Journal of Shandong University (Health Sciences) ›› 2018, Vol. 56 ›› Issue (5): 46-51.doi: 10.6040/j.issn.1671-7554.0.2018.171

Previous Articles    

Effects of simvastatin on TGF-β induced epithelial-to-mesenchymal transition in ovarian cancer

HE Pengjuan1, YAN Lei2, FAN Mingjun1, LIU Xiangbin1, ZHAO Xingbo1   

  1. 1. Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affilicated to Shandong University;
    2. Department of Gynecology, Hospital for Reproductive Medicine Affiliated to Shandong University, Jinan 250021, Shandong, China
  • Received:2018-02-01 Published:2022-09-27

Abstract: Objective To investigate the effects of simvastatin on epithelial-to-mesenchymal transition(EMT)induced by transforming growth factor-β(TGF-β)in ovarian cancer cells(Skvo3 and A2780). Methods The ovarian cancer cells were divided into the control group, simvastatin group, TGF-β group, and simvastatin+TGF-β group. The effects of simvastatin and TGF-β at different concentrations on the cell proliferation were detected with CCK-8. The migration and invasion ability were assessed with wound healing assay and Transwell assay respectively. The changes of EMT and signaling pathway were determined with Western blotting. Results In Skvo3 and A2780 cells, simvastatin reduced cell proliferation and TGF-β-promoted cell proliferation, decreased cell migration and invasion, and reduced TGF-β-induced cell migration and invasion, and reversed EMT and TGF-β-induced EMT. Further experiments showed that simvastatin could reduce the expression of sperm-associated antigen 9(SPAG9)/c-Jun N-terminal kinase(JNK)pathway and reverse TGF-β-induced SPAG9 /JNK pathway(P<0.05). Conclusion Simvastatin can reduce the proliferation, migration, invasion and EMT induced by TGF-β in ovarian cancer cells, possibly by regulating SPAG9 / JNK pathway.

Key words: Ovarian cancer, Simvastatin, Transforming growth factor-β, Epithelial-to-mesenchymal transition, SPAG9/JNK pathway

CLC Number: 

