Oxymatrine suppresses proliferation and facilitates apoptosis of human ovarian cancer cells through upregulating microRNA‑29b and downregulating matrix metalloproteinase‑2 expression

Li,Jingwei; Jiang,Kailei; Zhao,Fujie

doi:10.3892/mmr.2015.3977

Oxymatrine suppresses proliferation and facilitates apoptosis of human ovarian cancer cells through upregulating microRNA‑29b and downregulating matrix metalloproteinase‑2 expression

Authors:
- Jingwei Li
- Kailei Jiang
- Fujie Zhao
View Affiliations

Affiliations: Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
Published online on: June 22, 2015 https://doi.org/10.3892/mmr.2015.3977
Pages: 5369-5374

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

Oxymatrine, an alkaloid extracted from medicinal plants of the genus Sophora, has a wide range of pharmacological effects. Previous studies have revealed that oxymatrine can inhibit proliferation and metastasis of tumor cells through reducing matrix metalloproteinase‑2 (MMP‑2) mRNA expression. However, the expression of MMP‑2 in ovarian cancer is significantly higher than that in normal ovaries. Furthermore, the expression of microRNA‑29b (miR‑29b) in ovarian carcinoma is significantly lower than that in normal ovaries. Therefore, MMP‑2 and miR‑29b are tumor suppressor factors involved in ovarian cancer. To evaluate the anti-cancer effects of oxymatrine the OVCAR‑3 ovary cancer cell line was treated with oxymatrine at the concentrations of 0, 0.5, 1 and 2 mg/ml. Assessment of the proliferation and apoptosis of OVCAR‑3 cells showed that oxymatrine had an inhibitory effect on ovarian cancer cells. Furthermore, oxymatrine decreased the protein levels of MMP‑2 and increased the expression levels of miR‑29b in OVCAR‑3 cells. Through transfection of miR‑29b precursor into OVCAR‑3 cells, it was demonstrated that miR‑29b regulated MMP‑2 expression in OVCAR‑3 cells. In addition, anti‑miR‑29b antibodies were used to verify that the apoptotic effect of oxymatrine was due to upregulating miR‑29b and downregulating MMP‑2 expression. These results showed that oxymatrine suppresses the proliferation and facilitates apoptosis of human ovarian cancer cells through upregulating miR‑29b and downregulating MMP‑2 expression.

