MicroRNA‑206 regulates the epithelial‑mesenchymal transition and inhibits the invasion and metastasis of prostate cancer cells by targeting Annexin A2

Yang,Ning; Wang,Ling; Liu,Jun; Liu,Li; Huang,Jiangbo; Chen,Xian; Luo,Zhigang

doi:10.3892/ol.2018.8395

MicroRNA‑206 regulates the epithelial‑mesenchymal transition and inhibits the invasion and metastasis of prostate cancer cells by targeting Annexin A2

Authors:
- Ning Yang
- Ling Wang
- Jun Liu
- Li Liu
- Jiangbo Huang
- Xian Chen
- Zhigang Luo
View Affiliations

Affiliations: Department of Urology, The Second Affiliated Hospital of University of South China, Hengyang, Hunan 421001, P.R. China, Department of Pharmacology, The Medical School of Hunan University of Environment and Biology, Hengyang, Hunan 421001, P.R. China
Published online on: March 30, 2018 https://doi.org/10.3892/ol.2018.8395
Pages: 8295-8302
Copyright: © Yang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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

The present study investigated the molecular mechanism by which microRNA‑206 (miR‑206) targets Annexin A2 (ANXA2) expression and inhibits the invasion and metastasis of prostatic cancer cells through regulation of the epithelial‑mesenchymal transition (EMT). Using bioinformatics analysis, miR‑206 was identified as the most promising candidate miRNA that targeted ANXA2. Prostate tissue specimens from 60 patients with prostate cancer, 30 patients with metastatic prostate cancer and 20 patients with benign prostatic hyperplasia (BPH) were examined for ANXA2 protein expression by immunohistochemistry and western blotting and for miR‑206 expression by reverse transcription‑quantitative polymerase chain reaction. Additionally, human prostate cancer PC‑3 cells were transfected with miR‑206 mimics, miR‑206 inhibitors or a negative control sequence, and expression of ANXA2, E‑cadherin and N‑cadherin was detected by western blotting. Transwell assays were performed to determine the effect of altered miR‑206 expression on the invasive behavior of PC‑3 cells. Bioinformatics analysis predicted complementary binding between miR‑206 and ANXA2 mRNA. ANXA2 protein expression was detected in a significantly higher proportion of BPH tissues (95%, 19/20) when compared with prostate cancer tissues (51.7%, 31/60; P<0.05). Similarly, ANXA2 was expressed in a significantly higher proportion of metastatic prostate cancer samples than that of prostate cancer samples (P<0.05). Expression of miR‑206 was higher than that of ANXA2 in prostate cancer samples, but lower in BPH samples. Inhibition of miR‑206 expression in PC‑3 cells upregulated ANXA2 and E‑cadherin protein expression levels, downregulated N‑cadherin and vimentin, and promoted cell invasion in vitro. These data suggested that binding between miRNA‑206 and ANXA2 mRNA may regulate EMT signaling, thereby suppressing the invasion and metastasis of prostatic cancer cells.

