miR‑135a‑5p inhibits tumor invasion by targeting ANGPT2 in gallbladder cancer

Diao,Haiyan; Xu,Xing; Zhao,Bin; Yang,Guanghua

doi:10.3892/mmr.2021.12167

miR‑135a‑5p inhibits tumor invasion by targeting ANGPT2 in gallbladder cancer

Authors:
- Haiyan Diao
- Xing Xu
- Bin Zhao
- Guanghua Yang
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Affiliations: Department of General Surgery, The Seventh People's Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200137, P.R. China
Published online on: May 25, 2021 https://doi.org/10.3892/mmr.2021.12167
Article Number: 528
Copyright: © Diao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Gallbladder cancer (GBC) is the most aggressive cancer type in the biliary tract, and our previous studies observed that microRNA (miR)‑135a‑5p expression was downregulated in GBC tissues. However, few studies have focused on the mechanism of action of the miR‑135a‑5p target genes in GBC. The present study aimed to investigate the regulatory role of miR‑135a‑5p signaling in GBC. The present study found that miR‑135a‑5p expression was downregulated in GBC tissue, as detected by immunohistochemistry and reverse transcription‑quantitative PCR. In addition, overexpression of miR‑135a‑5p significantly inhibited the proliferation and migration of GBC‑SD cells. Using a luciferase activity assay, it was identified that angiopoietin‑2 (ANGPT2) was a potential target gene of miR‑135a‑5p in GBC. Knockdown of ANGPT2 expression significantly inhibited the proliferation and invasion of GBC‑SD cells. In conclusion, the present results suggested that miR‑135a‑5p affected GBC cell proliferation and invasion by targeting ANGPT2. Moreover, miR‑135a‑5p may be a potential biomarker for GBC progression and a potential target for GBC therapeutic intervention.

