MicroRNA‑539 inhibits cell proliferation, colony formation and invasion in pancreatic ductal adenocarcinoma by directly targeting IGF‑1R

Lin,Yongquan; Rong,Lihua; Zhao,Jingrong; Lin,Ronghui; Li,Shuhua

doi:10.3892/mmr.2018.9109

MicroRNA‑539 inhibits cell proliferation, colony formation and invasion in pancreatic ductal adenocarcinoma by directly targeting IGF‑1R

Authors:
- Yongquan Lin
- Lihua Rong
- Jingrong Zhao
- Ronghui Lin
- Shuhua Li
View Affiliations

Affiliations: Department of Emergency, Yidu Central Hospital of Weifang, Weifang, Shandong 262500, P.R. China, Department of General Surgery, The 89th Hospital of Chinese People's Liberation Army, Weifang, Shandong 262500, P.R. China, Health clinics, Qingzhou Yanghe River Authority, Qingzhou, Shandong 261021, P.R. China, Department of Emergency, Weifang People's Hospital, Weifang, Shandong 261000, P.R. China
Published online on: May 31, 2018 https://doi.org/10.3892/mmr.2018.9109
Pages: 1804-1811

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

MicroRNAs (miRNAs) possess oncogenic and tumour‑suppressive roles in the carcinogenesis and progression of pancreatic ductal adenocarcinoma (PDAC) by regulating the expression of numerous cancer‑related genes. Thus, the investigation on the expression and roles of miRNAs in PDAC may facilitate the identification of novel and effective targets for the clinical diagnosis and treatment of patients with PDAC. miRNA‑539 (miR‑539) has been studied in multiple types of human cancer. However, its expression and potential biological function in PDAC remain unclear. In the current study, the expression level, clinical significance, roles and underlying molecular mechanism of miR‑539 in PDAC. The present results demonstrated that miR‑539 expression was downregulated in PDAC tissues and cell lines. A low miR‑539 level was associated with TNM stage and lymph node metastasis of patients with PDAC. miR‑539 overexpression induced a significant reduction in the proliferation, colony formation and invasion of PDAC cells. Insulin‑like growth factor 1 receptor (IGF‑1R) was confirmed as a direct target gene of miR‑539 in PDAC. Further analysis indicated that IGF‑1R was overexpressed in PDAC tissues. Notably, the mRNA expression of IGF‑1R was negatively correlated with miR‑539 levels in PDAC tissues. In addition, the recovered IGF‑1R expression also partially counteracted the suppressive roles of miR‑539 overexpression in PDAC cells. Overall, miR‑539 may inhibit the aggressive behaviour of PDAC by directly targeting IGF‑1R and may serve as a novel therapeutic target for patients with this disease.

