can be helpful for the understanding of the molecular mechanism of PDAC.

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1	Hariharan D, Saied A and Kocher HM: Analysis of mortality rates for pancreatic cancer across the world. HPB. 10:58–62. 2008. View Article : Google Scholar : PubMed/NCBI
2	American Cancer Society: Cancer Facts & Figures 2012. American Cancer Society; Atlanta, GA, USA: 2012
3	Stat Fact Sheets SEER: Pancreas Cancer. National Cancer Institute; 2013
4	Ishiwata T: Pancreatic ductal adenocarcinoma: Basic and clinical challenges for better prognosis. J Carcinog Mutagen. S9:2157–2518. 2013.http://dx.doi.org/4172/2157-2518.S9-005
5	Siegel R, Ward E, Brawley O and Jemal A: Cancer statistics, 2011: The impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin. 61:212–236. 2011. View Article : Google Scholar : PubMed/NCBI
6	Partensky C: Toward a better understanding of pancreatic ductal adenocarcinoma: Glimmers of hope? Pancreas. 42:729–739. 2013. View Article : Google Scholar : PubMed/NCBI
7	Talamini R, Polesel J, Gallus S, Dal Maso L, Zucchetto A, Negri E, Bosetti C, Lucenteforte E, Boz G, Franceschi S, et al: Tobacco smoking, alcohol consumption and pancreatic cancer risk: A case-control study in Italy. Eur J Cancer. 46:370–376. 2010. View Article : Google Scholar : PubMed/NCBI
8	Gapstur SM, Jacobs EJ, Deka A, McCullough ML, Patel AV and Thun MJ: Association of alcohol intake with pancreatic cancer mortality in never smokers. Arch Intern Med. 171:444–451. 2011. View Article : Google Scholar : PubMed/NCBI
9	Jandaghi P, Najafabadi HS, Bauer AS, Papadakis AI, Fassan M, Hall A, Monast A, von Knebel Doeberitz M, Neoptolemos JP, Costello E, et al: Expression of DRD2 is increased in human pancreatic ductal adenocarcinoma and inhibitors slow tumor growth in mice. Gastroenterology. 151:1218–1231. 2016. View Article : Google Scholar : PubMed/NCBI
10	Teodorczyk M, Kleber S, Wollny D, Sefrin JP, Aykut B, Mateos A, Herhaus P, Sancho-Martinez I, Hill O, Gieffers C, et al: CD95 promotes metastatic spread via Sck in pancreatic ductal adenocarcinoma. Cell Death Differ. 22:1192–1202. 2015. View Article : Google Scholar : PubMed/NCBI
11	Cote GA, Gore AJ, McElyea SD, Heathers LE, Xu H, Sherman S and Korc M: A pilot study to develop a diagnostic test for pancreatic ductal adenocarcinoma based on differential expression of select miRNA in plasma and bile. Am J Gastroenterol. 109:1942–1952. 2014. View Article : Google Scholar : PubMed/NCBI
12	Ye Y, Chen J, Zhou Y, Fu Z, Zhou Q, Wang Y, Gao W, Zheng S, Zhao X, Chen T, et al: High expression of AFAP1-AS1 is associated with poor survival and short-term recurrence in pancreatic ductal adenocarcinoma. J Transl Med. 13:1372015. View Article : Google Scholar : PubMed/NCBI
13	Witkiewicz AK, McMillan EA, Balaji U, Baek G, Lin WC, Mansour J, Mollaee M, Wagner KU, Koduru P, Yopp A, et al: Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets. Nat Commun. 6:67442015. View Article : Google Scholar : PubMed/NCBI
14	Berger B, Peng J and Singh M: Computational solutions for omics data. Nat Rev Genet. 14:333–346. 2013. View Article : Google Scholar : PubMed/NCBI
15	Donahue TR, Tran LM, Hill R, Li Y, Kovochich A, Calvopina JH, Patel SG, Wu N, Hindoyan A, Farrell JJ, et al: Integrative survival-based molecular profiling of human pancreatic cancer. Clin Cancer Res. 18:1352–1363. 2012. View Article : Google Scholar : PubMed/NCBI
