Synergistic effects of eukaryotic co-expression plasmid-based STAT3-specific siRNA and LKB1 on ovarian cancer in vitro and in vivo Retraction in /10.3892/or.2021.8149

Pan,Yuan; Zhang,Liqun; Zhang,Xinyue; Liu,Ruizhi

doi:10.3892/or.2014.3623

Synergistic effects of eukaryotic co-expression plasmid-based STAT3-specific siRNA and LKB1 on ovarian cancer in vitro and in vivo

Retraction in: /10.3892/or.2021.8149

Authors:
- Yuan Pan
- Liqun Zhang
- Xinyue Zhang
- Ruizhi Liu
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Affiliations: Center for Reproductive Medicine, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
Published online on: November 25, 2014 https://doi.org/10.3892/or.2014.3623
Pages: 774-782

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Abstract

The signal transducer and activator of transcription 3 (STAT3) are ideal targets for ovarian cancer. Previous studies showed that downregulation of STAT3 using specific short hairpin RNAs (shRNA) can significantly reduce ovarian tumor growth. However, RNA interference does not fully ablate target gene expression due to idiosyncrasies associated with shRNAs and their targets. To enhance the therapeutic efficacy of STAT3-specific shRNA, we employed a combinatorial expression of STAT3-specific shRNA and liver kinase B1 (LKB1), a tumor suppressor. Thus, the LKB1 coding sequences and STAT3-specific shRNAs were constructed in a eukaryotic co-expression plasmid pCDNA3.1, and then transfected into ovarian cancer cells to evaluate the synergistic effects of this combination on anticancer activity and explore the relevant molecular mechanisms. Co-expression of STAT3‑specific siRNA and LKB1 (pSi-STAT3-LKB1) synergistically inhibited ovarian cancer cell growth, invasion and migration, induced cell apoptosis and arrested the cell cycle in vitro when compared with monotherapy. The results showed that the co-expression of plasmid pSi-STAT3-LKB1 inserted subcutaneously into ovarian tumor xenograft resulted in more significant inhibition of tumor growth. Further study showed that the synergistic anti-ovarian cancer effects of the co-expression of STAT3-specific siRNA and LKB1 may be associated with the upregulation of p-p53, p21 and downregulation of survivin, BCL-2 and cyclin D1. Results of the present study suggested that combined therapy with eukaryotic co-expression of the plasmid‑carrying STAT3-specific siRNA and LKB1 is a novel and efficient treatment strategy for human ovarian cancer.