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1	Rakić M, Patrlj L, Kopljar M, Kliček R, Kolovrat M, Loncar B and Busic Z: Gallbladder cancer. Hepatobiliary Surg Nutr. 3:221–226. 2014.
2	Sharma A, Sharma KL, Gupta A, Yadav A and Kumar A: Gallbladder cancer epidemiology, pathogenesis and molecular genetics: Recent update. World J Gastroenterol. 23:3978–3998. 2017. View Article : Google Scholar : PubMed/NCBI
3	Hundal R and Shaffer EA: Gallbladder cancer: Epidemiology and outcome. Clin Epidemiol. 6:99–109. 2014.PubMed/NCBI
4	Farr RJ, Joglekar MV and Hardikar AA: Circulating microRNAs in diabetes progression: Discovery, validation, and research translation. Exp Suppl. 106:215–244. 2015.PubMed/NCBI
5	Rupaimoole R and Slack FJ: MicroRNA therapeutics: Towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov. 16:203–222. 2017. View Article : Google Scholar : PubMed/NCBI
6	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
7	Xie Y, Li F, Li Z and Shi Z: miR-135a suppresses migration of gastric cancer cells by targeting TRAF5-mediated NF-κB activation. Onco Targets Ther. 12:975–984. 2019. View Article : Google Scholar : PubMed/NCBI
8	Xu B, Lu X, Zhao Y, Liu C, Huang X, Chen S, Zhu W, Zhang L and Chen M: MicroRNA-135a induces prostate cancer cell apoptosis via inhibition of STAT6. Oncol Lett. 17:1889–1895. 2019.PubMed/NCBI
9	Shi HZ, Wang DN, Xu F, Teng JH and Wang YL: miR-135a inhibits glioma cell proliferation and invasion by directly targeting FOXO1. Eur Rev Med Pharmacol Sci. 22:4215–4223. 2018.PubMed/NCBI
10	Lv YP, Shi W, Liu HX, Kong XJ and Dai DL: Identification of miR-146b-5p in tissues as a novel biomarker for prognosis of gallbladder carcinoma. Eur Rev Med Pharmacol Sci. 21:518–522. 2017.PubMed/NCBI
11	Peng HH, Zhang YD, Gong LS, Liu WD and Zhang Y: Increased expression of microRNA-335 predicts a favorable prognosis in primary gallbladder carcinoma. Onco Targets Ther. 6:1625–1630. 2013.PubMed/NCBI
12	Bao RF, Shu YJ, Hu YP, Wang XA, Zhang F, Liang HB, Ye YY, Li HF, Xiang SS, Weng H, et al: miR-101 targeting ZFX suppresses tumor proliferation and metastasis by regulating the MAPK/Erk and Smad pathways in gallbladder carcinoma. Oncotarget. 7:22339–22354. 2016. View Article : Google Scholar : PubMed/NCBI
13	Zhou H, Guo W, Zhao Y, Wang Y, Zha R, Ding J, Liang L, Yang G, Chen Z, Ma B and Yin B: MicroRNA-135a acts as a putative tumor suppressor by directly targeting very low density lipoprotein receptor in human gallbladder cancer. Cancer Sci. 105:956–965. 2014. View Article : Google Scholar : PubMed/NCBI
14	Yang G and Yin B: Therapeutic effects of long-circulating miR-135a-containing cationic immunoliposomes against gallbladder carcinoma. Sci Rep. 7:59822017. View Article : Google Scholar : PubMed/NCBI
15	Fiedler U and Augustin HG: Angiopoietins: A link between angiogenesis and inflammation. Trends Immunol. 27:552–558. 2006. View Article : Google Scholar : PubMed/NCBI
16	Huang H, Bhat A, Woodnutt G and Lappe R: Targeting the ANGPT-TIE2 pathway in malignancy. Nat Rev Cancer. 10:575–585. 2010. View Article : Google Scholar : PubMed/NCBI
17	Chen Z, Zhu S, Hong J, Soutto M, Peng D, Belkhiri A, Xu Z and El-Rifai W: Gastric tumour-derived ANGPT2 regulation by DARPP-32 promotes angiogenesis. Gut. 65:925–934. 2016. View Article : Google Scholar : PubMed/NCBI
18	Jary M, Vernerey D, Lecomte T, Dobi E, Ghiringhelli F, Monnien F, Godet Y, Kim S, Bouché O, Fratte S, et al: Prognostic value of angiopoietin-2 for death risk stratification in patients with metastatic colorectal carcinoma. Cancer Epidemiol Biomarkers Prev. 24:603–612. 2015. View Article : Google Scholar : PubMed/NCBI
19	Dreikhausen L, Blank S, Sisic L, Heger U, Weichert W, Jäger D, Bruckner T, Giese N, Grenacher L, Falk C, et al: Association of angiogenic factors with prognosis in esophageal cancer. BMC Cancer. 15:1212015. View Article : Google Scholar : PubMed/NCBI
20	Chen J, Yu Y, Chen X, He Y, Hu Q, Li H, Han Q, Ren F, Li J, Li C, et al: MiR-139-5p is associated with poor prognosis and regulates glycolysis by repressing PKM2 in gallbladder carcinoma. Cell Prolif. 51:e125102018. View Article : Google Scholar : PubMed/NCBI
21	Sun S, Wang R, Yi S, Li S, Wang L and Wang J: Roles of the microRNA3383p/NOVA1 axis in retinoblastoma. Mol Med Rep. 23:3942021. View Article : Google Scholar : PubMed/NCBI
