Inhibitory effects of STAT3 decoy oligodeoxynucleotides on human epithelial ovarian cancer cell growth in vivo

Zhang,Xiaolei; Liu,Peishu; Zhang,Bo; Mao,Hongluan; Shen,Liang; Ma,Yanhui

doi:10.3892/ijmm.2013.1431

Inhibitory effects of STAT3 decoy oligodeoxynucleotides on human epithelial ovarian cancer cell growth in vivo

Authors:
- Xiaolei Zhang
- Peishu Liu
- Bo Zhang
- Hongluan Mao
- Liang Shen
- Yanhui Ma
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Affiliations: Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China, Department of Clinical Medicine, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
Published online on: July 4, 2013 https://doi.org/10.3892/ijmm.2013.1431
Pages: 623-628

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Abstract

The signal transducer and activator of transcription 3 (STAT3) regulates target gene expression by binding to a consensus DNA sequence within the promoter of the target genes. The constitutive activation of STAT3 has been shown to contribute to tumorigenesis in ovarian cancer and it has been reported to be a key factor for drug resistance in ovarian cancer. STAT3-specific decoy oligodeoxynucleotides (ODNs) (STAT3 decoy ODNs) that contain a consensus DNA sequence inhibit the transcriptional activity of STAT3, leading to cancer cell death. However, their mechanisms of action are unclear and little information is available as to the effects and the toxicity of STAT3 decoy ODNs in vivo. In this study, we established subcutaneous xenografts of SKOV3 human ovarian cancer cells in nude mice, evaluated the antitumor effects of STAT3 decoy ODNs on xenografted nude mice, and investigated the mechanisms behind the antitumor effects of STAT3 decoy ODNs targeting the STAT3 signaling pathway in vivo. The results revealed that the STAT3 decoy ODN inhibited ovarian cancer cell growth and promoted ovarian cancer cell apoptosis in vivo. Western blot analysis indicated that the STAT3 decoy ODN downregulated the protein expression levels of matrix metalloproteinase (MMP)-2, MMP-9 and Bcl-2, and upregulated the protein expression levels of caspase-3 in vivo. H&E staining was used to detect the side-effects of the STAT3 decoy ODN in the vital organs of the nude mice. We found that there were no significant abnormalities in the vital organs of the nude mice apart from slight inflammation and necrosis in parts of the hepatic lobule. The data from the present study suggest that decoy ODNs targeting STAT3 may be an effective therapeutic approach for the treatment of ovarian cancer in vivo.