16	Gentleman RC, Carey VJ, Bates DM, Bolstad B, Dettling M, Dudoit S, Ellis B, Gautier L, Ge Y, Gentry J, et al: Bioconductor: Open software development for computational biology and bioinformatics. Genome Biol. 5:R802004. View Article : Google Scholar : PubMed/NCBI
17	Kerr MK: Linear models for microarray data analysis: Hidden similarities and differences. J Comput Biol. 10:891–901. 2003. View Article : Google Scholar : PubMed/NCBI
18	Hadley W: ggplot2: Elegant Graphics for Data Analysis. Springer; Switzerland: 2016
19	Dennis G Jr, Sherman BT, Hosack DA, Yang J, Gao W, Lane HC and Lempicki RA: DAVID: Database for Annotation, Visualization, and Integrated Discovery. Genome Biol. 4:32003. View Article : Google Scholar
20	Acunzo M and Croce CM: MicroRNA in cancer and cachexia - A mini-review. J Infect Dis. 212:(Suppl 1). S74–S77. 2015. View Article : Google Scholar : PubMed/NCBI
21	Kutmon M, Kelder T, Mandaviya P, Evelo CT and Coort SL: CyTargetLinker: A cytoscape app to integrate regulatory interactions in network analysis. PLoS One. 8:e821602013. View Article : Google Scholar : PubMed/NCBI
22	Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B and Ideker T: Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res. 13:2498–2504. 2003. View Article : Google Scholar : PubMed/NCBI
23	Aguirre-Gamboa R, Gomez-Rueda H, Martínez-Ledesma E, Martínez-Torteya A, Chacolla-Huaringa R, Rodriguez-Barrientos A, Tamez-Peña JG and Treviño V: SurvExpress: An online biomarker validation tool and database for cancer gene expression data using survival analysis. PLoS One. 8:e742502013. View Article : Google Scholar : PubMed/NCBI
24	Mollenhauer J, Roether I and Kern HF: Distribution of extracellular matrix proteins in pancreatic ductal adenocarcinoma and its influence on tumor cell proliferation in vitro. Pancreas. 2:14–24. 1987. View Article : Google Scholar : PubMed/NCBI
25	Pandol S, Edderkaoui M, Gukovsky I, Lugea A and Gukovskaya A: Desmoplasia of pancreatic ductal adenocarcinoma. Clin Gastroenterol Hepatol. 7:(Suppl 11). S44–47. 2009. View Article : Google Scholar : PubMed/NCBI
26	Mahadevan D and Von Hoff DD: Tumor-stroma interactions in pancreatic ductal adenocarcinoma. Mol Cancer Ther. 6:1186–1197. 2007. View Article : Google Scholar : PubMed/NCBI
27	Crowe DL and Ohannessian A: Recruitment of focal adhesion kinase and paxillin to beta1 integrin promotes cancer cell migration via mitogen activated protein kinase activation. BMC Cancer. 4:182004. View Article : Google Scholar : PubMed/NCBI
28	Schmitz KJ, Grabellus F, Callies R, Otterbach F, Wohlschlaeger J, Levkau B, Kimmig R, Schmid KW and Baba HA: High expression of focal adhesion kinase (p125^FAK) in node-negative breast cancer is related to overexpression of HER-2/neu and activated Akt kinase but does not predict outcome. Breast Cancer Res. 7:R194–R203. 2005. View Article : Google Scholar : PubMed/NCBI
29	Sawai H, Okada Y, Funahashi H, Matsuo Y, Takahashi H, Takeyama H and Manabe T: Activation of focal adhesion kinase enhances the adhesion and invasion of pancreatic cancer cells via extracellular signal-regulated kinase-1/2 signaling pathway activation. Mol Cancer. 4:372005. View Article : Google Scholar : PubMed/NCBI
30	Muniyan S, Haridas D, Chugh S, Rachagani S, Lakshmanan I, Gupta S, Seshacharyulu P, Smith LM, Ponnusamy MP and Batra SK: MUC16 contributes to the metastasis of pancreatic ductal adenocarcinoma through focal adhesion mediated signaling mechanism. Genes Cancer. 7:110–124. 2016.PubMed/NCBI
31	Mall AS: Analysis of mucins: Role in laboratory diagnosis. J Clin Pathol. 61:1018–1024. 2008. View Article : Google Scholar : PubMed/NCBI