View Figures

View References

1	Kim SI, Kim HS, Kim TH, Suh DH, Kim K, No JH, Chung HH, Kim YB and Song YS: Impact of underweight after treatment on prognosis of advanced-stage ovarian cancer. J Immunol Res. 2014:3495462014. View Article : Google Scholar : PubMed/NCBI
2	Barber A, Zhang T and Sentman CL: Correction: immunotherapy with chimeric NKG2D receptors leads to long-term tumor-free survival and development of host antitumor immunity in murine ovarian cancer. J Immunol. 193:15132014.
3	Muralidhar GG and Barbolina MV: Chemokine receptors in epithelial ovarian cancer. Int J Mol Sci. 15:361–376. 2013. View Article : Google Scholar
4	Shen CC, Kang YH, Zhao M, He Y, Cui DD, Fu YY, Yang LL and Gou LT: WNT16B from ovarian fibroblasts induces differentiation of regulatory T cells through β-catenin signal in dendritic cells. Int J Mol Sci. 15:12928–12939. 2014. View Article : Google Scholar : PubMed/NCBI
5	Liu J, Li J, Zhang JF and Xin XY: Combination of fenretinide and selenite inhibits proliferation and induces apoptosis in ovarian cancer cells. Int J Mol Sci. 14:21790–21804. 2013. View Article : Google Scholar : PubMed/NCBI
6	Ekinci T, Ozbay PO, Yiğit S, Yavuzcan A, Uysal S and Soylu F: The correlation between immunohistochemical expression of MMP-2 and the prognosis of epithelial ovarian cancer. Ginekol Pol. 85:121–130. 2014. View Article : Google Scholar : PubMed/NCBI
7	Grelewski PG and Bar JK: The role of p53 protein and MMP-2 tumor/stromal cells expression on progressive growth of ovarian neoplasms. Cancer Invest. 31:472–479. 2013. View Article : Google Scholar : PubMed/NCBI
8	Su Y, Gao L, Teng L, Wang Y, Cui J, Peng S and Fu S: Id1 enhances human ovarian cancer endothelial progenitor cell angiogenesis via PI3K/Akt and NF-κB/MMP-2 signaling pathways. J Transl Med. 11:1322013. View Article : Google Scholar
9	Laios A, Mohamed BM, Kelly L, Flavin R, Finn S, McEvoy L, Gallagher M, Martin C, Sheils O, Ring M, et al: Pre-treatment of platinum resistant ovarian cancer cells with an MMP-9/MMP-2 inhibitor prior to cisplatin enhances cytotoxicity as determined by high content screening. Int J Mol Sci. 14:2085–2103. 2013. View Article : Google Scholar : PubMed/NCBI
10	Wu DW, Hsu NY, Wang YC, Lee MC, Cheng YW, Chen CY and Lee H: c-Myc suppresses microRNA-29b to promote tumor aggressiveness and poor outcomes in non-small cell lung cancer by targeting FHIT. Oncogene. 34:2072–2082. 2015. View Article : Google Scholar
11	Parpart S, Roessler S, Dong F, Rao V, Takai A, Ji J, Qin LX, Ye QH, Jia HL, Tang ZY, et al: Modulation of miR-29 expression by α-fetoprotein is linked to the hepatocellular carcinoma epigenome. Hepatology. 60:872–883. 2014. View Article : Google Scholar : PubMed/NCBI
12	Wu Z, Huang X, Huang X, Zou Q and Guo Y: The inhibitory role of Mir-29 in growth of breast cancer cells. J Exp Clin Cancer Res. 32:982013. View Article : Google Scholar : PubMed/NCBI
13	Tan M, Wu J and Cai Y: Suppression of Wnt signaling by the miR-29 family is mediated by demethylation of WIF-1 in non-small-cell lung cancer. Biochem Biophys Res Commun. 438:673–679. 2013. View Article : Google Scholar : PubMed/NCBI
14	Wang C, Bian Z, Wei D and Zhang JG: miR-29b regulates migration of human breast cancer cells. Mol Cell Biochem. 352:197–207. 2011. View Article : Google Scholar : PubMed/NCBI
15	Yu PN, Yan MD, Lai HC, Huang RL, Chou YC, Lin WC, Yeh LT and Lin YW: Downregulation of miR-29 contributes to cisplatin resistance of ovarian cancer cells. Int J Cancer. 134:542–551. 2014. View Article : Google Scholar
16	Creighton CJ, Hernandez-Herrera A, Jacobsen A, Levine DA, Mankoo P, Schultz N, Du Y, Zhang Y, Larsson E, Sheridan R, et al: Integrated analyses of microRNAs demonstrate their widespread influence on gene expression in high-grade serous ovarian carcinoma. PLoS One. 7:e345462012. View Article : Google Scholar : PubMed/NCBI
