MicroRNA‑15a‑5p inhibits endometrial carcinoma proliferation, invasion and migration via downregulation of VEGFA and inhibition of the Wnt/β‑catenin signaling pathway

Wang,Honggang; Yang,Qingju; Li,Jieping; Chen,Wenping; Jin,Xiao; Wang,Yaowen

doi:10.3892/ol.2021.12570

MicroRNA‑15a‑5p inhibits endometrial carcinoma proliferation, invasion and migration via downregulation of VEGFA and inhibition of the Wnt/β‑catenin signaling pathway

Authors:
- Honggang Wang
- Qingju Yang
- Jieping Li
- Wenping Chen
- Xiao Jin
- Yaowen Wang
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Affiliations: Department of Clinical Laboratory, Weifang People's Hospital, Weifang, Shandong 261041, P.R. China, Department of Gynaecology, Linyi People's Hospital, Dezhou, Shandong 251500, P.R. China, Department of Anesthesiology, Qingdao Hospital of Traditional Chinese Medicine, Qingdao University, Qingdao, Shandong 266033, P.R. China, Department of Cardiothoracic Surgery, The People's Hospital of Zhangqiu Area, Jinan, Shandong 250200, P.R. China, Department of Rehabilitation Medicine, The People's Hospital of Zhangqiu Area, Jinan, Shandong 250200, P.R. China
Published online on: February 22, 2021 https://doi.org/10.3892/ol.2021.12570
Article Number: 310
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Endometrial carcinoma (EC) is one of the most common malignant gynecological tumors. Dysregulation of microRNAs (miRNAs/miRs) is frequently identified in human tumors, playing key regulatory roles in tumor growth and metastasis. The present study aimed to explore the functions and potential mechanisms of miR‑15a‑5p in EC progression. RT‑qPCR was used to detect the expression levels of miR‑15a‑5p and vascular endothelial growth factor A (VEGFA) mRNA. Western blot analysis was performed to examine the expression of related proteins. Functional assays, including proliferation and Transwell assays were performed to determine the roles of miR‑15a‑5p in EC progression. TargetScan and luciferase reporter assays were used to explore the potential target genes of miR‑15a‑5p. The results revealed that miR‑15a‑5p was underexpressed in EC tissue samples in comparison with that in matched normal tissue samples. The expression level of miR‑15a‑5p was associated with the clinicopathologic characteristics of EC patients. Notably, both in vitro and in vivo assays revealed that miR‑15a‑5p upregulation significantly inhibited EC growth and metastasis. Furthermore, bioinformatics analysis and dual luciferase reporter assay indicated that VEGFA was a candidate target of miR‑15a‑5p. Mechanistic investigation revealed that miR‑15a‑5p inhibited EC development via regulation of Wnt/β‑catenin pathway and targeting of VEGFA. In summary, the present results demonstrated that miR‑15a‑5p could inhibit EC development and may serve as a promising therapeutic biomarker in EC.

