Cancer-associated fibroblasts enhance the migration ability of ovarian cancer cells by increasing EZH2 expression

Xu,Linjuan; Deng,Qingchun; Pan,Yinglian; Peng,Minggang; Wang,Xiaoling; Song,Limian; Xiao,Man; Wang,Zehua

doi:10.3892/ijmm.2013.1549

Cancer-associated fibroblasts enhance the migration ability of ovarian cancer cells by increasing EZH2 expression

Authors:
- Linjuan Xu
- Qingchun Deng
- Yinglian Pan
- Minggang Peng
- Xiaoling Wang
- Limian Song
- Man Xiao
- Zehua Wang
View Affiliations

Affiliations: Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China, Department of Rehabilitation, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China
Published online on: November 7, 2013 https://doi.org/10.3892/ijmm.2013.1549
Pages: 91-96

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 tumor microenvironment is thought to affect malignant transformation and tumor progression. The histone methyltransferase, enhancer of zeste homologue 2 (EZH2), has recently been suggested to play a critical role in the tumorigenesis of several types of human cancer. The aim of this study was to investigate the effects of cancer-associated fibroblasts (CAFs) on the expression of EZH2 and the migration ability of ovarian cancer cells, in order to explore the link between the tumor microenvironment and epigenetic regulation. The ovarian cancer cell lines, A2780, SKOV3 and ES2, were indirectly co-cultured with primary ovarian CAFs or normal fibroblasts (NFs). The migration ability of the ovarian cancer cells was determined by Transwell migration assay. The expression levels of EZH2 were assessed by quantitative reverse transcription PCR (qRT-PCR) and western blot analysis. The A2780-shEZH2 cells (A2780 cells transfected with shRNA targeting EZH2) were indirectly co-cultured with CAFs or NFs, and the changes in the expression levels of EZH2 and the migration ability of the cells were detected. The migration ability of the A2780, SKOV3 and ES2 cells co-cultured with CAFs was significantly enhanced (P<0.05) compared with the NF group and the cells cultured alone. The expression of EZH2 in the A2780, SKOV3 and ES2 cells was significantly increased following co-culture with CAFs (P<0.001) compared with the cells cultured alone but not those cultured with NFs. The migration ability of the A2780-shEZH2 cells was not significantly increased following co-culture with CAFs (P>0.05). Our data indicate that CAFs enhance the migration ability of ovarian cancer cells partly by increasing EZH2 expression.

