Upregulation of Limk1 caused by microRNA-138 loss aggravates the metastasis of ovarian cancer by activation of Limk1/cofilin signaling

Chen,Puxiang; Zeng,Mengjun; Zhao,Yan; Fang,Xiaolin

doi:10.3892/or.2014.3461

Upregulation of Limk1 caused by microRNA-138 loss aggravates the metastasis of ovarian cancer by activation of Limk1/cofilin signaling

Authors:
- Puxiang Chen
- Mengjun Zeng
- Yan Zhao
- Xiaolin Fang
View Affiliations

Affiliations: Department of Gynecology and Obstetrics, the Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China
Published online on: September 2, 2014 https://doi.org/10.3892/or.2014.3461
Pages: 2070-2076

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

LIM kinase 1 (Limk1) is associated with cell proliferation and metastasis and its dysregulated expression has been observed in many types of cancer. The present study aimed to examine the role of Limk1 in the development of ovarian cancer, as well as the underlying molecular mechanism involved. The results showed that increased Limk1 and decreased miR-138 expression co-existed in ovarian cancer. Furthermore, knockout of Limk1 or the overexpression of miR-138 resulted in reduced cell invasion and migration, while silencing of miR-138 led to enhancement of the invasion and migration of ovarian cancer cells. Cell growth was inhibited by the overexpression of miR-138, although not by the knockout of Limk1. miR-138 directly targeted Limk1 and inhibited ovarian cancer cell growth by PCNA and Bcl-2. Moreover, Limk1/cofilin/p-cofilin is likely a critical signaling pathway involving in miR-138 modulation of ovarian cancer cell metastasis. The results provide evidence supporting miR-138/Limk1 as a novel diagnostic or therapeutic target for ovarian cancer.

