Abstract
Purpose
This study investigated the effect of shRNA targeting survivin on cultured ovarian cancer cells and on a murine ovarian cancer xenograft.
Methods
An RNAi plasmid for survivin was transfected into SKOV3 cells, and the effect of shRNA targeting survivin on the expression of survivin was determined. Transmission electron microscopy (TEM), flow cytometry, and TUNEL staining were used to assess apoptosis. The MTT assay was used to measure cell growth and changes in cisplatin sensitivity. SKOV3 cells were injected into nude mice, and the effect of shRNA targeting the survivin gene on tumor growth was assessed.
Results
SKOV3 cells transfected with an RNAi plasmid against survivin had increased apoptosis and slower growth. At the molecular level, these cells also had lower expression of survivin. Nude mice inoculated with SKOV3 cells developed cancers, and treatment with shRNA targeting survivin markedly inhibited the growth of these cancers with no obvious side effects.
Conclusions
Our studies of SKOV3 cells and ovarian cancer xenografts in nude mice indicate that shRNA targeting survivin has potential for the treatment of ovarian cancer.
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References
Altieri DC (2010) Survivin and IAP proteins in cell-death mechanisms. Biochem J 430:199–205
Anne TM, Taina TH (2010) Levels of Circulating TIMP-2 and MMP2-TIMP2 Complex Are Decreased in Squamous Cervical Carcinoma. Obstet Gynecol Int. doi:10.1155/2010/179351
Deng KX, Zhong L, Jiang MX, Wang PL, Chen Y (2005a) RNA interference silencing expression of survivin gene and reversing drug resistance of ovarian cancer cell line SKOV3/ADM. Zhonghua Fu Chan Ke Za Zhi 40:836–839 [Chinese]
Deng KX, Zhong L, Jiang MX, Chen WX, Chen Y, He H (2005b) Effect of RNAi-mediated survivin gene silencing on apoptosis of ovarian cancer cell lines SKOV3 and SKOV3/ADM. Ai Zheng 24:945–950 [Chinese]
Dutta A, Sen T, Banerji A, Das S, Chatterjee A (2009) Studies on multifunctional effect of all-trans retinoic acid (ATRA) on matrix metalloproteinase-2 (MMP-2) and its regulatory molecules in human breast cancer cells (MCF-7). J Oncol. doi:10.1155/2009/627840
Gong YI, Xu GM, Huang WD (2000) Expression of matrix metalloproteinases and the tissue inhibitors of metalloproteinases and their local invasiveness and metastasis in Chinese human pancreatic cancer. J Surg Oncol 73:95–99
Hanemaaier R, Verheijen JH, Mayuire TM, Visser H, Toet K, McDermott E, O’Higgins N, Duffy MJ (2000) Increased gelatinase-A and gelatinase-B activities in malignant vs benign breast tumors. Int J Cancer 86:204–207
Ikeguchi M, Kaibara N (2001) Changes in survivin messenger RNA level during cisplatin treatment in gastric cancer. Int J Mol Med 8:661–666
Ikeguchi M, Liu J, Kaibara N (2002) Expression of surviving mRNA and protein in gastric cancer cell line (MKN-45) during cisplatin treatment. Apoptosis 7:23–29
Jiang X, Wilford C, Duensing S, Munger K, Jones G, Jones D (2001) Participation of Survivin in mitotic and apoptotic activities of normal and tumor-derived cells. J Cell Biochem 83:342–354
Johnson AL, Langer JS, Bridgham JT (2002) Survivin as a cell cycle-related and antiapoptotic protein in granulosa cells. Endocrinology 143:3405–3413
Kahari VM, Saarialho-Kere U (1999) Matrix metalloproteinases and their inhibitors in tumour growth and invasion. Ann Med 31:34–45
Li G, Xie B, Li X, Chen Y, Wang Q, Xu Y, Xu-Welliver M, Zou L (2012) Down-regulation of survivin and Hypoxia-Inducible Factor-1α by β-elemene enhances the radiosensitivity of lung adenocarcinoma xenograft. Cancer Biother Radiopharm. [PMID: 22248028, Epub ahead of print]
