Inhibition of integrin β1 decreases the malignancy of ovarian cancer cells and potentiates anticancer therapy via the FAK/STAT1 signaling pathway

Zhang,Lei; Zou,Wen

doi:10.3892/mmr.2015.4443

Inhibition of integrin β1 decreases the malignancy of ovarian cancer cells and potentiates anticancer therapy via the FAK/STAT1 signaling pathway

Authors:
- Lei Zhang
- Wen Zou
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Affiliations: Department of Urology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China, Department of Oncology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China
Published online on: October 14, 2015 https://doi.org/10.3892/mmr.2015.4443
Pages: 7869-7876
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Integrin β1 (ITGB1) is frequently upregulated in ovarian cancer, and promotes ovarian tumorigenesis and cancer progression. However, the effects of ITGB1 inhibition on ovarian cancer progression and anticancer therapy remain to be elucidated. The results of the present study indicated that ITGB1 was upregulated in HO‑8910 and HO‑8910PM ovarian cancer cell lines, and knockdown of ITGB1 using short hairpin RNA markedly increased tumor cell apoptosis, decreased tumor cell adhesion and migration, and reduced tumor cell invasion by suppressing matrix metalloproteinase (MMP)‑2 and MMP‑9 expression. Furthermore, the results of the present study provided evidence regarding the role of ITGB1 inhibition in bevacizumab anticancer therapy. The activation of signal transducer and activator of transcription 1 (STAT1) by focal adhesion kinase (FAK) is involved in integrin‑mediated cell migration and adhesion. In the present study, the expression levels of FAK were markedly upregulated in ovarian cancer. The adherence and migratory potentials of ovarian cancer cells were significantly reduced when the FAK/STAT1 signaling pathway was inhibited by fludarabine. The results of the present study demonstrated that ITGB1 inhibition effectively reduced tumorigenesis and disease exacerbation, and contributed to bevacizumab anticancer therapy via the FAK/STAT1 signaling pathway, suggesting that inhibition of ITGB1 is a potential novel therapeutic strategy for ovarian carcinogenesis.