View Figures

View References

1	Nandana S and Chung LW: Prostate cancer progression and metastasis: Potential regulatory pathways for therapeutic targeting. Am J Clin Exp Urol. 2:92–101. 2014.PubMed/NCBI
2	Simons JW: Prostate cancer immunotherapy: Beyond immunity to curability. Cancer Immunol Res. 2:1034–1043. 2014. View Article : Google Scholar : PubMed/NCBI
3	Monastyrskaya K: Functional association between regulatory RNAs and the annexins. Int J Mol Sci. 19:E5912018. View Article : Google Scholar : PubMed/NCBI
4	Mussunoor S and Murray GI: The role of annexins in tumour development and progression. J Pathol. 216:131–140. 2008. View Article : Google Scholar : PubMed/NCBI
5	Mortimer JC, Laohavisit A, Macpherson N, Webb A, Brownlee C, Battey NH and Davies JM: Annexins: Multifunctional components of growth and adaptation. J Exp Bot. 59:533–544. 2008. View Article : Google Scholar : PubMed/NCBI
6	Zhang M, Chen D, Zhen Z, Ao J, Yuan X and Gao X: Annexin A2 positively regulates milk synthesis and proliferation of bovine mammary epithelial cells through the mTOR signaling pathway. J Cell Physiol. 233:2464–2475. 2018. View Article : Google Scholar : PubMed/NCBI
7	Sun MY, Xing RH, Gao XJ, Yu X, He HM, Gao N, Shi HY, Hu YY, Wang QX, Xu JH and Hou YC: ANXA2 regulates the behavior of SGC-7901 cells. Asian Pac J Cancer Prev. 14:6007–6012. 2013. View Article : Google Scholar : PubMed/NCBI
8	Jeon YR, Kim SY, Lee EJ, Kim YN, Noh DY, Park SY and Moon A: Identification of annexin II as a novel secretory biomarker for breast cancer. Proteomics. 13:3145–3156. 2013. View Article : Google Scholar : PubMed/NCBI
9	Lokman NA, Elder AS, Ween MP, Pyragius CE, Hoffmann P, Oehler MK and Ricciardelli C: Annexin A2 is regulated by ovarian cancer-peritoneal cell interactions and promotes metastasis. Oncotarget. 4:1199–1211. 2013. View Article : Google Scholar : PubMed/NCBI
10	Zhang HJ, Yao DF, Yao M, Huang H, Wang L, Yan MJ, Yan XD, Gu X, Wu W and Lu SL: Annexin A2 silencing inhibits invasion, migration, and tumorigenic potential of hepatoma cells. World J Gastroenterol. 19:3792–3801. 2013. View Article : Google Scholar : PubMed/NCBI
11	Zare M, Bastami M, Solali S and Alivand MR: Aberrant miRNA promoter methylation and EMT-involving miRNAs in breast cancer metastasis: Diagnosis and therapeutic implications. J Cell Physiol. 233:3729–3744. 2018. View Article : Google Scholar : PubMed/NCBI
12	Feng J, Fu Z, Guo J, Lu W, Wen K, Chen W, Wang H, Wei J and Zhang S: Overexpression of peroxiredoxin 2 inhibits TGF-β1-induced epithelial-mesenchymal transition and cell migration in colorectal cancer. Mol Med Rep. 10:867–873. 2014. View Article : Google Scholar : PubMed/NCBI
13	Bezdenezhnykh N, Semesiuk N, Lykhova O, Zhylchuk V and Kudryavets Y: Impact of stromal cell components of tumor microenvironment on epithelial-mesenchymal transition in breast cancer cells. Exp Oncol. 36:72–78. 2014.PubMed/NCBI
14	Mou H, Yu L, Zheng X, Liao Q, Hou X and Wu Y: p16 gene expression in pancreatic cancer tissue and its importance in diagnosis. J Biol Regul Homeost Agents. 31:1043–1047. 2017.PubMed/NCBI
15	Luo S, Xie C, Wu P, He J, Tang Y, Xu J and Zhao S: Annexin A2 is an independent prognostic biomarker for evaluating the malignant progression of laryngeal cancer. Exp Ther Med. 14:6113–6118. 2017.PubMed/NCBI
16	Murphy AG, Foley K, Rucki AA, Xia T, Jaffee EM, Huang CY and Zheng L: Stromal Annexin A2 expression is predictive of decreased survival in pancreatic cancer. Oncotarget. 8:106405–106414. 2017. View Article : Google Scholar : PubMed/NCBI
17	Shetty P, Patil VS, Mohan R, D'souza LC, Bargale A, Patil BR, Dinesh US, Haridas V and Kulkarni SP: Annexin A2 and its downstream IL-6 and HB-EGF as secretory biomarkers in the differential diagnosis of Her-2 negative breast cancer. Ann Clin Biochem. 54:463–471. 2017. View Article : Google Scholar : PubMed/NCBI
18	Cui JW and Wang YL: Expression and function of Annexin II in lung cancer tissue. Asian Pac J Trop Med. 6:150–152. 2013. View Article : Google Scholar : PubMed/NCBI
19	Dong Z, Yao M, Zhang H, Wang L, Huang H, Yan M, Wu W and Yao D: Inhibition of Annexin A2 gene transcription is a promising molecular target for hepatoma cell proliferation and metastasis. Oncol Lett. 7:28–34. 2014. View Article : Google Scholar : PubMed/NCBI