View Figures

View References

1	Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI
2	Modolell I, Guarner L and Malagelada JR: Vagaries of clinical presentation of pancreatic and biliary tract cancer. Ann Oncol. 10 Suppl 4:82–84. 1999. View Article : Google Scholar : PubMed/NCBI
3	Jiao F, Hu H, Yuan C and Wang L, Jiang W, Jin Z, Guo Z and Wang L: Elevated expression level of long noncoding RNA MALAT-1 facilitates cell growth, migration and invasion in pancreatic cancer. Oncol Rep. 32:2485–2492. 2014. View Article : Google Scholar : PubMed/NCBI
4	Maitra A and Hruban RH: Pancreatic cancer. Annu Rev Pathol. 3:157–188. 2008. View Article : Google Scholar : PubMed/NCBI
5	Moir J, White SA, French JJ, Littler P and Manas DM: Systematic review of irreversible electroporation in the treatment of advanced pancreatic cancer. Eur J Surg Oncol. 40:1598–1604. 2014. View Article : Google Scholar : PubMed/NCBI
6	Burkey MD, Feirman S, Wang H, Choudhury SR, Grover S and Johnston FM: The association between smokeless tobacco use and pancreatic adenocarcinoma: A systematic review. Cancer Epidemiol. 38:647–653. 2014. View Article : Google Scholar : PubMed/NCBI
7	Bartel DP: MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI
8	Bartel DP: MicroRNAs: Target recognition and regulatory functions. Cell. 136:215–233. 2009. View Article : Google Scholar : PubMed/NCBI
9	Fan Y, Shi C, Li T and Kuang T: MicroRNA-454 shows anti-angiogenic and anti-metastatic activity in pancreatic ductal adenocarcinoma by targeting LRP6. Am J Cancer Res. 7:139–147. 2017.PubMed/NCBI
10	Zhang G, Ai D, Yang X, Ji S, Wang Z and Feng S: MicroRNA-610 inhibits tumor growth of melanoma by targeting LRP6. Oncotarget. 8:97361–97370. 2017.PubMed/NCBI
11	Jin Y, Tao LP, Yao SC, Huang QK, Chen ZF, Sun YJ and Jin SQ: MicroRNA-582-5p suppressed gastric cancer cell proliferation via targeting AKT3. Eur Rev Med Pharmacol Sci. 21:5112–5120. 2017.PubMed/NCBI
12	Wang X and Wu X: The Role of MicroRNA-1207-5p in colorectal cancer. Clin Lab. 63:1875–1882. 2017. View Article : Google Scholar : PubMed/NCBI
13	Yang D, Du G, Xu A, Xi X and Li D: Expression of miR-149-3p inhibits proliferation, migration, and invasion of bladder cancer by targeting S100A4. Am J Cancer Res. 7:2209–2219. 2017.PubMed/NCBI
14	Liu S, Liu K, Zhang W, Wang Y, Jin Z, Jia B and Liu Y: miR-449a inhibits proliferation and invasion by regulating ADAM10 in hepatocellular carcinoma. Am J Transl Res. 8:2609–2619. 2016.PubMed/NCBI
15	Cheng RF, Wang J, Zhang JY, Sun L, Zhao YR, Qiu ZQ, Sun BC and Sun Y: MicroRNA-506 is up-regulated in the development of pancreatic ductal adenocarcinoma and is associated with attenuated disease progression. Chin J Cancer. 35:642016. View Article : Google Scholar : PubMed/NCBI
16	Tu MJ, Pan YZ, Qiu JX, Kim EJ and Yu AM: MicroRNA-1291 targets the FOXA2-AGR2 pathway to suppress pancreatic cancer cell proliferation and tumorigenesis. Oncotarget. 7:45547–45561. 2016. View Article : Google Scholar : PubMed/NCBI
17	Wen D, Li S, Jiang W, Zhu J, Liu J and Zhao S: miR-539 inhibits human colorectal cancer progression by targeting RUNX2. Biomed Pharmacother. 95:1314–1320. 2017. View Article : Google Scholar : PubMed/NCBI
18	Quan J, Qu J and Zhou L: MicroRNA-539 inhibits glioma cell proliferation and invasion by targeting DIXDC1. Biomed Pharmacother. 93:746–753. 2017. View Article : Google Scholar : PubMed/NCBI
19	Li S, Yang F, Wang M, Cao W and Yang Z: miR-378 functions as an onco-miRNA by targeting the ST7L/Wnt/β-catenin pathway in cervical cancer. Int J Mol Med. 40:1047–1056. 2017. View Article : Google Scholar : PubMed/NCBI
20	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
21	Xu JW, Wang TX, You L, Zheng LF, Shu H, Zhang TP and Zhao YP: 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:e928472014. View Article : Google Scholar : PubMed/NCBI
22	Hirakawa T, Yashiro M, Murata A, Hirata K, Kimura K, Amano R, Yamada N, Nakata B and Hirakawa K: IGF-1 receptor and IGF binding protein-3 might predict prognosis of patients with resectable pancreatic cancer. BMC Cancer. 13:3922013. View Article : Google Scholar : PubMed/NCBI
23	Subramani R, Lopez-Valdez R, Arumugam A, Nandy S, Boopalan T and Lakshmanaswamy R: Targeting insulin-like growth factor 1 receptor inhibits pancreatic cancer growth and metastasis. PLoS One. 9:e970162014. View Article : Google Scholar : PubMed/NCBI
24	Zheng D, Golubovskaya V, Kurenova E, Wood C, Massoll NA, Ostrov D, Cance WG and Hochwald SN: A novel strategy to inhibit FAK and IGF-1R decreases growth of pancreatic cancer xenografts. Mol Carcinog. 49:200–209. 2010.PubMed/NCBI