32	Saitou M, Goto M, Horinouchi M, Tamada S, Nagata K, Hamada T, Osako M, Takao S, Batra SK, Aikou T, et al: MUC4 expression is a novel prognostic factor in patients with invasive ductal carcinoma of the pancreas. J Clin Pathol. 58:845–852. 2005. View Article : Google Scholar : PubMed/NCBI
33	Zhu Y, Zhang JJ, Zhu R, Zhu Y, Liang WB, Gao WT, Yu JB, Xu ZK and Miao Y: The increase in the expression and hypomethylation of MUC4 gene with the progression of pancreatic ductal adenocarcinoma. Med Oncol. 28:(Suppl 1). S175–S184. 2011. View Article : Google Scholar : PubMed/NCBI
34	Jonckheere N, Skrypek N, Merlin J, Dessein AF, Dumont P, Leteurtre E, Harris A, Desseyn JL, Susini C, Frénois F, et al: The mucin MUC4 and its membrane partner ErbB2 regulate biological properties of human CAPAN-2 pancreatic cancer cells via different signalling pathways. PLoS One. 7:e322322012. View Article : Google Scholar : PubMed/NCBI
35	Goan YG, Zhou B, Hu E, Mi S and Yen Y: Overexpression of ribonucleotide reductase as a mechanism of resistance to 2,2-difluorodeoxycytidine in the human KB cancer cell line. Cancer Res. 59:4204–4207. 1999.PubMed/NCBI
36	Eriksson S and Martin DW Jr: Ribonucleotide reductase in cultured mouse lymphoma cells. Cell cycle-dependent variation in the activity of subunit protein M2. J Biol Chem. 256:9436–9440. 1981.PubMed/NCBI
37	Duxbury MS, Ito H, Zinner MJ, Ashley SW and Whang EE: RNA interference targeting the M2 subunit of ribonucleotide reductase enhances pancreatic adenocarcinoma chemosensitivity to gemcitabine. Oncogene. 23:1539–1548. 2004. View Article : Google Scholar : PubMed/NCBI
38	Duxbury MS and Whang EE: RRM2 induces NF-kappaB-dependent MMP-9 activation and enhances cellular invasiveness. Biochem Biophys Res Commun. 354:190–196. 2007. View Article : Google Scholar : PubMed/NCBI
39	Carr MW, Roth SJ, Luther E, Rose SS and Springer TA: Monocyte chemoattractant protein 1 acts as a T-lymphocyte chemoattractant. Proc Natl Acad Sci USA. 91:3652–3656. 1994. View Article : Google Scholar : PubMed/NCBI
40	Monti P, Leone BE, Marchesi F, Balzano G, Zerbi A, Scaltrini F, Pasquali C, Calori G, Pessi F, Sperti C, et al: The CC chemokine MCP-1/CCL2 in pancreatic cancer progression: Regulation of expression and potential mechanisms of antimalignant activity. Cancer Res. 63:7451–7461. 2003.PubMed/NCBI
41	Kalbasi A, Komar CA, Tooker GM, Liu M, Lee JW, Gladney WL, Ben-Josef E and Beatty GL: Tumor-derived CCL2 mediates resistance to radiotherapy in pancreatic ductal adenocarcinoma. Clin Cancer Res. 23:137–148. 2017. View Article : Google Scholar : PubMed/NCBI
42	Tan MC, Goedegebuure PS, Belt BA, Flaherty B, Sankpal N, Gillanders WE, Eberlein TJ, Hsieh CS and Linehan DC: Disruption of CCR5-dependent homing of regulatory T cells inhibits tumor growth in a murine model of pancreatic cancer. J Immunol. 182:1746–1755. 2009. View Article : Google Scholar : PubMed/NCBI
43	Zhang ML, Lu S, Zhou L and Zheng SS: Correlation between ECT2 gene expression and methylation change of ECT2 promoter region in pancreatic cancer. Hepatobiliary Pancreat Dis Int. 7:533–538. 2008.PubMed/NCBI
44	Hrabar D, Aralica G, Gomercic M, Ljubicic N, Kruslin B and Tomas D: Epithelial and stromal expression of syndecan-2 in pancreatic carcinoma. Anticancer Res. 30:2749–2753. 2010.PubMed/NCBI
45	Lesina M, Kurkowski MU, Ludes K, Rose-John S, Treiber M, Klöppel G, Yoshimura A, Reindl W, Sipos B, Akira S, et al: Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. Cancer Cell. 19:456–469. 2011. View Article : Google Scholar : PubMed/NCBI