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1	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2012. CA Cancer J Clin. 62:10–29. 2012. View Article : Google Scholar : PubMed/NCBI
2	Cannistra SA: Cancer of the ovary. N Engl J Med. 351:2519–2529. 2004. View Article : Google Scholar : PubMed/NCBI
3	Kipps E, Tan DS and Kaye SB: Meeting the challenge of ascites in ovarian cancer: new avenues for therapy and research. Nat Rev Cancer. 13:273–282. 2013. View Article : Google Scholar : PubMed/NCBI
4	Telleria CM: Repopulation of ovarian cancer cells after chemotherapy. Cancer Growth Metastasis. 6:15–21. 2013. View Article : Google Scholar : PubMed/NCBI
5	Duan Z, Foster R, Bell DA, et al: 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
6	Darnell JE Jr: STATs and gene regulation. Science. 277:1630–1635. 1997. View Article : Google Scholar : PubMed/NCBI
7	Lu Y, Fukuyama S, Yoshida R, et al: Loss of SOCS3 gene expression converts STAT3 function from anti-apoptotic to proapoptotic. J Biol Chem. 281:36683–36690. 2006. View Article : Google Scholar : PubMed/NCBI
8	Yu H and Jove R: The STATs of cancer - new molecular targets come of age. Nat Rev Cancer. 4:97–105. 2004. View Article : Google Scholar : PubMed/NCBI
9	Catlett-Falcone R, Landowski TH, Oshiro MM, et al: 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
10	Grandis JR, Drenning SD, Zeng Q, et al: Constitutive activation of Stat3 signaling abrogates apoptosis in squamous cell carcinogenesis in vivo. Proc Natl Acad Sci USA. 97:4227–4232. 2000. View Article : Google Scholar : PubMed/NCBI
11	Yan X, Fraser M, Qiu Q and Tsang BK: Over-expression of PTEN sensitizes human ovarian cancer cells to cisplatin-induced apoptosis in a p53-dependent manner. Gynecol Oncol. 102:348–355. 2006. View Article : Google Scholar : PubMed/NCBI
12	Epling-Burnette PK, Liu JH, Catlett-Falcone R, et al: Inhibition of STAT3 signaling leads to apoptosis of leukemic large granular lymphocytes and decreased Mcl-1 expression. J Clin Invest. 107:351–362. 2001. View Article : Google Scholar : PubMed/NCBI
13	Mora LB, Buettner R, Seigne J, et al: Constitutive activation of Stat3 in human prostate tumors and cell lines: direct inhibition of Stat3 signaling induces apoptosis of prostate cancer cells. Cancer Res. 62:6659–6666. 2002.PubMed/NCBI
14	Scholz A, Heinze S, Detjen KM, et al: Activated signal transducer and activator of transcription 3 (STAT3) supports the malignant phenotype of human pancreatic cancer. Gastroenterology. 125:891–905. 2003. View Article : Google Scholar : PubMed/NCBI
15	Song L, Turkson J, Karras JG, Jove R and Haura EB: Activation of Stat3 by receptor tyrosine kinases and cytokines regulates survival in human non-small cell carcinoma cells. Oncogene. 22:4150–4165. 2003. View Article : Google Scholar : PubMed/NCBI
16	Kanda N, Seno H, Konda Y, et al: STAT3 is constitutively activated and supports cell survival in association with survivin expression in gastric cancer cells. Oncogene. 23:4921–4929. 2004. View Article : Google Scholar : PubMed/NCBI
17	Li L and Shaw PE: Autocrine-mediated activation of STAT3 correlates with cell proliferation in breast carcinoma lines. J Biol Chem. 277:17397–17405. 2002. View Article : Google Scholar : PubMed/NCBI
18	Aittomäki S and Pesu M: Therapeutic targeting of the Jak/STAT pathway. Basic Clin Pharmacol Toxicol. 114:18–23. 2014. View Article : Google Scholar
19	Huang K, Li LA, Meng YG, You YQ, Fu XY and Song L: Arctigenin promotes apoptosis in ovarian cancer cells via the iNOS/NO/STAT3/survivin signalling. Basic Clin Pharmacol Toxicol. May 19–2014.(Epub ahead of print). View Article : Google Scholar
20	Han Z, Feng J, Hong Z, et al: Silencing of the STAT3 signaling pathway reverses the inherent and induced chemoresistance of human ovarian cancer cells. Biochem Biophys Res Commun. 435:188–194. 2013. View Article : Google Scholar : PubMed/NCBI