22	Ma Y, Ma L, Guo Q and Zhang S: Expression of bone morphogenetic protein-2 and its receptors in epithelial ovarian cancer and their influence on the prognosis of ovarian cancer patients. J Exp Clin Cancer Res. 29:852010. View Article : Google Scholar : PubMed/NCBI
23	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
24	Ma DJ, Cao Z, Wang BS and Sun YL: Effect of silencing hepatocyte growth factor receptor c-Met expression on biological characteristics of colon cancer cells. Zhonghua Zhong Liu Za Zhi. 42:362–368. 2020.(In Chinese). PubMed/NCBI
25	Liu Y, Fu X, Wang X, Liu Y and Song X: Long non-coding RNA OIP5-AS1 facilitates the progression of ovarian cancer via the miR-128-3p/CCNG1 axis. Mol Med Rep. 23:3882021. View Article : Google Scholar : PubMed/NCBI
26	Anaya J: OncoLnc: Linking TCGA survival data to mRNAs, miRNAs, and lncRNAs. PeerJ Comput Sci. 2:e672016. View Article : Google Scholar
27	Rebane A and Akdis CA: MicroRNAs in allergy and asthma. Curr Allergy Asthma Rep. 14:4242014. View Article : Google Scholar : PubMed/NCBI
28	Cao Z, Qiu J, Yang G, Liu Y, Luo W, You L, Zheng L and Zhang T: MiR-135a biogenesis and regulation in malignancy: A new hope for cancer research and therapy. Cancer Biol Med. 17:569–582. 2020. View Article : Google Scholar : PubMed/NCBI
29	Yang C, Zheng X, Ye K, Sun Y, Lu Y, Fan Q and Ge H: miR-135a inhibits the invasion and migration of esophageal cancer stem cells through the hedgehog signaling pathway by targeting Smo. Mol Ther Nucleic Acids. 19:841–852. 2020. View Article : Google Scholar : PubMed/NCBI
30	Shi H, Ji Y, Zhang D, Liu Y and Fang P: MiR-135a inhibits migration and invasion and regulates EMT-related marker genes by targeting KLF8 in lung cancer cells. Biochem Biophys Res Commun. 465:125–130. 2015. View Article : Google Scholar : PubMed/NCBI
31	Chen Y, Zhang J, Wang H, Zhao J, Xu C, Du Y, Luo X, Zheng F, Liu R, Zhang H and Ma D: miRNA-135a promotes breast cancer cell migration and invasion by targeting HOXA10. BMC Cancer. 12:1112012. View Article : Google Scholar : PubMed/NCBI
32	Mao XP, Zhang LS, Huang B, Zhou SY, Liao J, Chen LW, Qiu SP and Chen JX: Mir-135a enhances cellular proliferation through post-transcriptionally regulating PHLPP2 and FOXO1 in human bladder cancer. J Transl Med. 13:862015. View Article : Google Scholar : PubMed/NCBI
33	Ren JW, Li ZJ and Tu C: MiR-135 post-transcriptionally regulates FOXO1 expression and promotes cell proliferation in human malignant melanoma cells. Int J Clin Exp Pathol. 8:6356–6366. 2015.PubMed/NCBI
34	Nagel R, le Sage C, Diosdado B, van der Waal M, Oude Vrielink JA, Bolijn A, Meijer GA and Agami R: Regulation of the adenomatous polyposis coli gene by the miR-135 family in colorectal cancer. Cancer Res. 68:5795–5802. 2008. View Article : Google Scholar : PubMed/NCBI
35	Fukagawa S, Miyata K, Yotsumoto F, Kiyoshima C, Nam SO, Anan H, Katsuda T, Miyahara D, Murata M, Yagi H, et al: MicroRNA-135a-3p as a promising biomarker and nucleic acid therapeutic agent for ovarian cancer. Cancer Sci. 108:886–896. 2017. View Article : Google Scholar : PubMed/NCBI
36	Xu B, Tao T, Wang Y, Fang F, Huang Y, Chen S, Zhu W and Chen M: hsa-miR-135a-1 inhibits prostate cancer cell growth and migration by targeting EGFR. Tumour Biol. 37:14141–14151. 2016. View Article : Google Scholar : PubMed/NCBI
37	Tang Y, Cao G, Zhao G, Wang C and Qin Q: LncRNA differentiation antagonizing non-protein coding RNA promotes proliferation and invasion through regulating miR-135a/NLRP37 axis in pancreatic cancer. Invest New Drugs. 38:714–721. 2020. View Article : Google Scholar : PubMed/NCBI
38	Rakoczy PE, Brankov M, Fonceca A, Zaknich T, Rae BC and Lai CM: Enhanced recombinant adeno-associated virus-mediated vascular endothelial growth factor expression in the adult mouse retina: A potential model for diabetic retinopathy. Diabetes. 52:857–863. 2003. View Article : Google Scholar : PubMed/NCBI
39	Song Z, Wu Y, Yang J, Yang D and Fang X: Progress in the treatment of advanced gastric cancer. Tumour Biol. 39:10104283177146262017. View Article : Google Scholar : PubMed/NCBI
40	Rigamonti N, Kadioglu E, Keklikoglou I, Wyser Rmili C, Leow CC and De Palma M: Role of angiopoietin-2 in adaptive tumor resistance to VEGF signaling blockade. Cell Rep. 8:696–706. 2014. View Article : Google Scholar : PubMed/NCBI
41	Xu Y, Zhang Y, Wang Z, Chen N, Zhou J and Liu L: The role of serum angiopoietin-2 levels in progression and prognosis of lung cancer: A meta-analysis. Medicine (Baltimore). 96:e80632017. View Article : Google Scholar : PubMed/NCBI