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1	Yang W, Han W, Ye S, Liu D, Wu J, Liu H, Li C and Chen H: Fibroblast activation protein-α promotes ovarian cancer cell proliferation and invasion via extracellular and intracellular signaling mechanisms. Exp Mol Pathol. 95:105–110. 2013. View Article : Google Scholar : PubMed/NCBI
2	Heyman L, Kellouche S, Fernandes J, Dutoit S, Poulain L and Carreiras F: Vitronectin and its receptors partly mediate adhesion of ovarian cancer cells to peritoneal mesothelium in vitro. Tumour Biol. 29:231–244. 2008. View Article : Google Scholar : PubMed/NCBI
3	Gotzmann J, Mikula M, Eger A, Schulte-Hermann R, Foisner R, Beug H and Mikulits W: Molecular aspects of epithelial cell plasticity: Implications for local tumor invasion and metastasis. Mutat Res. 566:9–20. 2004. View Article : Google Scholar : PubMed/NCBI
4	Foubert P and Varner JA: Integrins in tumor angiogenesis and lymphangiogenesis. Methods Mol Biol. 757:471–486. 2012. View Article : Google Scholar
5	Garmy-Susini B and Varner JA: Roles of integrins in tumor angiogenesis and lymphangiogenesis. Lymphat Res Biol. 6:155–163. 2008. View Article : Google Scholar : PubMed/NCBI
6	Tchaicha JH, Reyes SB, Shin J, Hossain MG, Lang FF and McCarty JH: Glioblastoma angiogenesis and tumor cell invasiveness are differentially regulated by β8 integrin. Cancer Res. 71:6371–6381. 2011. View Article : Google Scholar : PubMed/NCBI
7	Buczek-Thomas JA, Chen N and Hasan T: Integrin-mediated adhesion and signalling in ovarian cancer cells. Cell Signal. 10:55–63. 1998. View Article : Google Scholar : PubMed/NCBI
8	Lau MT, So WK and Leung PC: Integrin β1 mediates epithelial growth factor-induced invasion in human ovarian cancer cells. Cancer Lett. 320:198–204. 2012. View Article : Google Scholar : PubMed/NCBI
9	Tucker GC: Integrins: Molecular targets in cancer therapy. Curr Oncol Rep. 8:96–103. 2006. View Article : Google Scholar : PubMed/NCBI
10	Cordes N and Park CC: Beta1 integrin as a molecular therapeutic target. Int J Radiat Biol. 83:753–760. 2007. View Article : Google Scholar : PubMed/NCBI
11	Desgrosellier JS and Cheresh DA: Integrins in cancer: Biological implications and therapeutic opportunities. Nat Rev Cancer. 10:9–22. 2010. View Article : Google Scholar
12	Meads MB, Gatenby RA and Dalton WS: Environment-mediated drug resistance: A major contributor to minimal residual disease. Nat Rev Cancer. 9:665–674. 2009. View Article : Google Scholar : PubMed/NCBI
13	Hazlehurst LA, Landowski TH and Dalton WS: Role of the tumor microenvironment in mediating de novo resistance to drugs and physiological mediators of cell death. Oncogene. 22:7396–7402. 2003. View Article : Google Scholar : PubMed/NCBI
14	Matsunaga T, Fukai F, Miura S, Nakane Y, Owaki T, Kodama H, Tanaka M, Nagaya T, Takimoto R, Takayama T and Niitsu Y: Combination therapy of an anticancer drug with the FNIII14 peptide of fibronectin effectively overcomes cell adhesion-mediated drug resistance of acute myelogenous leukemia. Leukemia. 22:353–360. 2008. View Article : Google Scholar
15	Golubovskaya VM, Kweh FA and Cance WG: Focal adhesion kinase and cancer. Histol Histopathol. 24:503–510. 2009.PubMed/NCBI
16	Lark AL, Livasy CA, Dressler L, Moore DT, Millikan RC, Geradts J, Iacocca M, Cowan D, Little D, Craven RJ and Cance W: High focal adhesion kinase expression in invasive breast carcinomas is associated with an aggressive phenotype. Mod Pathol. 18:1289–1294. 2005. View Article : Google Scholar : PubMed/NCBI
17	Ucar DA and Hochwald SN: FAK and interacting proteins as therapeutic targets in pancreatic cancer. Anticancer Agents Med Chem. 10:742–746. 2010. View Article : Google Scholar
18	Lechertier T and Hodivala-Dilke K: Focal adhesion kinase and tumour angiogenesis. J Pathol. 226:404–412. 2012. View Article : Google Scholar
19	Mitra SK and Schlaepfer DD: Integrin-regulated FAK-Src signaling in normal and cancer cells. Curr Opin Cell Biol. 18:516–523. 2006. View Article : Google Scholar : PubMed/NCBI