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1	Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C and Thun MJ: Cancer statistics. CA Cancer J Clin. 56:106–130. 2006.
2	Edwards BK, Brown ML, Wingo PA, Howe HL, Ward E, Ries LA, et al: Annual report to the nation on the status of cancer, 1975–2002, featuring population-based trends in cancer treatment. J Natl Cancer Inst. 97:1407–1427. 2005.
3	Bromberg JF: Activation of STAT proteins and growth control. Bioessays. 23:161–169. 2001. View Article : Google Scholar : PubMed/NCBI
4	Buettner R, Mora LB and Jove R: Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention. Clin Cancer Res. 8:945–954. 2002.PubMed/NCBI
5	Catlett-Falcone R, Landowski TH, Oshiro MM, Turkson J, Levitzki A, Savino R, Ciliberto G, Moscinski L, Fernandez-Luna JL, Nunez G, Dalton WS and Jove R: Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity. 10:105–115. 1999. View Article : Google Scholar : PubMed/NCBI
6	Gao B, Shen X, Kunos G, Meng Q, Goldberg ID, Rosen EM and Fan S: Constitutive activation of JAK-STAT3 signaling by BRCA1 in human prostate cancer cells. FEBS Lett. 488:179–184. 2001. View Article : Google Scholar : PubMed/NCBI
7	Al Zaid Siddiquee K and Turkson J: STAT3 as a target for inducing apoptosis in solid and hematological tumors. Cell Res. 18:254–267. 2008.PubMed/NCBI
8	Lo HW, Hsu SC, Ali-Seyed M, Gunduz M, Xia W, Wei Y, Bartholomeusz G, Shih JY and Hung MC: Nuclear interaction of EGFR and STAT3 in the activation of the iNOS/NO pathway. Cancer Cell. 7:575–589. 2005. View Article : Google Scholar : PubMed/NCBI
9	Park OK, Schaefer TS and Nathans D: In vitro activation of Stat3 by epidermal growth factor receptor kinase. Proc Natl Acad Sci USA. 93:13704–13708. 1996. View Article : Google Scholar : PubMed/NCBI
10	Turkson J and Jove R: STAT proteins: novel molecular targets for cancer drug discovery. Oncogene. 19:6613–6626. 2000. View Article : Google Scholar : PubMed/NCBI
11	Bromberg J and Darnell JE Jr: The role of STATs in transcriptional control and their impact on cellular function. Oncogene. 19:2648–2673. 2000. View Article : Google Scholar
12	Landen CN Jr, Lin YG, Armaiz Pena GN, et al: Neuroendocrine modulation of signal transducer and activator of transcription 3 in ovarian cancer. Cancer Res. 67:10389–10396. 2007. View Article : Google Scholar : PubMed/NCBI
13	Duan Z, Foster R, Bell DA, Mahoney J, Wolak K, Vaidya A, Hampel C, Lee H and Seiden MV: Signal transducers and activators of transcription 3 pathway activation in drug-resistant ovarian cancer. Clin Cancer Res. 12:5055–5063. 2006. View Article : Google Scholar : PubMed/NCBI
14	Nefedova Y and Gabrilovich DI: Targeting of Jak/STAT pathway in antigen presenting cells in cancer. Curr Cancer Drug Targets. 7:71–77. 2007. View Article : Google Scholar : PubMed/NCBI
15	Schlessinger K and Levy DE: Malignant transformation but not normal cell growth depends on signal transducer and activator of transcription 3. Cancer Res. 65:5828–5834. 2005. View Article : Google Scholar : PubMed/NCBI
16	Cai L, Zhang G, Tong X, You Q, An Y, Wang Y, Guo L, Wang T, Zhu D and Zheng J: Growth inhibition of human ovarian cancer cells by blocking STAT3 activation with small interfering RNA. Eur J Obstet Gynecol Reprod Biol. 148:73–80. 2010. View Article : Google Scholar : PubMed/NCBI
17	Yang L, Ma X, Xiao L, Tang M, Weng X, Sun L and Cao Y: Uniquely modified RNA oligonucleotides targeting STAT3 suppress melanoma growth both in vitro and in vivo. Cancer Biol Ther. 8:2065–2072. 2009. View Article : Google Scholar : PubMed/NCBI
18	Gu J, Li G, Sun T, Su Y, Zhang X, Shen J, Tian Z and Zhang J: Blockage of the STAT3 signaling pathway with a decoy oligonucleotide suppresses growth of human malignant glioma cells. J Neurooncol. 89:9–17. 2008. View Article : Google Scholar : PubMed/NCBI
19	Souissi I, Najjar I, Ah-Koon L, et al: A STAT3-decoy oligonucleotide induces cell death in a human colorectal carcinoma cell line by blocking nuclear transfer of STAT3 and STAT3-bound NF-κB. BMC Cell Biology. 12:142011.PubMed/NCBI
