MicroRNA-187 inhibits tumor growth and metastasis via targeting of IGF-1R in hepatocellular carcinoma

Han,Xinqiang; Wang,Xuemin; Zhao,Baolei; Chen,Gang; Sheng,Yuguo; Wang,Wenming; Teng,Mujian

doi:10.3892/mmr.2017.6788

MicroRNA-187 inhibits tumor growth and metastasis via targeting of IGF-1R in hepatocellular carcinoma

Authors:
- Xinqiang Han
- Xuemin Wang
- Baolei Zhao
- Gang Chen
- Yuguo Sheng
- Wenming Wang
- Mujian Teng
View Affiliations

Affiliations: Department of Interventional Medicine and Vascular Surgery, The Affiliated Hospital of Binzhou Medical University, Binzhou, Shandong 256603, P.R. China, Department of Gastroenterology, The Affiliated Hospital of Binzhou Medical University, Binzhou, Shandong 256603, P.R. China, Department of Hepatobiliary Surgery, The Affiliated Hospital of Binzhou Medical University, Binzhou, Shandong 256603, P.R. China, Department of Hepatobiliary Surgery, Qianfoshan Hospital Affiliated to Shandong University, Jinan, Shandong 250014, P.R. China
Published online on: June 15, 2017 https://doi.org/10.3892/mmr.2017.6788
Pages: 2241-2246

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

Hepatocellular carcinoma (HCC) is the primary and most frequently occurring type of malignant liver cancer, accounting for 70-85% of total liver cancer cases worldwide. It has previously been demonstrated that the aberrant expression of microRNAs (miR) contributes to carcinogenesis and progression of various human malignancies, including HCC. However, mechanisms underlying the differential expression and specific roles of miR‑187 in HCC remain to be elucidated, particularly regarding how the modulation of malignant phenotypes in HCC cells occurs. The present study demonstrated that miR‑187 was significantly downregulated in HCC tissues and cell lines. Restoration of miR‑187 expression inhibited cell proliferation, migration and invasion in HCC. Furthermore, insulin‑like growth factor 1 receptor (IGF‑1R) was demonstrated to act as a direct target gene of miR‑187 in HCC. IGF‑1R knockdown mimicked the effects of miR‑187 overexpression in HCC, resulting in a significant inhibition of cell proliferation, migration and invasion. The results of the present study demonstrated that miR‑187 acted as a tumor suppressor in HCC progression via direct targeting of IGF‑1R. miR‑187 may therefore exhibit the potential to act as a novel and therapeutic target for HCC treatment in the future.