21	Jiang Q, Dai L, Cheng L, et al: Efficient inhibition of intraperitoneal ovarian cancer growth in nude mice by liposomal delivery of short hairpin RNA against STAT3. J Obstet Gynaecol Res. 39:701–709. 2013. View Article : Google Scholar
22	Zhang L, Gao L, Li Y, et al: Effects of plasmid-based Stat3-specific short hairpin RNA and GRIM-19 on PC-3M tumor cell growth. Clin Cancer Res. 14:559–568. 2008. View Article : Google Scholar : PubMed/NCBI
23	Elbashir SM, Harborth J, Weber K and Tuschl T: Analysis of gene function in somatic mammalian cells using small interfering RNAs. Methods. 26:199–213. 2002. View Article : Google Scholar : PubMed/NCBI
24	Hemminki A, Markie D, Tomlinson I, et al: A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature. 391:184–187. 1998. View Article : Google Scholar : PubMed/NCBI
25	Esteller M, Avizienyte E, Corn PG, et al: Epigenetic inactivation of LKB1 in primary tumors associated with the Peutz-Jeghers syndrome. Oncogene. 19:164–168. 2000. View Article : Google Scholar : PubMed/NCBI
26	Andrade-Vieira R, Xu Z, Colp P and Marignani PA: Loss of LKB1 expression reduces the latency of ErbB2-mediated mammary gland tumorigenesis, promoting changes in metabolic pathways. PLoS One. 8:e565672013. View Article : Google Scholar : PubMed/NCBI
27	Zhuang Z, Wang K, Cheng X, et al: LKB1 inhibits breast cancer partially through repressing the Hedgehog signaling pathway. PLoS One. 8:e674312013. View Article : Google Scholar : PubMed/NCBI
28	Wang YQ, Dai WM, Chu XY, Yang B, Zhao M and Sun Y: Downregulation of LKB1 suppresses Stat3 activity to promote the proliferation of esophageal carcinoma cells. Mol Med Rep. 9:2400–2404. 2014.PubMed/NCBI
29	Wang GM, Ren ZX, Wang PS, et al: Plasmid-based Stat3-specific siRNA and GRIM-19 inhibit the growth of thyroid cancer cells in vitro and in vivo. Oncol Rep. 32:573–580. 2014.PubMed/NCBI
30	Du Y, Shi A, Han B, et al: COX-2 silencing enhances tamoxifen antitumor activity in breast cancer in vivo and in vitro. Int J Oncol. 44:1385–1393. 2014.PubMed/NCBI
31	Wen LJ, Gao LF, Jin CS, et al: Small interfering RNA survivin and GRIM-19 co-expression salmonella plasmid inhibited the growth of laryngeal cancer cells in vitro and in vivo. Int J Clin Exp Pathol. 6:2071–2081. 2013.PubMed/NCBI
32	Li X, Li Y, Hu J, et al: Plasmid-based E6-specific siRNA and co-expression of wild-type p53 suppresses the growth of cervical cancer in vitro and in vivo. Cancer Lett. 335:242–250. 2013. View Article : Google Scholar : PubMed/NCBI
33	Li L, Yu C, Ren J, et al: Synergistic effects of eukaryotic coexpression plasmid carrying LKB1 and FUS1 genes on lung cancer in vitro and in vivo. J Cancer Res Clin Oncol. 140:895–907. 2014. View Article : Google Scholar : PubMed/NCBI
34	Tiainen M, Vaahtomeri K, Ylikorkala A and Mäkelä TP: Growth arrest by the LKB1 tumor suppressor: induction of p21^WAF1/^CIP1. Hum Mol Genet. 11:1497–1504. 2002. View Article : Google Scholar : PubMed/NCBI
35	Tiainen M, Ylikorkala A and Mäkelä TP: Growth suppression by Lkb1 is mediated by a G₁ cell cycle arrest. Proc Natl Acad Sci USA. 96:9248–9251. 1999. View Article : Google Scholar
36	Kim DW, Chung HK, Park KC, et al: Tumor suppressor LKB1 inhibits activation of signal transducer and activator of tran scription 3 (STAT3) by thyroid oncogenic tyrosine kinase rearranged in transformation (RET)/papillary thyroid carcinoma (PTC). Mol Endocrinol. 21:3039–3049. 2007. View Article : Google Scholar : PubMed/NCBI
37	Braicu EI, Gasimli K, Richter R, et al: Role of serum VEGFA, TIMP2, MMP2 and MMP9 in monitoring response to adjuvant radiochemotherapy in patients with primary cervical cancer - results of a companion protocol of the randomized NOGGO-AGO phase III clinical trial. Anticancer Res. 34:385–391. 2014.PubMed/NCBI
38	Ou W, Ye S, Yang W, et al: Enhanced antitumor effect of cisplatin in human NSCLC cells by tumor suppressor LKB1. Cancer Gene Ther. 19:489–498. 2012. View Article : Google Scholar : PubMed/NCBI