Integrin αv promotes proliferation by activating ERK 1/2 in the human lung cancer cell line A549

Fu,Shijie; Fan,Limin; Pan,Xufeng; Sun,Yifeng; Zhao,Heng

doi:10.3892/mmr.2014.2860

Integrin αv promotes proliferation by activating ERK 1/2 in the human lung cancer cell line A549

Authors:
- Shijie Fu
- Limin Fan
- Xufeng Pan
- Yifeng Sun
- Heng Zhao
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Affiliations: Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai 200030, P.R. China
Published online on: November 4, 2014 https://doi.org/10.3892/mmr.2014.2860
Pages: 1266-1271

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Abstract

Lung cancer is a leading cause of cancer-related death worldwide, and non-small cell lung cancer (NSCLC) constitutes ~85% of lung cancers. However, the mechanisms underlying the progression of NSCLC remain unclear. In this study, we found the mRNA and protein expression levels of integrin αv are both increased in NSCLC tissues compared to healthy ones, which indicates that integrin αv may play an important role in NSCLC progression. To further investigate the roles of integrin αv in NSCLC, we overexpressed the integrin αv gene in the NSCLC cell line A549, and found that the cell proliferative ability increased. The apoptosis of A549 cells was inhibited with overexpression of integrin αv. To elucidate the molecular mechanism underlying the role of integrin αv in promoting NSCLC progression, we studied the expression of proteins from a number of important pathways associated with tumorigenesis, and found that the extracellular signal regulated protein kinase (ERK)1/2 signaling pathway may be involved in the mediation of the observed integrin αv effects. component of an important pathway for tumorigenesis, the ERK 1/2. Following inhibition of ERK 1/2 signaling, the proliferation of A549 cells induced by integrin αv was reduced, while the inhibition of apoptosis was attenuated. Our findings demonstrate that integrin αv promotes the proliferation of the human lung cancer cell line A549 by activating the ERK 1/2 signaling pathway, which suggests that this pathway may be a promising target for the treatment of human lung cancer.