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1	Mahecha AM and Wang H: The influence of vascular endothelial growth factor-A and matrix metalloproteinase-2 and −9 in angiogenesis, metastasis, and prognosis of endometrial cancer. Onco Targets Ther. 10:4617–4624. 2017. View Article : Google Scholar : PubMed/NCBI
2	Ray M and Fleming G: Management of advanced-stage and recurrent endometrial cancer. Semin Oncol. 36:145–154. 2009. View Article : Google Scholar : PubMed/NCBI
3	Davidson BA, Foote J, Clark LH, Broadwater G, Ehrisman J, Gehrig P, Graybill W, Alvarez Secord A and Havrilesky LJ: Tumor grade and chemotherapy response in endometrioid endometrial cancer. Gynecol Oncol Rep. 17:3–6. 2016. View Article : Google Scholar : PubMed/NCBI
4	Chen HX, Xu XX, Tan BZ, Zhang Z and Zhou XD: MicroRNA-29b inhibits angiogenesis by targeting VEGFA through the MAPK/ERK and PI3K/Akt signaling pathways in endometrial carcinoma. Cell Physiol Biochem. 41:933–946. 2017. View Article : Google Scholar : PubMed/NCBI
5	Pasquinelli AE: MicroRNAs and their targets: Recognition, regulation and an emerging reciprocal relationship. Nat Rev Genet. 13:271–282. 2012. View Article : Google Scholar : PubMed/NCBI
6	Krist B, Florczyk U, Pietraszek-Gremplewicz K, Jozkowicz A and Dulak J: The Role of miR-378a in metabolism, angiogenesis, and muscle biology. Int J Endocrinol. 2015:2817562015. View Article : Google Scholar : PubMed/NCBI
7	Srivastava AK, Banerjee A, Cui T, Han C, Cai S, Liu L, Wu D, Cui R, Li Z, Zhang X, et al: Inhibition of miR-328-3p impairs cancer stem cell function and prevents metastasis in ovarian cancer. Cancer Res. 79:2314–2326. 2019. View Article : Google Scholar : PubMed/NCBI
8	Kouri FM, Hurley LA, Daniel WL, Day ES, Hua Y, Hao L, Peng CY, Merkel TJ, Queisser MA, Ritner C, et al: miR-182 integrates apoptosis, growth, and differentiation programs in glioblastoma. Genes Dev. 29:732–745. 2015. View Article : Google Scholar : PubMed/NCBI
9	Zhang FB, Du Y, Tian Y, Ji ZG and Yang PQ: miR-1299 functions as a tumor suppressor to inhibit the proliferation and metastasis of prostate cancer by targeting NEK2. Eur Rev Med Pharmacol Sci. 23:530–538. 2019.PubMed/NCBI
10	Peng H, Wang L, Su Q, Yi K, Du J and Wang Z: miR-31-5p promotes the cell growth, migration and invasion of colorectal cancer cells by targeting NUMB. Biomed Pharmacother. 109:208–216. 2019. View Article : Google Scholar : PubMed/NCBI
11	Zhen Z, Dong F, Shen H, Wang QG, Yang L and Hu J: miR-524 inhibits cell proliferation and induces cell apoptosis in thyroid cancer via targeting SPAG9. Eur Rev Med Pharmacol Sci. 22:3812–3818. 2018.PubMed/NCBI
12	Zheng X, Xu K, Zhu L, Mao M, Zhang F and Cui L: miR-486-5p Act as a biomarker in endometrial carcinoma: Promotes cell proliferation, migration, invasion by targeting MARK1. Onco Targets Ther. 13:4843–4853. 2020. View Article : Google Scholar : PubMed/NCBI
13	Wang C and Liu B: miR-101-3p induces autophagy in endometrial carcinoma cells by targeting EZH2. Arch Gynecol Obstet. 297:1539–1548. 2018. View Article : Google Scholar : PubMed/NCBI
14	Zhang HC, Han YY, Zhang XM, Xiao N, Jiang T, Zhu S, Wang EP and Chen CB: miR-522 facilitates the prosperities of endometrial carcinoma cells by directly binding to monoamine oxidase B. Kaohsiung J Med Sci. 35:598–606. 2019. View Article : Google Scholar : PubMed/NCBI
15	Sales CB, Buim ME, de Souza RO, de Faro Valverde L, Mathias Machado MC, Reis MG, Soares FA, Ramos EA and Gurgel Rocha CA: Elevated VEGFA mRNA levels in oral squamous cell carcinomas and tumor margins: A preliminary study. J Oral Pathol Med. 45:481–485. 2016. View Article : Google Scholar : PubMed/NCBI
16	Claesson-Welsh L and Welsh M: VEGFA and tumour angiogenesis. J Intern Med. 273:114–127. 2013. View Article : Google Scholar : PubMed/NCBI
17	Peng T, Li Z, Li D and Wang S: MACC1 promotes angiogenesis in cholangiocarcinoma by upregulating VEGFA. Onco Targets Ther. 12:1893–1903. 2019. View Article : Google Scholar : PubMed/NCBI
18	Horwitz E, Stein I, Andreozzi M, Nemeth J, Shoham A, Pappo O, Schweitzer N, Tornillo L, Kanarek N, Quagliata L, et al: Human and mouse VEGFA-amplified hepatocellular carcinomas are highly sensitive to sorafenib treatment. Cancer Discov. 4:730–743. 2014. View Article : Google Scholar : PubMed/NCBI
19	Luo X and Feng GS: VEGFA genomic amplification tailors treatment of HCCs with sorafenib. Cancer Discov. 4:640–641. 2014. View Article : Google Scholar : PubMed/NCBI