25	Farhana L, Dawson MI, Murshed F, Das JK, Rishi AK and Fontana JA: Upregulation of miR-150* and miR-630 induces apoptosis in pancreatic cancer cells by targeting IGF-1R. PLoS One. 8:e610152013. View Article : Google Scholar : PubMed/NCBI
26	Tian X, Hao K, Qin C, Xie K, Xie X and Yang Y: Insulin-like growth factor 1 receptor promotes the growth and chemoresistance of pancreatic cancer. Dig Dis Sci. 58:2705–2712. 2013. View Article : Google Scholar : PubMed/NCBI
27	Moser C, Schachtschneider P, Lang SA, Gaumann A, Mori A, Zimmermann J, Schlitt HJ, Geissler EK and Stoeltzing O: Inhibition of insulin-like growth factor-I receptor (IGF-IR) using NVP-AEW541, a small molecule kinase inhibitor, reduces orthotopic pancreatic cancer growth and angiogenesis. Eur J Cancer. 44:1577–1586. 2008. View Article : Google Scholar : PubMed/NCBI
28	Qadir MI and Faheem A: miRNA: A diagnostic and therapeutic tool for pancreatic cancer. Crit Rev Eukaryot Gene Expr. 27:197–204. 2017. View Article : Google Scholar : PubMed/NCBI
29	Liang S, Gong X, Zhang G, Huang G, Lu Y and Li Y: MicroRNA-140 regulates cell growth and invasion in pancreatic duct adenocarcinoma by targeting iASPP. Acta Biochim Biophys Sin (Shanghai). 48:174–181. 2016. View Article : Google Scholar : PubMed/NCBI
30	Keklikoglou I, Hosaka K, Bender C, Bott A, Koerner C, Mitra D, Will R, Woerner A, Muenstermann E1, Wilhelm H, et al: 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. View Article : Google Scholar : PubMed/NCBI
31	Zhu C, Zhou R, Zhou Q, Chang Y and Jiang M: microRNA-539 suppresses tumor growth and tumorigenesis and overcomes arsenic trioxide resistance in hepatocellular carcinoma. Life Sci. 166:34–40. 2016. View Article : Google Scholar : PubMed/NCBI
32	Liu Y, Hong W, Zhou C, Jiang Z, Wang G, Wei G and Li X: miR-539 inhibits FSCN1 expression and suppresses hepatocellular carcinoma migration and invasion. Oncol Rep. 37:2593–2602. 2017. View Article : Google Scholar : PubMed/NCBI
33	Zhang H, Li S, Yang X, Qiao B, Zhang Z and Xu Y: miR-539 inhibits prostate cancer progression by directly targeting SPAG5. J Exp Clin Cancer Res. 35:602016. View Article : Google Scholar : PubMed/NCBI
34	Lv LY, Wang YZ, Zhang Q, Zang HR and Wang XJ: miR-539 induces cell cycle arrest in nasopharyngeal carcinoma by targeting cyclin-dependent kinase 4. Cell Biochem Funct. 33:534–540. 2015. View Article : Google Scholar : PubMed/NCBI
35	Jin H and Wang W: MicroRNA-539 suppresses osteosarcoma cell invasion and migration in vitro and targeting Matrix metallopeptidase-8. Int J Clin Exp Pathol. 8:8075–8082. 2015.PubMed/NCBI
36	Gu L and Sun W: MiR-539 inhibits thyroid cancer cell migration and invasion by directly targeting CARMA1. Biochem Biophys Res Commun. 464:1128–1133. 2015. View Article : Google Scholar : PubMed/NCBI
37	Hu Q, Gong JP, Li J, Zhong SL, Chen WX, Zhang JY, Ma TF, Ji H, Lv MM, Zhao JH and Tang JH: Down-regulation of miRNA-452 is associated with adriamycin-resistance in breast cancer cells. Asian Pac J Cancer Prev. 15:5137–5142. 2014. View Article : Google Scholar : PubMed/NCBI
38	An Y, Cai L, Wang Y, Zhu D, Guan Y and Zheng J: Onkologie. Onkologie. 32:638–644. 2009. View Article : Google Scholar : PubMed/NCBI
39	E C, Li J, Shao D, Zhang D, Pan Y, Chen L and Zhang X: The insulin-like growth factor-I receptor inhibitor picropodophyllin-induced selective apoptosis of hepatocellular carcinoma cell through a caspase-dependent mitochondrial pathway. Oncol Res. 21:103–110. 2013. View Article : Google Scholar : PubMed/NCBI
40	Sichani MM, Yazdi FS, Moghaddam NA, Chehrei A, Kabiri M, Naeimi A and Taheri D: Prognostic value of insulin-like growth factor-I receptor expression in renal cell carcinoma. Saudi J Kidney Dis Transpl. 21:69–74. 2010.PubMed/NCBI
41	Zhao S, Qiu Z, He J, Li L and Li W: Insulin-like growth factor receptor 1 (IGF1R) expression and survival in non-small cell lung cancer patients: A meta-analysis. Int J Clin Exp Pathol. 7:6694–6704. 2014.PubMed/NCBI
42	Gryko M, Kiśluk J, Cepowicz D, Zińczuk J, Kamocki Z, Guzińska-Ustymowicz K, Pryczynicz A, Czyżewska J, Kemona A and Kędra B: Expression of insulin-like growth factor receptor type 1 correlate with lymphatic metastases in human gastric cancer. Pol J Pathol. 65:135–140. 2014. View Article : Google Scholar : PubMed/NCBI
43	Xie QX, Lin XC, Zhang MF, Han CX and Guo YH: Expression of IGF-I and IGF-IR in bladder cancer. Ai Zheng. 23:707–709. 2004.(In Chinese). PubMed/NCBI