Liu Q, Fu H, Xing R, Tie Y, Zhu J, Sun Z, Zheng X (2008) Survivin knockdown combined with apoptin overexpression inhibits cell growth significantly. Cancer Biol Ther 7:1053–1060
Lukaszewicz-Zajac M, Mroczko B, Szmitkowski M (2009) The significance of metalloproteinases and their inhibitors in gastric cancer. Postepy Hig Med Dosw 63:258–265
McGuire WP, Hoskins WJ, Brady MF, Kucera PR, Partridge EE, Look KY, Clarke-Pearson DL, Davidson M (1996) Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and IV ovarian cancer. N Engl J Med 334:1–6
Mroczko B, Groblewska M, Okulczyk B, Kedra B, Szmitkowski M (2010) The diagnostic value of matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of matrix metalloproteinases 1 (TIMP-1) determination in the sera of colorectal adenoma and cancer patients. Int J Colorectal Dis 25:1177–1184
Muller D, Quantin B, Gesnel MC, Millon-Collard R, Abecassis J, Breathnach R (1994) The collagenase gene family in humans consists of at least four members. Biochem J 253:187–192
Nelson AR, Fingleton B, Rothenberg ML, Matrisian LM (2000) Matrix metalloproteinase: biologic activity and clinical implication. J Clin Oncol 18:1135–11491
Pecot CV, Calin GA, Coleman RL, Lopez-Berestein G, Sood AK (2011) RNA interference in the clinic: challenges and future directions. Nat Rev Cancer 11:59–67
Posadas EM, Davidson B, Kohn EC (2004) Proteomics and ovarian cancer: implications for diagnosis and treatment: a critical review the recent literature. Curr Opin Oncol 16:478–484
Shen J, Liu J, Long Y, Miao Y, Su M, Zhang Q, Han H, Hao X (2009) Knockdown of survivin expression by siRNAs enhances chemosensitivity of prostate cancer cells and attenuates its tumorigenicity. Acta Biochim Biophys Sin (Shanghai) 41:223–230
Vivas-Mejia PE, Rodriguez-Aguayo C, Han HD, Shahzad MM, Valiyeva F, Shibayama M, Chavez-Reyes A, Sood AK, Lopez-Berestein G (2011) Silencing survivin splice variant 2B leads to antitumor activity in taxane–resistant ovarian cancer. Clin Cancer Res 17:3716–3726
Vu TH, Werb Z (2000) Matrix metalloproteinases: effectors of development and normal physiology. Genes Dev 14:2123–2133
Yamamoto H, Ngan CY, Monden M (2008) Cancer cells survive with survivin. Cancer Sci 99:1709–1714
Ye S, Humphries S, Henney A (1998) Matrix metalloproteinases: implication in vascular matrix remodelling during atherogenesis. Clin Sci 94:103–110
Zhang X, Li N, Wang YH, Huang Y, Xu NZ, Wu LY (2009) Effects of survivin siRNA on growth, apoptosis and chemosensitivity of ovarian cancer cells SKOV3/DDP. Zhonghua Zhong Liu Za Zhi 31:174–177 [Chinese]
Zhen HN, Li LW, Zhang W, Fei Z, Shi CH, Yang TT, Bai WT, Zhang X (2007) Short hairpin RNA targeting survivin inhibits growth and angiogenesis of glioma U251 cells. Int J Oncol 31:1111–1117
Zhou J, Gan N, Zhang W, Lu W, Xie X (2010) Proliferation suppression and apoptosis of ovarian carcinoma cells induced by small interfering RNA against vascular endothelial growth factor. J Obstet Gynaecol Res 36:232–238
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Jun Xing and Chang-Ru Jia had equal contribution to this paper.
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Xing, J., Jia, CR., Wang, Y. et al. Effect of shRNA targeting survivin on ovarian cancer. J Cancer Res Clin Oncol 138, 1221–1229 (2012). https://doi.org/10.1007/s00432-012-1196-0
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DOI: https://doi.org/10.1007/s00432-012-1196-0