  • R737.31
[1] Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015[J]. CA Cancer J Clin, 2016, 66(2): 115-132.
[2] Chakrabarti R, Hwang J, Andres Blanco M, et al. Elf5 inhibits the epithelial mesenchymal transition in mammary gland development and breastcancer metastasis by transcriptionally repressing Snail2[J]. Nat Cell Biol, 2012, 14(11): 1212-1222.
[3] Zhang HJ, Wang HY, Zhang HT, et al. Transforming growth factor-β1 promotes lung adenocarcinoma invasion and metastasis by epithelial-to-mesenchymal transition[J]. Mol Cell Biochem, 2011, 355(1-2): 309-314.
[4] Rennert G, Rennert HS, Pinchev M, et al. The effect of bisphosphonates on the risk of endometrial and ovarian malignancies[J]. Gynecol Oncol, 2014, 133(2): 309-313.
[5] Fang Z, Tang Y, Fang J, et al. Simvastatin inhibits renal cancer cell growth and metastasis via AKT/mTOR, ERK and JAK2/STAT3 pathway[J]. PLoS One, 2013, 8(5): e62823.
[6] Jagadish N, Rana R, Selvi R, et al. Characterization of a novel human sperm-associated antigen 9(SPAG9)having structural homology with c-Jun N-terminal kinase-interacting protein[J]. Biochem J, 2005, 389(Pt 1): 73-82.
[7] Zhang L, Yan L, Zhao X, et al. SPAG9 promotes endometrial carcinoma cell invasion through regulation of genes related to the epithelial-mesenchymal transition[J]. Eur J Gynaecol Oncol, 2016, 37(3): 312-319.
[8] Mirandola L, J Cannon M, Cobos E, et al. Cancer testis antigens:novel biomarkers and targetable proteins for ovarian cancer[J]. Int Rev Immunol, 2011, 30(2-3): 127-137.
[9] Giancotti FG. Mechanisms governing metastatic dormancy and reactivation[J]. Cell, 2013, 155(4): 750-764.
[10] Thiery JP, Sleeman JP. Complex networks orchestrate epithelial-mesenchymal transitions[J]. Nat Rev Mol Cell Biol, 2006, 7(2): 131-142.
[11] Maeda M, Johnson KR, Wheelock MJ. Cadherin switching: essential for behavioral but not morphological changes during an epithelium-to-mesenchyme transition[J]. J Cell Sci, 2005, 118(Pt 5): 873-887.
[12] Neel DS, Bivona TG. Secrets of drug resistance in NSCLC exposed by new molecular definition of EMT[J]. Clin Cancer Res, 2013, 19(1): 3-5.
[13] Wendt MK, Tian M, Schiemann WP. Deconstructing the mechanisms and consequences of TGF-beta-induced EMT during cancer progression[J]. Cell Tissue Res, 2012, 347(1): 85-101.
[14] Robinson E, Nandi M, Wilkinson LL, et al. Preclinical evaluation of statins as a treatment for ovarian cancer[J]. Gynecol Oncol, 2013, 129(2): 417-424.
[15] Lee J, Jung KH, Park YS, et al. Simvastatin plus irinotecan, 5-fluorouracil, and leucovorin(FOLFIRI)as first-line chemotherapy inmetastatic colorectal patients: a multicenter phase II study[J]. Cancer Chemother Pharmacol, 2009, 64(4): 657-663.
[16] Cuello F M, Kato C S, Díaz S D, et al. Effects of statins in cancer[J]. Rev Med Chil, 2013, 141(2): 227-236.
[17] Schointuch MN, Gilliam TP, Stine JE, et al. Simvastatin, an HMGCoA reductase inhibitor, exhibits anti-metastatic and anti-tumorigenic effects in endometrial cancer[J]. Gynecol Oncol, 2014, 134(2): 346-355.
[18] Stine JE, Guo H, Sheng X, et al. The HMG-CoA reductase inhibitor, simvastatin, exhibits antimetastatic and anti-tumorigenic effects in ovarian cancer[J]. Oncotarget, 2015, 71: 946-960.
[19] Chen XF, Zhang HJ, Wang HB, et al. Transforming growth factor-β1 induces epithelial-to-mesenchymal transition in human lung cancer cells via PI3K/Akt and MEK/Erk1/2 signaling pathways[J]. Mol Biol Rep,2012, 39(4): 3549-3556.
[20] Liu Q, Zhang Y, Mao H, et al. A crosstalk between the Smad and JNK signaling in the TGF-beta-induced epithelial-mesenchymal transition in rat peritoneal mesothelial cells[J]. PLoS One, 2012, 7(2): e32009.
[21] Pallet N, Thervet E, Anglicheau D. c-Jun-N-terminal kinase signaling is involved in cyclosporine-induced epithelial phenotypic changes[J]. J Transplant, 2012, 2012: 348604.
[22] Avruch J. MAP kinase pathways: the first twenty years[J]. Biochim Biophys Acta, 2007, 1773(8): 1150-1160.