View Figures

View References

1	Kigawa J: New strategy for overcoming resistance to chemotherapy of ovarian cancer. Yonago Acta Med. 56:43–50. 2013.PubMed/NCBI
2	Miles GD, Seiler M, Rodriguez L, Rajagopal G and Bhanot G: Identifying microRNA/mRNA dysregulations in ovarian cancer. BMC Res Notes. 5:1642012. View Article : Google Scholar : PubMed/NCBI
3	Ozols RF: Treatment goals in ovarian cancer. Int J Gynecol Cancer. 15(Suppl 1): 3–11. 2005. View Article : Google Scholar : PubMed/NCBI
4	Davila M, Frost AR, Grizzle WE and Chakrabarti R: LIM kinase 1 is essential for the invasive growth of prostate epithelial cells: implications in prostate cancer. J Biol Chem. 278:36868–36875. 2003. View Article : Google Scholar : PubMed/NCBI
5	Zhou Y, Su J, Shi L, Liao Q and Su Q: DADS downregulates the Rac1-ROCK1/PAK1-LIMK1-ADF/cofilin signaling pathway, inhibiting cell migration and invasion. Oncol Rep. 29:605–612. 2013.PubMed/NCBI
6	Nishimura Y, Yoshioka K, Bernard O, Bereczky B and Itoh K: A role of LIM kinase 1/cofilin pathway in regulating endocytic trafficking of EGF receptor in human breast cancer cells. Histochem Cell Biol. 126:627–638. 2006. View Article : Google Scholar : PubMed/NCBI
7	Chen Q, Jiao D, Hu H, et al: Downregulation of LIMK1 level inhibits migration of lung cancer cells and enhances sensitivity to chemotherapy drugs. Oncol Res. 20:491–498. 2013. View Article : Google Scholar : PubMed/NCBI
8	Jang I, Jeon BT, Jeong EA, et al: Pak1/LIMK1/Cofilin pathway contributes to tumor migration and invasion in human non-small sell lung sarcinomas and sell lines. Korean J Physiol Pharmacol. 16:159–165. 2012. View Article : Google Scholar : PubMed/NCBI
9	Zhang W, Gan N and Zhou J: Immunohistochemical investigation of the correlation between LIM kinase 1 expression and development and progression of human ovarian carcinoma. J Int Med Res. 40:1067–1073. 2012. View Article : Google Scholar : PubMed/NCBI
10	Lin H, Dai T, Xiong H, et al: Unregulated miR-96 induces cell proliferation in human breast cancer by downregulating transcriptional factor FOXO3a. PloS One. 5:e157972010. View Article : Google Scholar : PubMed/NCBI
11	Zhang H, Zhang H, Zhao M, et al: MiR-138 inhibits tumor growth through repression of EZH2 in non-small cell lung cancer. Cell Physiol Biochem. 31:56–65. 2013. View Article : Google Scholar : PubMed/NCBI
12	Jin Y, Chen D, Cabay RJ, Wang A, Crowe DL and Zhou X: Role of microRNA-138 as a potential tumor suppressor in head and neck squamous cell carcinoma. Int Rev Cell Mol Biol. 303:357–385. 2013. View Article : Google Scholar : PubMed/NCBI
13	Liu X, Jiang L, Wang A, Yu J, Shi F and Zhou X: MicroRNA-138 suppresses invasion and promotes apoptosis in head and neck squamous cell carcinoma cell lines. Cancer Lett. 286:217–222. 2009. View Article : Google Scholar : PubMed/NCBI
14	Liu X, Wang C, Chen Z, et al: MicroRNA-138 suppresses epithelial-mesenchymal transition in squamous cell carcinoma cell lines. Biochem J. 440:23–31. 2011. View Article : Google Scholar : PubMed/NCBI
15	Wang W, Zhao LJ, Tan YX, Ren H and Qi ZT: MiR-138 induces cell cycle arrest by targeting cyclin D3 in hepatocellular carcinoma. Carcinogenesis. 33:1113–1120. 2012. View Article : Google Scholar : PubMed/NCBI
16	Gong H, Song L, Lin C, et al: Downregulation of miR-138 sustains NF-kappaB activation and promotes lipid raft formation in esophageal squamous cell carcinoma. Clin Cancer Res. 19:1083–1093. 2013. View Article : Google Scholar : PubMed/NCBI
17	Long L, Huang G, Zhu H, Guo Y, Liu Y and Huo J: Down-regulation of miR-138 promotes colorectal cancer metastasis via directly targeting TWIST2. J Transl Med. 11:2752013. View Article : Google Scholar : PubMed/NCBI
18	Wang Q, Tang H, Yin S and Dong C: Downregulation of microRNA-138 enhances the proliferation, migration and invasion of cholangiocarcinoma cells through the upregulation of RhoC/p-ERK/MMP-2/MMP-9. Oncol Rep. 29:2046–2052. 2013.PubMed/NCBI
19	Yeh YM, Chuang CM, Chao KC and Wang LH: MicroRNA-138 suppresses ovarian cancer cell invasion and metastasis by targeting SOX4 and HIF-1alpha. Int J Cancer. 133:867–878. 2013. View Article : Google Scholar : PubMed/NCBI
20	Wan L, Zhang L, Fan K and Wang J: miR-27b targets LIMK1 to inhibit growth and invasion of NSCLC cells. Mol Cell Biochem. 390:85–91. 2014. View Article : Google Scholar : PubMed/NCBI
21	Zhang HS, Zhao JW, Wang H, et al: LIM kinase 1 is required for insulin-dependent cell growth of osteosarcoma cell lines. Mol Med Rep. 9:103–108. 2014.PubMed/NCBI
22	Manetti F: Recent findings confirm LIM domain kinases as emerging target candidates for cancer therapy. Curr Cancer Drug Targets. 12:543–560. 2012. View Article : Google Scholar : PubMed/NCBI
23	Golubovskaya VM, Sumbler B, Ho B, Yemma M and Cance WG: MiR-138 and MiR-135 directly target focal adhesion kinase, inhibit cell invasion, and increase sensitivity to chemotherapy in cancer cells. Anticancer Agents Med Chem. 14:18–28. 2014. View Article : Google Scholar : PubMed/NCBI