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1	Pfister DG, Johnson DH, Azzoli CG, et al: American Society of Clinical Oncology treatment of unresectable non-small-cell lung cancer guideline: update 2003. J Clin Oncol. 22:330–353. 2004. View Article : Google Scholar
2	Jemal A, Siegel R, Xu J and Ward E: Cancer statistics, 2010. CA Cancer J Clin. 60:277–300. 2010. View Article : Google Scholar : PubMed/NCBI
3	Hynes RO: Integrins: bidirectional, allosteric signaling machines. Cell. 110:673–687. 2002. View Article : Google Scholar : PubMed/NCBI
4	Giancotti FG and Ruoslahti E: Integrin signaling. Science. 285:1028–1032. 1999. View Article : Google Scholar : PubMed/NCBI
5	Brakebusch C, Bouvard D, Stanchi F, Sakai T and Fässler R: Integrins in invasive growth. J Clin Invest. 109:999–1006. 2002. View Article : Google Scholar : PubMed/NCBI
6	Guo W and Giancotti FG: Integrin signalling during tumour progression. Nat Rev Mol Cell Biol. 5:816–826. 2004. View Article : Google Scholar : PubMed/NCBI
7	Sun H, Hu K, Wu M, et al: Contact by melanoma cells causes malignant transformation of human epithelial-like stem cells via alpha V integrin activation of transforming growth factor β1 signaling. Exp Biol Med (Maywood). 236:352–365. 2011. View Article : Google Scholar
8	Canonici A, Steelant W, Rigot V, et al: Insulin-like growth factor-I receptor, E-cadherin and alpha v integrin form a dynamic complex under the control of alpha-catenin. Int J Cancer. 122:572–582. 2008. View Article : Google Scholar
9	Vellon L, Menendez JA and Lupu R: A bidirectional ‘alpha(v)beta(3) integrin-ERK1/ERK2 MAPK’ connection regulates the proliferation of breast cancer cells. Mol Carcinog. 45:795–804. 2006. View Article : Google Scholar : PubMed/NCBI
10	Hazelbag S, Kenter GG, Gorter A, et al: Overexpression of the alpha v beta 6 integrin in cervical squamous cell carcinoma is a prognostic factor for decreased survival. J Pathol. 212:316–324. 2007. View Article : Google Scholar : PubMed/NCBI
11	Nip J, Shibata H, Loskutoff DJ, Cheresh DA and Brodt P: Human melanoma cells derived from lymphatic metastases use integrin alpha v beta 3 to adhere to lymph node vitronectin. J Clin Invest. 90:1406–1413. 1992. View Article : Google Scholar : PubMed/NCBI
12	Hosotani R, Kawaguchi M, Masui T, et al: Expression of integrin alphaVbeta3 in pancreatic carcinoma: relation to MMP-2 activation and lymph node metastasis. Pancreas. 25:e30–e35. 2002. View Article : Google Scholar : PubMed/NCBI
13	McCabe NP, De S, Vasanji A, Brainard J and Byzova TV: Prostate cancer specific integrin alphavbeta3 modulates bone metastatic growth and tissue remodeling. Oncogene. 26:6238–6243. 2007. View Article : Google Scholar : PubMed/NCBI
14	Felding-Habermann B, O’Toole TE, Smith JW, et al: Integrin activation controls metastasis in human breast cancer. Proc Natl Acad Sci USA. 98:1853–1858. 2001. View Article : Google Scholar : PubMed/NCBI
15	Landen CN, Kim TJ, Lin YG, et al: Tumor-selective response to antibody-mediated targeting of alphavbeta3 integrin in ovarian cancer. Neoplasia. 10:1259–1267. 2008.PubMed/NCBI
16	Engers R and Gabbert HE: Mechanisms of tumor metastasis: cell biological aspects and clinical implications. J Cancer Res Clin Oncol. 126:682–692. 2000. View Article : Google Scholar
17	Hood JD and Cheresh DA: Role of integrins in cell invasion and migration. Nat Rev Cancer. 2:91–100. 2002. View Article : Google Scholar
18	Adachi M, Taki T, Higashiyama M, Kohno N, Inufusa H and Miyake M: Significance of integrin alpha5 gene expression as a prognostic factor in node-negative non-small cell lung cancer. Clin Cancer Res. 6:96–101. 2000.PubMed/NCBI
19	Han JY, Kim HS, Lee SH, Park WS, Lee JY and Yoo NJ: Immunohistochemical expression of integrins and extracellular matrix proteins in non-small cell lung cancer: correlation with lymph node metastasis. Lung Cancer. 41:65–70. 2003. View Article : Google Scholar : PubMed/NCBI
20	Takada Y, Ye X and Simon S: The integrins. Genome Biol. 8:2152007. View Article : Google Scholar : PubMed/NCBI
21	Kikkawa H, Kaihou M, Horaguchi N, et al: Role of integrin alpha(v)beta3 in the early phase of liver metastasis: PET and IVM analyses. Clin Exp Metastasis. 19:717–725. 2002. View Article : Google Scholar
22	Jin Y, Tong DY, Chen JN, et al: Overexpression of osteopontin, αvβ3 and Pim-1 associated with prognostically important clinicopathologic variables in non-small cell lung cancer. PLoS One. 7:e485752012. View Article : Google Scholar
23	Elayadi AN, Samli KN, Prudkin L, et al: A peptide selected by biopanning identifies the integrin alphavbeta6 as a prognostic biomarker for nonsmall cell lung cancer. Cancer Res. 67:5889–5895. 2007. View Article : Google Scholar : PubMed/NCBI
24	Bates RC: Colorectal cancer progression: integrin alphavbeta6 and the epithelial-mesenchymal transition (EMT). Cell Cycle. 4:1350–1352. 2005. View Article : Google Scholar : PubMed/NCBI
25	Bates RC and Mercurio AM: The epithelial-mesenchymal transition (EMT) and colorectal cancer progression. Cancer Biol Ther. 4:365–370. 2005. View Article : Google Scholar : PubMed/NCBI
26	Bates RC, Bellovin DI, Brown C, et al: Transcriptional activation of integrin beta6 during the epithelial-mesenchymal transition defines a novel prognostic indicator of aggressive colon carcinoma. J Clin Invest. 115:339–347. 2005. View Article : Google Scholar : PubMed/NCBI
27	Ramos DM, Dang D and Sadler S: The role of the integrin alpha v beta6 in regulating the epithelial to mesenchymal transition in oral cancer. Anticancer Res. 29:125–130. 2009.PubMed/NCBI
28	Morgan MR, Thomas GJ, Russell A, Hart IR and Marshall JF: The integrin cytoplasmic-tail motif EKQKVDLSTDC is sufficient to promote tumor cell invasion mediated by matrix metalloproteinase (MMP)-2 or MMP-9. J Biol Chem. 279:26533–26539. 2004. View Article : Google Scholar : PubMed/NCBI
29	Faisal Khan KM, Laurie GW, McCaffrey TA and Falcone DJ: Exposure of cryptic domains in the alpha 1-chain of laminin-1 by elastase stimulates macrophages urokinase and matrix metalloproteinase-9 expression. J Biol Chem. 277:13778–13786. 2002. View Article : Google Scholar : PubMed/NCBI
30	Khan KM and Falcone DJ: Role of laminin in matrix induction of macrophage urokinase-type plasminogen activator and 92-kDa metalloproteinase expression. J Biol Chem. 272:8270–8275. 1997. View Article : Google Scholar : PubMed/NCBI
31	Brognard J and Dennis PA: Variable apoptotic response of NSCLC cells to inhibition of the MEK/ERK pathway by small molecules or dominant negative mutants. Cell Death Differ. 9:893–904. 2002. View Article : Google Scholar : PubMed/NCBI
32	Gollob JA, Wilhelm S, Carter C and Kelley SL: Role of Raf kinase in cancer: therapeutic potential of targeting the Raf/MEK/ERK signal transduction pathway. Semin Oncol. 33:392–406. 2006. View Article : Google Scholar : PubMed/NCBI