Abstract
The objective of this study was to investigate the role of αv-integrin subunit (ITGAV, CD51) in invasion and metastasis of the laryngeal and hypopharyngeal squamous cell carcinomas and to evaluate whether an antisense oligonucleotide sequence (ASONs) targeting ITGAV gene can result in proliferative inhibition and induce to apoptosis of laryngeal carcinoma cell lines (Hep-2). Firstly, a tissue microarray contained 75 primary carcinomas, 29 non-cancerous normal tissues and 20 metastatic lymph nodes was constructed and used to detect the expression of ITGAV by immunohistochemistry. The changes of ITGAV expression from each group were assessed and correlated to the clinical parameters of the patients. Secondly, the ASONs targeting ITGAV gene was transfected into Hep-2 cells in vitro. The proliferative ability of the cells after transfection was measured by MTT assay and the apoptosis was detected using flow cytometry. Results showed that the expression of ITGAV was significantly correlated with differentiation and lymph node metastasis of these cancers. In vitro test showed that the proliferative ability of Hep-2 cells was significantly inhibited by ASONs in a way of concentration- and time-depending mode, and a significant apoptosis of Hep-2 cells was also observed after ASONs transfection. In conclusion, the expression of ITGAV was significantly correlated with differentiation and metastasis of the laryngeal and hypopharyngeal carcinomas; down-regulation of ITGAV gene could inhibit proliferation of Hep-2 cells and induce to its apoptosis. These results suggest that ITGAV gene may become a promising prognostic marker and new treatment target for these cancers.
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Hynes RO (1992) Integrins: versatility, modulation, and signaling in cell adhesion. Cell 69:11–25
Albelda SM, Buck CA (1990) Integrins and other cell adhesion molecules. FASEB J 4:2868–2880
Clezardin P (1998) Recent insights into the role of integrins in cancer metastasis. Cell Mol Life Sci 4:541–548
Varner JA, Cheresh DA (1996) Integrins and cancer. Curr Opin Cell Biol 8:724–730
Aplin AE, Howe AK, Juliano RL (1999) Cell adhesion molecules, signal transduction and cell growth. Curr Opin Cell Biol 11:737–744
Renshaw MW, Ren XD, Schwartz MA (1997) Growth factor activation of MAP kinase requires cell adhesion. EMBO J 16:5592–5599
Klemke RL, Cai S, Giannini AL, Gallagher PJ, de Lanerolle P, Cheresh DA (1997) Regulation of cell motility by mitogen-activated protein kinase. J Cell Biol 137:481–492
Hood JD, Bednarski M, Frausto R, Guccione S, Reisfeld RA, Xiang R, Cheresh DA (2002) Tumor regression by targeted gene delivery to the neovasculature. Science 296:2404–2407
Heino J (1993) Integrin-type extracellular matrix receptors in cancer and inflammation. Ann Med 25:335–342
Fawcett J, Harris AL (1992) Cell adhesion molecule and cancer. Curr Opin Oncol 4:142–148
Rudolph R, Cheresh D (1990) Cell adhesion mechanisms and their potential impact on wound healing and tumor control. Clin Plast Surg 17:457–462
Hynes RO (2002) Integrins: bidirectional, allosteric signaling machines. Cell 110:673–687
van der Flier A, Sonnenberg A (2001) Function and interactions of integrins. Cell Tissue Res 305:285–298
Enenstein J, Kramer RH (1994) Confocal microscopic analysis of integrin expression on the microvasculature and its sprouts in the neonatal foreskin. J Invest Dermatol 103:381–386
Brooks PC, Clark RA, Cheresh DA (1994) Requirement of vascular integrin αvβ3 for angiogenesis. Science 264:569–571
Brooks PC, Montgomery AM, Rosenfeld M, Reisfeld RA, Hu T, Klier G, Cheresh DA (1994) Integrin αvβ3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell 79:1157–1164
Storgard CM, Stupack DG, Jonczyk A, Goodman SL, Fox RI, Cheresh DA (1999) Decreased angiogenesis and arthritic disease in rabbits treated with an αvβ3 antagonist. J Clin Invest 103:47–54
Felding-Habermann B, Mueller BM, Romerdahl CA, Cheresh DA (1992) Involvement of integrin αv gene expression in human melanoma tumorigenicity. J Clin Invest 89:2018–2022