View Figures

View References

1	Perz JF, Armstrong GL, Farrington LA, Hutin YJ and Bell BP: The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol. 45:529–538. 2006. View Article : Google Scholar : PubMed/NCBI
2	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2015. CA Cancer J Clin. 65:5–29. 2015. View Article : Google Scholar : PubMed/NCBI
3	Schwartz M, Roayaie S and Konstadoulakis M: Strategies for the management of hepatocellular carcinoma. Nat Clin Pract Oncol. 4:424–432. 2007. View Article : Google Scholar : PubMed/NCBI
4	Poon RT and Fan ST: Hepatectomy for hepatocellular carcinoma: Patient selection and postoperative outcome. Liver Transpl. 10 2 Suppl 1:S39–S45. 2004. View Article : Google Scholar : PubMed/NCBI
5	Yu MC and Yuan JM: Environmental factors and risk for hepatocellular carcinoma. Gastroenterology. 127 5 Spuul 1:S72–S78. 2004. View Article : Google Scholar : PubMed/NCBI
6	El-Serag HB and Rudolph KL: Hepatocellular carcinoma: Epidemiology and molecular carcinogenesis. Gastroenterology. 132:2557–2576. 2007. View Article : Google Scholar : PubMed/NCBI
7	Park KU, Seo YS, Lee YH, Park J, Hwang I, Kang KJ, Nam J, Kim SW and Kim JY: Altered microRNA expression profile in hepatitis B virus-related hepatocellular carcinoma. Gene. 573:278–284. 2015. View Article : Google Scholar : PubMed/NCBI
8	Han DH, Choi GH, Kim KS, Choi JS, Park YN, Kim SU, Park JY, Ahn SH and Han KH: Prognostic significance of the worst grade in hepatocellular carcinoma with heterogeneous histologic grades of differentiation. J Gastroenterol Hepatol. 28:1384–1390. 2013. View Article : Google Scholar : PubMed/NCBI
9	Bosch FX, Ribes J, Diaz M and Cléries R: Primary liver cancer: Worldwide incidence and trends. Gastroenterology. 127:(5 Suppl 1): S5–S16. 2004. View Article : Google Scholar
10	Zhang Y, Guo X, Xiong L, Kong X, Xu Y, Liu C, Zou L, Li Z, Zhao J and Lin N: MicroRNA-101 suppresses SOX9-dependent tumorigenicity and promotes favorable prognosis of human hepatocellular carcinoma. FEBS Lett. 586:4362–4370. 2012. View Article : Google Scholar : PubMed/NCBI
11	Harlan LC, Parsons HM, Wiggins CL, Stevens JL and Patt YZ: Treatment of hepatocellular carcinoma in the community: Disparities in standard therapy. Liver Cancer. 4:70–83. 2015. View Article : Google Scholar : PubMed/NCBI
12	Croce CM and Calin GA: miRNAs, cancer, and stem cell division. Cell. 122:6–7. 2005. View Article : Google Scholar : PubMed/NCBI
13	Papaconstantinou I, Karakatsanis A, Gazouli M, Polymeneas G and Voros D: The role of microRNAs in liver cancer. Eur J Gastroenterol Hepatol. 24:223–228. 2012. View Article : Google Scholar : PubMed/NCBI
14	Ambros V: The functions of animal microRNAs. Nature. 431:350–355. 2004. View Article : Google Scholar : PubMed/NCBI
15	Bartel DP: MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI
16	Rottiers V, Najafi-Shoushtari SH, Kristo F, Gurumurthy S, Zhong L, Li Y, Cohen DE, Gerszten RE, Bardeesy N, Mostoslavsky R and Näär AM: MicroRNAs in metabolism and metabolic diseases. Cold Spring Harb Symp Quant Biol. 76:225–233. 2011. View Article : Google Scholar : PubMed/NCBI
17	Lujambio A and Lowe SW: The microcosmos of cancer. Nature. 482:347–355. 2012. View Article : Google Scholar : PubMed/NCBI
18	Dou C, Wang Y, Li C, Liu Z, Jia Y, Li Q, Yang W, Yao Y, Liu Q and Tu K: MicroRNA-212 suppresses tumor growth of human hepatocellular carcinoma by targeting FOXA1. Oncotarget. 6:13216–13228. 2015. View Article : Google Scholar : PubMed/NCBI
19	Wang X, Chen J, Li F, Lin Y, Zhang X, Lv Z and Jiang J: miR-214 inhibits cell growth in hepatocellular carcinoma through suppression of β-catenin. Biochem Biophys Res Commun. 428:525–531. 2012. View Article : Google Scholar : PubMed/NCBI
20	Garzon R, Calin GA and Croce CM: MicroRNAs in cancer. Annu Rev Med. 60:167–179. 2009. View Article : Google Scholar : PubMed/NCBI
21	Zhao G, Wang T, Huang QK, Pu M, Sun W, Zhang ZC, Ling R and Tao KS: MicroRNA-548a-5p promotes proliferation and inhibits apoptosis in hepatocellular carcinoma cells by targeting Tg737. World J Gastroenterol. 22:5364–5373. 2016. View Article : Google Scholar : PubMed/NCBI