20	Kirshner J, Schumann D and Shively JE: CEACAM1, a cell-cell adhesion molecule, directly associates with annexin II in a three-dimensional model of mammary morphogenesis. J Bio Chem. 278:50338–50345. 2003. View Article : Google Scholar
21	Yee DS, Narula N, Ramzy I, Boker J, Ahlering TE, Skarecky DW and Ornstein DK: Reduced annexin II protein expression in high-grade prostatic intraepithelial neoplasia and prostate cancer. Arch Pathol Lab Med. 131:902–908. 2007.PubMed/NCBI
22	Ohno Y, Izumi M, Kawamura T, Nishimura T, Mukai K and Tachibana M: Annexin II represents metastatic potential in clear-cell renal cell carcinoma. Br J Cancer. 101:287–294. 2009. View Article : Google Scholar : PubMed/NCBI
23	Zhang W, Zhao P, Xu XL, Cai L, Song ZS, Cao DY, Tao KS, Zhou WP, Chen ZN and Dou KF: Annexin A2 promotes the migration and invasion of human hepatocellular carcinoma cells in vitro by regulating the shedding of CD147-harboring microvesicles from tumor cells. PLoS One. 8:e672682013. View Article : Google Scholar : PubMed/NCBI
24	Oh M, Rhee S, Moon JH, Chae H, Lee S, Kang J and Kim S: Literature-based condition-specific miRNA-mRNA target prediction. PLoS One. 12:e01749992017. View Article : Google Scholar : PubMed/NCBI
25	Dweep H, Sticht C, Pandey P and Gretz N: miRWalk-database: Prediction of possible miRNA binding sites by ‘walking’ the genes of three genomes. J Biomed Inform. 44:839–847. 2011. View Article : Google Scholar : PubMed/NCBI
26	Xiao H, Xiao W, Cao J, Li H, Guan W, Guo X, Chen K, Zheng T, Ye Z, Wang J and Xu H: miR-206 functions as a novel cell cycle regulator and tumor suppressor in clear-cell renal cell carcinoma. Cancer Lett. 374:107–116. 2016. View Article : Google Scholar : PubMed/NCBI
27	Ren XL, He GY, Li XM, Men H, Yi LZ, Lu GF, Xin SN, Wu PX, Li YL, Liao WT, et al: MicroRNA-206 functions as a tumor suppressor in colorectal cancer by targeting FMNL2. J Cancer Res Clin Oncol. 142:581–592. 2016. View Article : Google Scholar : PubMed/NCBI
28	Keklikoglou I, Hosaka K, Bender C, Bott A, Koerner C, Mitra D, Will R, Woerner A, Muenstermann E, 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
29	Chen L, Li YS, Cui J, Ning JN, Wang GS, Qian GS, Lu KZ and Yi B: MiR-206 controls the phenotypic modulation of pulmonary arterial smooth muscle cells induced by serum from rats with hepatopulmonary syndrome by regulating the target gene, annexin A2. Cell Physiol Biochem. 34:1768–1779. 2014. View Article : Google Scholar : PubMed/NCBI
30	Scanlon CS, Van Tubergen EA, Inglehart RC and D'Silva NJ: Biomarkers of epithelial-mesenchymal transition in squamous cell carcinoma. J Dent Res. 92:114–121. 2013. View Article : Google Scholar : PubMed/NCBI
31	Martínez-Ramírez AS, Garay E, García-Carrancá A and Vázquez-Cuevas FG: The P2RY2 receptor induces carcinoma cell migration and EMT through cross-talk with epidermal growth factor receptor. J Cell Biochem. 117:1016–1026. 2016. View Article : Google Scholar : PubMed/NCBI
32	Carvalho-Cruz P, Alisson-Silva F, Todeschini AR and Dias WB: Cellular glycosylation senses metabolic changes and modulates cell plasticity during epithelial to mesenchymal transition. Dev Dyn. 247:481–491. 2018. View Article : Google Scholar : PubMed/NCBI
33	Kaushik NK, Kaushik N, Yoo KC, Uddin N, Kim JS, Lee SJ and Choi EH: Low doses of PEG-coated gold nanoparticles sensitize solid tumors to cold plasma by blocking the PI3K/AKT-driven signaling axis to suppress cellular transformation by inhibiting growth and EMT. Biomaterials. 87:118–130. 2016. View Article : Google Scholar : PubMed/NCBI
34	Yu AQ, Ding Y, Li CL, Yang Y, Yan SR and Li DS: TALEN-induced disruption of Nanog expression results in reduced proliferation, invasiveness and migration, increased chemosensitivity and reversal of EMT in HepG2 cells. Oncol Rep. 35:1657–1663. 2016. View Article : Google Scholar : PubMed/NCBI
35	Chen HN, Yuan K, Xie N, Wang K, Huang Z, Chen Y, Dou Q, Wu M, Nice EC, Zhou ZG and Huang C: PDLIM1 Stabilizes the E-Cadherin/β-Catenin complex to prevent epithelial-mesenchymal transition and metastatic potential of colorectal cancer cells. Cancer Res. 76:1122–1134. 2016. View Article : Google Scholar : PubMed/NCBI