Eliceiri BP, Cheresh DA (1999) The role of alphav integrins during angiogenesis: insights into potential mechanisms of action and clinical development. J Clin Invest 103:1227–1230
Mao L, Hong WK, Papadimitrakopoulou VA (2004) Focus on head and neck cancer. Cancer Cell 5:311–316
Liu M, Lawson G, Delos M, Jamart J, Remacle M (1997) Expression of E-Cadherin adhesion molecule in vocal cord carcinoma. Eur Arch Otorhinolaryngol 254:417–421
Liu M, Lawson G, Delos M, Jamart J, Chatelain B, Remacle M, Marbaix E (2003) Prognostic value of cell proliferation markers, tumour suppressor proteins and cell adhesion molecules in primary squamous cell carcinoma of the larynx and hypopharynx. Eur Arch Otorhinolaryngol 260:28–34
Rosai J, Carcangiu ML, DeLellis RA (1992) Atlas of tumor pathology—tumors of the larynx, 3rd series. Armed Force Institute of Pathology, Washington
Kronenwett R, Graf T, Nedbal W, Weber M, Steidl U, Rohr UP, Mohler T, Haas R (2002) Inhibition of angiogenesis in vitro by αv integrin-directed antisense oligonucleotides. Cancer Gene Ther 9:587–596
Sanders RJ, Mainiero F, Giancotti FG (1998) The role of integrins in tumorigenesis and metastasis. Cancer Invest 16:329–344
Goldberg I, Davidson B, Reich R, Gotlieb WH, Ben-Baruch G, Bryne M, Berner A, Nesland JM, Kopolovic J (2001) αv-integrin expression is a novel marker of poor prognosis in advanced-stage ovarian carcinoma. Clin Cancer Res 7:4073–4079
Nikkola J, Vihinen P, Vlaykova T, Hahka-Kemppinen M, Heino J, Pyrhönen S (2004) Integrin chains beta1 and alphav as prognostic factors in human metastatic melanoma. Melanoma Res 14:29–37
Townsend PA, Villanova I, Uhlmann E, Peyman A, Knolle J, Baron R, Teti A, Horton MA (2000) An antisense oligonucleotide targeting the alphaV integrin gene inhibits adhesion and induces apoptosis in breast cancer cells. Eur J Cancer 36:397–409
Huang S, Stupack D, Liu A, Cheresh D, Nemerow GR (2000) Cell growth and matrix invasion of EBV-immortalized human B lymphocytes is regulated by expression of alpha(v) integrins. Oncogene 19:1915–1923
Kozlova NI, Morozevich GE, Chubukina AN, Berman AE (2001) Integrin alphavbeta3 promotes anchorage-dependent apoptosis in human intestinal carcinoma cells. Oncogene 20:4710–4717
Wewer UM, Shaw LM, Albrechtsen R, Mercurio AM (1997) The integrin α6ß1 promotes the survival of metastatic human breast carcinoma cells in mice. Am J Pathol 151:1191–1198
Gui GP, Wells CA, Browne PD, Yeomans P, Jordan S, Puddefoot JR, Vinson GP, Carpenter R (1995) Integrin expression in primary breast cancer and its relation to axillary nodal status. Surgery 117:102–108
Mizejewski Gerald J (1999) Role of integrins in cancer: survey of expression patterns. Proc Soc Exp Biol Med 222:124–138
Thiery JP (2002) Epithelial–mesenchymal transitions in tumour progression. Nat Rev Cancer 2:442–454
Chamoux E, Bolduc L, Lehoux JG, Gallo-Payet N (2001) Identification of extracellular matrix components and their integrin receptors in the human fetal adrenal gland. J Clin Endocrinol Metab 86:2090–2098
Tucker GC (2003) Alpha v integrin inhibitors and cancer therapy. Curr Opin Investig Drugs 4:722–731
Brooks PC, Montgomery AM, Rosenfeld M, Reisfeld RA, Hu T, Klier G, Cheresh DA (1994) Integrin αvβ3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell 79:1157–1164
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This study was granted by the Natural Science Foundation (D200631) and Overseas Foundation of Education Bureau (1151HZ029) of Heilongjiang Province, and Scientific Research Foundation of Harbin Bureau of Science and Technology (2006RFLXS028), P. R. China.
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Lu, J.G., Sun, Y.N., Wang, C. et al. Role of the αv-integrin subunit in cell proliferation, apoptosis and tumor metastasis of laryngeal and hypopharyngeal squamous cell carcinomas: a clinical and in vitro investigation. Eur Arch Otorhinolaryngol 266, 89–96 (2009). https://doi.org/10.1007/s00405-008-0675-z
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DOI: https://doi.org/10.1007/s00405-008-0675-z