20	Chen X, Xu X, Pan B, Zeng K, Xu M, Liu X, He B, Pan Y, Sun H and Wang S: miR-150-5p suppresses tumor progression by targeting VEGFA in colorectal cancer. Aging (Albany NY). 10:3421–3437. 2018. View Article : Google Scholar : PubMed/NCBI
21	Guset G, Costi S, Lazar E, Dema A, Cornianu M, Vernic C and Păiuşan L: Expression of vascular endothelial growth factor (VEGF) and assessment of microvascular density with CD34 as prognostic markers for endometrial carcinoma. Rom J Morphol Embryol. 51:677–682. 2010.PubMed/NCBI
22	Panda H, Pelakh L, Chuang TD, Luo X, Bukulmez O and Chegini N: Endometrial miR-200c is altered during transformation into cancerous states and targets the expression of ZEBs, VEGFA, FLT1, IKKβ, KLF9, and FBLN5. Reprod Sci. 19:786–796. 2012. 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	Garcia DM, Baek D, Shin C, Bell GW, Grimson A and Bartel DP: Weak seed-pairing stability and high target-site abundance decrease the proficiency of lsy-6 and other microRNAs. Nat Struct Mol Biol. 18:1139–1146. 2011. View Article : Google Scholar : PubMed/NCBI
25	Grimson A, Farh KK, Johnston WK, Garrett-Engele P, Lim LP and Bartel DP: MicroRNA targeting specificity in mammals: Determinants beyond seed pairing. Mol Cell. 27:91–105. 2007. View Article : Google Scholar : PubMed/NCBI
26	SGO Clinical Practice Endometrial Cancer Working Group, ; Burke WM, Orr J, Leitao M, Salom E, Gehrig P, Olawaiye AB, Brewer M, Boruta D, Villella J, et al: Endometrial cancer: A review and current management strategies: Part I. Gynecol Oncol. 134:385–392. 2014. View Article : Google Scholar : PubMed/NCBI
27	Yang CH, Zhang XY, Zhou LN, Wan Y, Song LL, Gu WL, Liu R, Ma YN, Meng HR, Tian YL and Zhang Y: LncRNA SNHG8 participates in the development of endometrial carcinoma through regulating c-MET expression by miR-152. Eur Rev Med Pharmacol Sci. 22:1629–1637. 2018.PubMed/NCBI
28	Teague EM, Print CG and Hull ML: The role of microRNAs in endometriosis and associated reproductive conditions. Hum Reprod Update. 16:142–165. 2010. View Article : Google Scholar : PubMed/NCBI
29	Lamouille S, Connolly E, Smyth JW, Akhurst RJ and Derynck R: TGF-β-induced activation of mTOR complex 2 drives epithelial-mesenchymal transition and cell invasion. J Cell Sci. 125:1259–1273. 2012. View Article : Google Scholar : PubMed/NCBI
30	Bullock MD, Sayan AE, Packham GK and Mirnezami AH: MicroRNAs: Critical regulators of epithelial to mesenchymal (EMT) and mesenchymal to epithelial transition (MET) in cancer progression. Biol Cell. 104:3–12. 2012. View Article : Google Scholar : PubMed/NCBI
31	Nusse R and Clevers H: Wnt/beta-catenin signaling, disease, and emerging therapeutic modalities. Cell. 169:985–999. 2017. View Article : Google Scholar : PubMed/NCBI
32	Majidinia M, Aghazadeh J, Jahanban-Esfahlani R and Yousefi B: The roles of Wnt/beta-catenin pathway in tissue development and regenerative medicine. J Cell Physiol. 233:5598–5612. 2018. View Article : Google Scholar : PubMed/NCBI
33	Shen YN, He HG, Shi Y, Cao J, Yuan JY, Wang ZC, Shi CF, Zhu N, Wei YP, Liu F, et al: Kruppel-like factor 8 promotes cancer stem cell-like traits in hepatocellular carcinoma through Wnt/β-catenin signaling. Mol Carcinog. 56:751–760. 2017. View Article : Google Scholar : PubMed/NCBI
34	Shen Q, He T and Yuan H: Hsa_circ_0002577 promotes endometrial carcinoma progression via regulating miR-197/CTNND1 axis and activating Wnt/β-catenin pathway. Cell Cycle. 18:1229–1240. 2019. View Article : Google Scholar : PubMed/NCBI
35	Park SA, Kim LK, Kim YT, Heo TH and Kim HJ: Long non-coding RNA steroid receptor activator promotes the progression of endometrial cancer via Wnt/β-catenin signaling pathway. Int J Biol Sci. 16:99–115. 2020. View Article : Google Scholar : PubMed/NCBI
36	Chen P, Xing T, Wang Q, Liu A, Liu H, Hu Y, Ji Y, Song Y and Wang D: MicroRNA-202 inhibits cell migration and invasion through targeting FGF2 and inactivating Wnt/β-catenin signaling in endometrial carcinoma. Biosci Rep. 39:BSR201906802019. View Article : Google Scholar : PubMed/NCBI
37	Kontos CK, Tsiakanikas P, Avgeris M, Papadopoulos IN and Scorilas A: miR-15a-5p, A novel prognostic biomarker, predicting recurrent colorectal adenocarcinoma. Mol Diagn Ther. 21:453–464. 2017. View Article : Google Scholar : PubMed/NCBI
38	Long J, Jiang C, Liu B, Fang S and Kuang M: MicroRNA-15a-5p suppresses cancer proliferation and division in human hepatocellular carcinoma by targeting BDNF. Tumour Biol. 37:5821–5828. 2016. View Article : Google Scholar : PubMed/NCBI