View Figures

View References

1	Sarojini S, Tamir A, Lim H, et al: Early detection biomarkers for ovarian cancer. J Oncol. 2012:7090492012. View Article : Google Scholar : PubMed/NCBI
2	Bijron JG, Bol GM, Verheijen RH and van Diest PJ: Epigenetic biomarkers in the diagnosis of ovarian cancer. Expert Opin Med Diagn. 6:421–438. 2012. View Article : Google Scholar : PubMed/NCBI
3	Naora H and Montell DJ: Ovarian cancer metastasis: integrating insights from disparate model organisms. Nat Rev Cancer. 5:355–366. 2005. View Article : Google Scholar : PubMed/NCBI
4	Chou J and Werb Z: MicroRNAs play a big role in regulating ovarian cancer-associated fibroblasts and the tumor microenvironment. Cancer Discov. 2:1078–1080. 2012. View Article : Google Scholar : PubMed/NCBI
5	Mitra AK, Zillhardt M, Hua Y, et al: MicroRNAs reprogram normal fibroblasts into cancer-associated fibroblasts in ovarian cancer. Cancer Discov. 2:1100–1108. 2012. View Article : Google Scholar : PubMed/NCBI
6	Finak G, Bertos N, Pepin F, et al: Stromal gene expression predicts clinical outcome in breast cancer. Nat Med. 14:518–527. 2008. View Article : Google Scholar : PubMed/NCBI
7	Wintzell M, Hjerpe E, Avall Lundqvist E and Shoshan M: Protein markers of cancer-associated fibroblasts and tumor-initiating cells reveal subpopulations in freshly isolated ovarian cancer ascites. BMC Cancer. 12:3592012. View Article : Google Scholar
8	Ko SY, Barengo N, Ladanyi A, et al: HOXA9 promotes ovarian cancer growth by stimulating cancer-associated fibroblasts. J Clin Invest. 122:3603–3617. 2012. View Article : Google Scholar : PubMed/NCBI
9	Schauer IG, Sood AK, Mok S and Liu J: Cancer-associated fibroblasts and their putative role in potentiating the initiation and development of epithelial ovarian cancer. Neoplasia. 13:393–405. 2011.PubMed/NCBI
10	Zhang Y, Tang H, Cai J, et al: Ovarian cancer-associated fibroblasts contribute to epithelial ovarian carcinoma metastasis by promoting angiogenesis, lymphangiogenesis and tumor cell invasion. Cancer Lett. 303:47–55. 2011. View Article : Google Scholar
11	Cai J, Tang H, Xu L, et al: Fibroblasts in omentum activated by tumor cells promote ovarian cancer growth, adhesion and invasiveness. Carcinogenesis. 33:20–29. 2012. View Article : Google Scholar : PubMed/NCBI
12	Cao R, Wang L, Wang H, et al: Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science. 298:1039–1043. 2002. View Article : Google Scholar : PubMed/NCBI
13	Kirmizis A, Bartley SM, Kuzmichev A, et al: Silencing of human polycomb target genes is associated with methylation of histone H3 Lys 27. Genes Dev. 18:1592–1605. 2004. View Article : Google Scholar : PubMed/NCBI
14	Simon JA and Lange CA: Roles of the EZH2 histone methyltransferase in cancer epigenetics. Mutat Res. 647:21–29. 2008. View Article : Google Scholar : PubMed/NCBI
15	Hu S, Yu L, Li Z, et al: Overexpression of EZH2 contributes to acquired cisplatin resistance in ovarian cancer cells in vitro and in vivo. Cancer Biol Ther. 10:788–795. 2010. View Article : Google Scholar : PubMed/NCBI
16	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
17	Sehouli J, Loddenkemper C, Cornu T, et al: Epigenetic quantification of tumor-infiltrating T-lymphocytes. Epigenetics. 6:236–246. 2011. View Article : Google Scholar : PubMed/NCBI
18	Shahrzad S, Bertrand K, Minhas K and Coomber BL: Induction of DNA hypomethylation by tumor hypoxia. Epigenetics. 2:119–125. 2007. View Article : Google Scholar : PubMed/NCBI
19	Kalluri R and Zeisberg M: Fibroblasts in cancer. Nat Rev Cancer. 6:392–401. 2006. View Article : Google Scholar
20	Shimoda M, Mellody KT and Orimo A: Carcinoma-associated fibroblasts are a rate-limiting determinant for tumour progression. Semin Cell Dev Biol. 21:19–25. 2010. View Article : Google Scholar : PubMed/NCBI
21	Xing F, Saidou J and Watabe K: Cancer associated fibroblasts (CAFs) in tumor microenvironment. Front Biosci (Landmark Ed). 15:166–179. 2010. View Article : Google Scholar : PubMed/NCBI
22	Li H, Cai Q, Godwin AK and Zhang R: Enhancer of zeste homolog 2 promotes the proliferation and invasion of epithelial ovarian cancer cells. Mol Cancer Res. 8:1610–1618. 2010. View Article : Google Scholar : PubMed/NCBI
23	Matsumoto K and Nakamura T: Hepatocyte growth factor and the Met system as a mediator of tumor-stromal interactions. Int J Cancer. 119:477–483. 2006. View Article : Google Scholar : PubMed/NCBI
24	Orimo A, Gupta PB, Sgroi DC, et al: Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell. 121:335–348. 2005. View Article : Google Scholar
25	Lu C, Han HD, Mangala LS, et al: Regulation of tumor angiogenesis by EZH2. Cancer Cell. 18:185–197. 2010. View Article : Google Scholar : PubMed/NCBI