22	Ruan T, He X, Yu J and Hang Z: MicroRNA-186 targets Yes-associated protein 1 to inhibit Hippo signaling and tumorigenesis in hepatocellular carcinoma. Oncol Lett. 11:2941–2945. 2016.PubMed/NCBI
23	Zhao J, Lei T, Xu C, Li H, Ma W, Yang Y, Fan S and Liu Y: MicroRNA-187, down-regulated in clear cell renal cell carcinoma and associated with lower survival, inhibits cell growth and migration though targeting B7-H3. Biochem Biophys Res Commun. 438:439–444. 2013. View Article : Google Scholar : PubMed/NCBI
24	Wang ZS, Zhong M, Bian YH, Mu YF, Qin SL, Yu MH and Qin J: MicroRNA-187 inhibits tumor growth and invasion by directly targeting CD276 in colorectal cancer. Oncotarget. 7:44266–44276. 2016.PubMed/NCBI
25	Casanova-Salas I, Masiá E, Armiñán A, Calatrava A, Mancarella C, Rubio-Briones J, Scotlandi K, Vicent MJ and López-Guerrero JA: miR-187 targets the androgen-regulated gene ALDH1A3 in prostate cancer. PLoS One. 10:e01255762015. View Article : Google Scholar : PubMed/NCBI
26	Azad F Mirzadeh, Naeli P, Malakootian M, Baradaran A, Tavallaei M, Ghanei M and Mowla SJ: Two lung development-related microRNAs, miR-134 and miR-187, are differentially expressed in lung tumors. Gene. 577:221–226. 2016. View Article : Google Scholar : PubMed/NCBI
27	Sun C, Li S, Yang C, Xi Y, Wang L, Zhang F and Li D: MicroRNA-187-3p mitigates non-small cell lung cancer (NSCLC) development through down-regulation of BCL6. Biochem Biophys Res Commun. 471:82–88. 2016. View Article : Google Scholar : PubMed/NCBI
28	Chao A, Lin CY, Lee YS, Tsai CL, Wei PC, Hsueh S, Wu TI, Tsai CN, Wang CJ, Chao AS, et al: Regulation of ovarian cancer progression by microRNA-187 through targeting disabled homolog-2. Oncogene. 31:764–775. 2012. View Article : Google Scholar : PubMed/NCBI
29	Lynam-Lennon N, Bibby BA, Mongan AM, Marignol L, Paxton CN, Geiersbach K, Bronner MP, O'Sullivan J, Reynolds J and Maher SG: Low miR-187 expression promotes resistance to chemoradiation therapy in vitro and correlates with treatment failure in patients with esophageal adenocarcinoma. Mol Med. 22:2016. View Article : Google Scholar : PubMed/NCBI
30	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
31	Ma Y, Cheng Q, Ren Z, Xu L, Zhao Y, Sun J, Hu S and Xiao W: Induction of IGF-1R expression by EGR-1 facilitates the growth of prostate cancer cells. Cancer Lett. 317:150–156. 2012. View Article : Google Scholar : PubMed/NCBI
32	Wei YH, Tang HX, Liao YD, Fu SL, Xu LQ, Chen G, Zhang C, Ju S, Liu ZG, You LK, et al: Effects of insulin-like growth factor 1 receptor and its inhibitor AG1024 on the progress of lung cancer. J Huazhong Univ Sci Technolog Med Sci. 35:834–841. 2015. View Article : Google Scholar : PubMed/NCBI
33	Gryko M, Kisluk 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
34	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
35	Singh RK, Gaikwad SM, Jinager A, Chaudhury S, Maheshwari A and Ray P: IGF-1R inhibition potentiates cytotoxic effects of chemotherapeutic agents in early stages of chemoresistant ovarian cancer cells. Cancer Lett. 354:254–262. 2014. View Article : Google Scholar : PubMed/NCBI
36	Chen HX and Sharon E: IGF-1R as an anti-cancer target-trials and tribulations. Chin J Cancer. 32:242–252. 2013. View Article : Google Scholar : PubMed/NCBI
37	Singh I, Amin H, Rah B and Goswami A: Targeting EGFR and IGF 1R: A promising combination therapy for metastatic cancer. Front Biosci (Schol Ed). 5:231–246. 2013. View Article : Google Scholar : PubMed/NCBI
38	Yue L, Wang Y, Wang H, Gao H, Liang J, Sui A, Xiang J, Zhou F, Xu C, Zhao W, et al: Inhibition of hepatocellular carcinoma cell growth by an anti-insulin-like growth factor-I receptor monoclonal antibody. Oncol Rep. 28:1453–1460. 2012.PubMed/NCBI
39	Zhang YW, Yan DL, Wang W, Zhao HW, Lu X, Wu JZ and Zhou JR: Knockdown of insulin-like growth factor I receptor inhibits the growth and enhances chemo-sensitivity of liver cancer cells. Curr Cancer Drug Targets. 12:74–84. 2012. View Article : Google Scholar : PubMed/NCBI
40	Yao WF, Liu JW, Sheng GL and Huang DS: Blockade of IGF-IR exerts anticancer effects in hepatocellular carcinoma. Mol Med Rep. 4:719–722. 2011.PubMed/NCBI