[23] Ha JH, Yan M, Gomathinayagam R, et al. Aberrant expression of JNK-associated leucine-zipper protein, JLP, promotes accelerated growth of ovarian cancer[J]. Oncotarget, 2016, 7(45): 72845-72859.
[24] Yu P, Yan L, Zhao X, et al. Expression and clinical significance of sperm-associated antigen 9 in patients ith endometrialcarcinoma[J]. Int J Gynecol Cancer, 2012, 22(1): 87-93.
[1] GAO Xiu-Rui, ZANG Heng-Chang. In vitro release of compound niacin extended-release and simvastatin immediaterelease double-layer tablets [J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2209, 47(6): 109-113.
[2] ZHANG Bingfen, ZHOU Shenghong, WANG Zhe. Trillium Saponins ameliorates pulmonary fibrosis in rats by inhibiting TGF-β/Smad3 and Wnt/β-catenin signaling pathways [J]. Journal of Shandong University (Health Sciences), 2022, 60(8): 23-29.
[3] LI Honghao, YU Jing, CHEN Yali, GUO Shougang. Evaluation of CD4+CD25+FoxP3+ regulatory T cells and FoxP3 mRNA expression in 20 NMOSD patients [J]. Journal of Shandong University (Health Sciences), 2022, 60(4): 50-54.
[4] Chunfang HA,Ruyue LI. Research progress of drug resistance in ovarian cancer and targeted therapy strategy [J]. Journal of Shandong University (Health Sciences), 2021, 59(9): 117-123.
[5] ZHANG Qian, QIN Mingming, HE Xuejia, CAI Qiujing, ZHANG Yamin, LI Qingsu, ZHU Weiwei. Effects of calcitriol on EMT induced by TGF-β1 in asthma [J]. Journal of Shandong University (Health Sciences), 2021, 59(7): 10-18.
[6] WANG Zhengyang, XIA Yan, SHI Kaixuan, TAO Kun, WANG Xiaojie. Effects of Trametinib on PAX8 expression in ovarian cancer [J]. Journal of Shandong University (Health Sciences), 2021, 59(10): 23-29.
[7] WANG Baojin, ZHAO Xinxin, LI Xia, MA Qian, WANG Xinyue, SUN Yang, SHI Zhongna. miR-203 targeting Survivin to inhibit the proliferation, migration and invasion of ovarian cancer cells [J]. Journal of Shandong University (Health Sciences), 2020, 58(12): 23-28.
[8] YANG Jiaxin, SHEN Keng, WANG Yao. Status and prospect of fertility preservation treatment for gynecologic malignancies [J]. Journal of Shandong University (Health Sciences), 2018, 56(5): 1-7.
[9] ZHANG Ying, YANG Jiaxin, CAO Dongyan, YU Mei, SHEN Keng, HUANG Huifang, PAN Lingya, WU Ming, LANG Jinghe, YOU Yan. Prognostic factors for oncology and fertility outcomes of early stage epithelial ovarian cancer patients who accepted fertility-sparing surgery [J]. Journal of Shandong University (Health Sciences), 2018, 56(5): 13-17.
[10] SONG Yu, MAO Yang, LIU Qingmei, QIAO Lei, TIE Yuanyuan, LU Lu, ZHANG Lei. Effect of Tongxinluo on three-dimensional strain of atherosclerotic vulnerable plaque in rabbits [J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2017, 55(5): 1-7.
[11] TANG Xi, HU Ya, XU Yanhua, WANG Chunlin, QIU Ping, WANG Xianghui. MiR- 498 inhibits A549 cells EMT by targeting FOXM1 [J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2017, 55(4): 39-43.
[12] LU Heng, LIU Yanguo, LI Shuguang, CHEN Xiaokang, TIAN Qi, YI Cuihua, WANG Xiuwen. Regulation of epithelial ovarian carcinoma SKOV-3 cell migration by YKL-40 [J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2017, 55(1): 33-38.
[13] ZHAO Lu, JIAO Jun, ZHANG Teng, JIAO Xinlin, CUI Baoxia. Expression of LXRα in ovarian carcinoma and effects of T0901317 on SKOV3 cell line [J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2017, 55(1): 49-53.
[14] NIU Jiyuan, WANG Fangli, ZHANG Ruibin, GAO Qingzhen, YUN Ping, WANG Qi, ZHANG Shan, BAI Xue, WANG Xiaoping. Effect of local slow-release coated sirolmus on fistula neointimal hyperplasia [J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2016, 54(8): 17-21.
[15] XIAO Junchao, JIANG Wen, NAN Hui, WANG Peirong. A recombinant adenovirus fiber knob protein sensitizes ovarian cancer cells to cetuximab therapy [J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2016, 54(5): 1-5.
Viewed
Full text


Abstract

Cited

  Shared   
  Discussed   
No Suggested Reading articles found!