17	Wu XS, Yang T, Gu J, Li ML, Wu WG, Weng H, Ding Q, Mu JS, Bao RF, Shu YJ, et al: Effects of oxymatrine on the apoptosis and proliferation of gallbladder cancer cells. Anticancer Drugs. 25:1005–1015. 2014. View Article : Google Scholar
18	Yang Z, Yin R, Cong Y, Yang Z, Zhou E, Wei Z, Liu Z, Cao Y and Zhang N: Oxymatrine lightened the inflammatory response of LPS-induced mastitis in mice through affecting NF-κB and MAPKs signaling pathways. Inflammation. 37:2047–2055. 2014. View Article : Google Scholar : PubMed/NCBI
19	Zhang Y, Piao B, Zhang Y, Hua B, Hou W, Xu W, Qi X, Zhu X, Pei Y and Lin H: Oxymatrine diminishes the side population and inhibits the expression of β-catenin in MCF-7 breast cancer cells. Med Oncol. 28(Suppl 1): S99–S107. 2011. View Article : Google Scholar
20	Zhang Y, Liu H, Jin J, Zhu X, Lu L and Jiang H: The role of endogenous reactive oxygen species in oxymatrine-induced caspase-3-dependent apoptosis in human melanoma A375 cells. Anticancer Drugs. 21:494–501. 2010. View Article : Google Scholar : PubMed/NCBI
21	Wu C, Huang W, Guo Y, et al: Oxymatrine inhibits the proliferation of prostate cancer cells in vitro and in vivo. Mol Med Rep. 11:4129–4134. 2015.PubMed/NCBI
22	Chen H, Zhang J, Luo J, Lai F, Wang Z, Tong H, Lu D, Bu H, Zhang R and Lin S: Antiangiogenic effects of oxymatrine on pancreatic cancer by inhibition of the NF-κB-mediated VEGF signaling pathway. Oncol Rep. 30:589–595. 2013.PubMed/NCBI
23	Ho JW, Ngan Hon PL and Chim WO: Effects of oxymatrine from Ku Shen on cancer cells. Anticancer Agents Med Chem. 9:823–826. 2009. View Article : Google Scholar : PubMed/NCBI
24	Dong XQ, Du Q, Yu WH, Zhang ZY, Zhu Q, Che ZH, Chen F, Wang H and Chen J: Anti-inflammatory effects of oxymatrine through inhibition of nuclear factor-kappa B and mitogen-activated protein kinase activation in lipopolysaccharide-induced BV2 Microglia Cells. Iran J Pharm Res. 12:165–174. 2013.PubMed/NCBI
25	Ling Q, Xu X, Wei X, Wang W, Zhou B, Wang B and Zheng S: Oxymatrine induces human pancreatic cancer PANC-1 cells apoptosis via regulating expression of Bcl-2 and IAP families, and releasing of cytochrome c. J Exp Clin Cancer Res. 30:662011. View Article : Google Scholar : PubMed/NCBI
26	Seo JM, Park S and Kim JH: Leukotriene B4 receptor-2 promotes invasiveness and metastasis of ovarian cancer cells through signal transducer and activator of transcription 3 (STAT3)-dependent up-regulation of matrix metalloproteinase 2. J Biol Chem. 287:13840–13849. 2012. View Article : Google Scholar : PubMed/NCBI
27	Li LQ, Li XL, Wang L, Du WJ, Guo R, Liang HH, Liu X, Liang DS, Lu YJ, Shan HL, et al: Matrine inhibits breast cancer growth via miR-21/PTEN/Akt pathway in MCF-7 cells. Cell Physiol Biochem. 30:631–641. 2012. View Article : Google Scholar : PubMed/NCBI
28	Zhang Y, Sun S, Chen J, Ren P, Hu Y, Cao Z, Sun H and Ding Y: Oxymatrine induces mitochondria dependent apoptosis in human osteosarcoma MNNG/HOS cells through inhibition of PI3K/Akt pathway. Tumour Biol. 35:1619–1625. 2014. View Article : Google Scholar
29	Gong J, Li J, Wang Y, Liu C, Jia H, Jiang C, Wang Y, Luo M, Zhao H, Dong L, et al: Characterization of microRNA-29 family expression and investigation of their mechanistic roles in gastric cancer. Carcinogenesis. 35:497–506. 2014. View Article : Google Scholar
30	Jiang H, Zhang G, Wu JH and Jiang CP: Diverse roles of miR-29 in cancer (review). Oncol Rep. 31:1509–1516. 2014.PubMed/NCBI
31	Cittelly DM, Finlay-Schultz J, Howe EN, Spoelstra NS, Axlund SD, Hendricks P, Jacobsen BM, Sartorius CA and Richer JK: Progestin suppression of miR-29 potentiates dedif-ferentiation of breast cancer cells via KLF4. Oncogene. 32:2555–2564. 2013. View Article : Google Scholar