20	Jiang J, Grieb B, Thyagarajan A and Sliva D: Ganoderic acids suppress growth and invasive behavior of breast cancer cells by modulating AP-1 and NF-kappaB signaling. Int J Mol Med. 21:577–584. 2008.PubMed/NCBI
21	Bird IM: Extraction of RNA from cells and tissue. Methods Mol Med. 108:139–148. 2005.
22	Song J, Zhang J, Wang J, Cao Z, Wang J, Guo X and Dong W: β1 integrin modulates tumor growth and apoptosis of human colorectal cancer. Oncol Rep. 32:302–308. 2014.
23	Liu B, Che W, Xue J, Zheng C, Tang K, Zhang J, Wen J and Xu Y: SIRT4 prevents hypoxia-induced apoptosis in H9c2 cardiomyoblast cells. Cell Physiol Biochem. 32:655–662. 2013. View Article : Google Scholar
24	Liang CC, Park AY and Guan JL: In vitro scratch assay: A convenient and inexpensive method for analysis of cell migration in vitro. Nat Protoc. 2:329–333. 2007. View Article : Google Scholar : PubMed/NCBI
25	Monaco S, Gioia M, Rodriguez J, Fasciglione GF, Di Pierro D, Lupidi G, Krippahl L, Marini S and Coletta M: Modulation of the proteolytic activity of matrix metalloproteinase-2 (gelatinase A) on fibrinogen. Biochem J. 402:503–513. 2007. View Article : Google Scholar :
26	Omanakuttan A, Nambiar J, Harris RM, Bose C, Pandurangan N, Varghese RK, Kumar GB, Tainer JA, Banerji A, Perry JJ, et al: Anacardic acid inhibits the catalytic activity of matrix metalloproteinase-2 and matrix metalloproteinase-9. Mol Pharmacol. 82:614–622. 2012. View Article : Google Scholar : PubMed/NCBI
27	Tomao F, Papa A, Rossi L, Caruso D, Panici PB, Venezia M and Tomao S: Current status of bevacizumab in advanced ovarian cancer. Onco Targets Ther. 6:889–899. 2013.PubMed/NCBI
28	Zhang L, Wang D, Jiang W, Edwards D, Qiu W, Barroilhet LM, Rho JH, Jin L, Seethappan V, Vitonis A, et al: Activated networking of platelet activating factor receptor and FAK/STAT1 induces malignant potential in BRCA1-mutant at-risk ovarian epithelium. Reprod Biol Endocrinol. 8:742010. View Article : Google Scholar : PubMed/NCBI
29	Xie B, Zhao J, Kitagawa M, Durbin J, Madri JA, Guan JL and Fu XY: Focal adhesion kinase activates Stat1 in integrin-mediated cell migration and adhesion. J Biol Chem. 276:19512–19523. 2001. View Article : Google Scholar : PubMed/NCBI
30	Casey RC and Skubitz AP: CD44 and beta1 integrins mediate ovarian carcinoma cell migration toward extracellular matrix proteins. Clin Exp Metastasis. 18:67–75. 2000. View Article : Google Scholar
31	Mannello F, Tonti G and Papa S: Matrix metalloproteinase inhibitors as anticancer therapeutics. Curr Cancer Drug Targets. 5:285–298. 2005. View Article : Google Scholar : PubMed/NCBI
32	Radisky ES and Radisky DC: Matrix metalloproteinase-induced epithelial-mesenchymal transition in breast cancer. J Mammary Gland Biol Neoplasia. 15:201–212. 2010. View Article : Google Scholar : PubMed/NCBI
33	Pontiggia O, Sampayo R, Raffo D, Motter A, Xu R, Bissell MJ, Joffé EB and Simian M: The tumor microenvironment modulates tamoxifen resistance in breast cancer: A role for soluble stromal factors and fibronectin through β1 integrin. Breast Cancer Res Treat. 133:459–471. 2012. View Article : Google Scholar
34	Carbonell WS, DeLay M, Jahangiri A, Park CC and Aghi MK: β1 integrin targeting potentiates antiangiogenic therapy and inhibits the growth of bevacizumab-resistant glioblastoma. Cancer Res. 73:3145–3154. 2013. View Article : Google Scholar : PubMed/NCBI
35	Kanda R, Kawahara A, Watari K, Murakami Y, Sonoda K, Maeda M, Fujita H, Kage M, Uramoto H, Costa C, et al: Erlotinib resistance in lung cancer cells mediated by integrin β1/Src/Akt-driven bypass signaling. Cancer Res. 73:6243–6253. 2013. View Article : Google Scholar : PubMed/NCBI
36	Ju L, Zhou C, Li W and Yan L: Integrin beta1 over-expression associates with resistance to tyrosine kinase inhibitor gefitinib in non-small cell lung cancer. J Cell Biochem. 111:1565–1574. 2010. View Article : Google Scholar : PubMed/NCBI
37	Yamamoto N, Kinoshita T, Nohata N, Itesako T, Yoshino H, Enokida H, Nakagawa M, Shozu M and Seki N: Tumor suppressive microRNA-218 inhibits cancer cell migration and invasion by targeting focal adhesion pathways in cervical squamous cell carcinoma. Int J Oncol. 42:1523–1532. 2013.PubMed/NCBI