20	Zhang X, Liu P, Zhang B, Wang A and Yang M: Role of STAT3 decoy oligodeoxynucleotides on cell invasion and chemosensitivity in human epithelial ovarian cancer cells. Cancer Genet Cytogenet. 197:46–53. 2010. View Article : Google Scholar : PubMed/NCBI
21	Leong PL, Andrews GA, Johnson DE, Dyer KF, Xi S, Mai JC, Robbins PD, Gadiparthi S, Burke NA, Watkins SF and Grandis JR: Targeted inhibition of Stat3 with a decoy oligonucleotide abrogates head and neck cancer cell growth. Proc Natl Acad Sci USA. 100:4138–4143. 2003. View Article : Google Scholar : PubMed/NCBI
22	Zhang X, Zhang L, Wang L, Wei H and Tian Z: Therapeutic effects of STAT3-decoy oligodeoxynucleotide on human lung cancer in xenograft mice. BMC Cancer. 7:1492007. View Article : Google Scholar : PubMed/NCBI
23	Devalapally H, Duan Z, Seiden MV and Amiji MM: Modulation of drug resistance in ovarian adenocarcinoma by enhancing intracellular ceramide using tamoxifen-loaded biodegradable polymeric nanoparticles. Clin Cancer Res. 14:3193–3203. 2008. View Article : Google Scholar
24	Mao HL, Liu PS, Zheng JF, Zhang PH, Zhou LG, Xin G and Liu C: Transfection of Smac/DIABLO sensitizes drug-resistant tumor cells to TRAIL or paclitaxel-induced apoptosis in vitro. Pharmacol Res. 56:483–492. 2007. View Article : Google Scholar : PubMed/NCBI
25	Bromberg J: Stat proteins and oncogenesis. J Clin Invest. 109:1139–1142. 2002. View Article : Google Scholar : PubMed/NCBI
26	Fletcher S, Turkson J and Gunning PT: Molecular approaches towards the inhibition of the signal transducer and activator of transcription 3 (Stat3) protein. ChemMedChem. 3:1159–1168. 2008. View Article : Google Scholar : PubMed/NCBI
27	Leeman RJ, Lui VW and Grandis JR: STAT3 as a therapeutic target in head and neck cancer. Expert Opin Biol Ther. 6:231–241. 2006. View Article : Google Scholar : PubMed/NCBI
28	Colomiere M, Findlay J, Ackland L and Ahmed N: Epidermal growth factor-induced ovarian carcinoma cell migration is associated with JAK2/STAT3 signals and changes in the abundance and localization of alpha6beta1 integrin. Int J Biochem Cell Biol. 41:1034–1045. 2009. View Article : Google Scholar : PubMed/NCBI
29	Jing N and Tweardy DJ: Targeting Stat3 in cancer therapy. Anticancer Drugs. 16:601–607. 2005. View Article : Google Scholar : PubMed/NCBI
30	Shen J, Li R and Li G: Inhibitory effects of decoy-ODN targeting activated STAT3 on human glioma growth in vivo. In Vivo. 23:237–243. 2009.PubMed/NCBI
31	Liotta LA and Stetler-Stevenson WG: Tumor invasion and metastasis: an imbalance of positive and negative regulation. Cancer Res. 51(Suppl 18): 5054S–5059S. 1991.PubMed/NCBI
32	Belotti D, Paganoni P, Manenti L, Garofalo A, Marchini S, Taraboletti G and Giavazzi R: Matrix metalloproteinases (MMP9 and MMP2) induce the release of vascular endothelial growth factor (VEGF) by ovarian carcinoma cells: implications for ascites formation. Cancer Res. 63:5224–5229. 2003.
33	dos Santos LG, Lopes-Costa PV, dos Santos AR, Facina G and da Silva BB: Bcl-2 oncogene expression in estrogen receptor-positive and negative breast carcinoma. Eur J Gynaecol Oncol. 29:459–461. 2008.
34	Alas S and Bonavida B: Inhibition of constitutive STAT3 activity sensitizes resistant non-Hodgkin's lymphoma and multiple myeloma to chemotherapeutic drug-mediated apoptosis. Clin Cancer Res. 9:316–326. 2003.
35	Selvendiran K, Koga H, Ueno T, et al: Luteolin promotes degradation in signal transducer and activator of transcription 3 in human hepatoma cells: an implication for the antitumor potential of flavonoids. Cancer Res. 66:4826–4834. 2006. View Article : Google Scholar : PubMed/NCBI
36	Enari M, Sakahira H, Yokoyama H, Okawa K, Iwamatsu A and Nagata S: A caspase-activated DNase that degrades DNA during apoptosis and its inhibitor ICAD. Nature. 391:43–50. 1998. View Article : Google Scholar : PubMed/NCBI
37	Kamada S, Kikkawa U, Tsujimoto Y and Hunter T: Nuclear translocation of caspase-3 is dependent on its proteolytic activation and recognition of a substrate-like protein(s). J Biol Chem. 280:857–860. 2005. View Article : Google Scholar : PubMed/NCBI