Abstract
Integrin controls cell adhesion to extracellular matrix and plays an important role in regulating the proliferation and apoptosis of cells. In order to explore the role of ITGA3 gene polymorphisms in the pathogenesis and clinicopathological characteristics of osteosarcoma, we embarked on a study including a group of 118 patients and a group of 126 healthy controls. TaqMan PCR genotyping technology was used to detect the genotypes of ITGA3 gene SNPs (rs2230392, rs2285524 and rs16948627) in the peripheral blood. Then, associations of the SNP (rs2230392, rs2285524 and rs16948627) genotypes with the incidence risk and tumor characteristics of osteosarcoma were evaluated. A significant difference (P = 0.02) in the genotype frequency distribution of rs2230392 was observed between case and control groups. The analysis showed that patients carrying AA genotype had a higher risk of osteosarcoma (OR 2.34, 95 % CI 1.18–4.64) than those with GG genotype. Regarding rs2230392, men carrying AA genotype had a higher risk of osteosarcoma (OR 3.37, 95 % CI 1.25–9.11). Compared with those with GG genotype, patients carrying AA genotype had a twofold increased risk of osteosarcoma metastasis (OR 2.46, 95 % CI 1.09–5.57). Survival analysis showed that for rs2230392, survival time of osteosarcoma patients with three different genotypes was significantly different. Polymorphisms of ITGA3 gene rs2230392 may affect the incidence, metastasis and survival of osteosarcoma, which may clinically become a new target for predicting the risk of osteosarcoma, and have prognostic value.
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References
Picci P. Osteosarcoma (osteogenic sarcoma). Orphanet J Rare Dis. 2007;2:6.
Unni KK. Osteosarcoma of bone. J Orthop Sci. 1998;3(5):287–94.
Subbiah V, Kurzrock R. Phase 1 clinical trials for sarcomas: the cutting edge. Curr Opin Oncol. 2011;23(4):352–60.
Lu BJ, Wang YQ, Wei XJ, Rong LQ, Wei D, Yan CM, et al. Expression of WNT-5a and ROR2 correlates with disease severity in osteosarcoma. Mol Med Rep. 2012;5(4):1033–6.
PosthumaDeBoer J, Witlox MA, Kaspers GJ, van Royen BJ. Molecular alterations as target for therapy in metastatic osteosarcoma: a review of literature. Clin Exp Metastasis. 2011;28(5):493–503.
Foster L, Dall GF, Reid R, Wallace WH, Porter DE. Twentieth-century survival from osteosarcoma in childhood. Trends from 1933 to 2004. J Bone Joint Surg Br. 2007;89(9):1234–8.
Chou AJ, Geller DS, Gorlick R. Therapy for osteosarcoma: where do we go from here? Paediatr Drugs. 2008;10(5):315–27.
Schwartz MA, Schaller MD, Ginsberg MH. Integrins: emerging paradigms of signal transduction. Annu Rev Cell Dev Biol. 1995;11:549–99.
Taddei I, Faraldo MM, Teuliere J, Deugnier MA, Thiery JP, Glukhova MA. Integrins in mammary gland development and differentiation of mammary epithelium. J Mammary Gland Biol Neoplasia. 2003;8(4):383–94.
Hood JD, Cheresh DA. Role of integrins in cell invasion and migration. Nat Rev Cancer. 2002;2(2):91–100.
Takada Y, Ye X, Simon S. The integrins. Genome Biol. 2007;8(5):215.
Schneider JG, Amend SR, Weilbaecher KN. Integrins and bone metastasis: integrating tumor cell and stromal cell interactions. Bone. 2011;48(1):54–65.
Kreidberg JA. Functions of alpha3beta1 integrin. Curr Opin Cell Biol. 2000;12(5):548–53.
Tsuji T. Physiological and pathological roles of alpha3beta1 integrin. J Membr Biol. 2004;200(3):115–32.
Morini M, Mottolese M, Ferrari N, Ghiorzo F, Buglioni S, Mortarini R, et al. The alpha 3 beta 1 integrin is associated with mammary carcinoma cell metastasis, invasion, and gelatinase B (MMP-9) activity. Int J Cancer. 2000;87(3):336–42.
Wang H, Fu W, Im JH, Zhou Z, Santoro SA, Iyer V, et al. Tumor cell alpha3beta1 integrin and vascular laminin-5 mediate pulmonary arrest and metastasis. J Cell Biol. 2004;164(6):935–41.
Lamar JM, Pumiglia KM, DiPersio CM. An immortalization-dependent switch in integrin function up-regulates MMP-9 to enhance tumor cell invasion. Cancer Res. 2008;68(18):7371–9.
Mercurio AM, Bachelder RE, Chung J, O’Connor KL, Rabinovitz I, Shaw LM, et al. Integrin laminin receptors and breast carcinoma progression. J Mammary Gland Biol Neoplasia. 2001;6(3):299–309.
Chia J, Kusuma N, Anderson R, Parker B, Bidwell B, Zamurs L, et al. Evidence for a role of tumor-derived laminin-511 in the metastatic progression of breast cancer. Am J Pathol. 2007;170(6):2135–48.
Marinkovich MP. Tumour microenvironment: laminin 332 in squamous-cell carcinoma. Nat Rev Cancer. 2007;7(5):370–80.
Frazer KA, Ballinger DG, Cox DR, Hinds DA, Stuve LL, Gibbs RA, et al. A second generation human haplotype map of over 3.1 million SNPs. Nature. 2007;449(7164):851–61.
Savage SA, Mirabello L, Wang Z, Gastier-Foster JM, Gorlick R, Khanna C, et al. Genome-wide association study identifies two susceptibility loci for osteosarcoma. Nat Genet. 2013;45(7):799–803.
Kahler AK, Djurovic S, Kulle B, Jonsson EG, Agartz I, Hall H, et al. Association analysis of schizophrenia on 18 genes involved in neuronal migration: MDGA1 as a new susceptibility gene. Am J Med Genet Part B Neuropsychiatr Genet. 2008;147B(7):1089–100.
Brendle A, Lei H, Brandt A, Johansson R, Enquist K, Henriksson R, et al. Polymorphisms in predicted microRNA-binding sites in integrin genes and breast cancer: ITGB4 as prognostic marker. Carcinogenesis. 2008;29(7):1394–9.
Langsenlehner U, Renner W, Yazdani-Biuki B, Eder T, Wascher TC, Paulweber B, et al. Integrin alpha-2 and beta-3 gene polymorphisms and breast cancer risk. Breast Cancer Res Treat. 2006;97(1):67–72.
Naumov VA, Generozov EV, Solovyov YN, Aliev MD, Kushlinsky NE. Association of FGFR3 and MDM2 gene nucleotide polymorphisms with bone tumors. Bull Exp Biol Med. 2012;153(6):869–73.
Hao T, Feng W, Zhang J, Sun YJ, Wang G. Association of four ERCC1 and ERCC2 SNPs with survival of bone tumour patients. Asian Pac J Cancer Prev. 2012;13(8):3821–4.
Caronia D, Patino-Garcia A, Perez-Martinez A, Pita G, Moreno LT, Zalacain-Diez M, et al. Effect of ABCB1 and ABCC3 polymorphisms on osteosarcoma survival after chemotherapy: a pharmacogenetic study. PLoS ONE. 2011;6(10):e26091.
Liu Y, Lv B, He Z, Zhou Y, Han C, Shi G, et al. Lysyl oxidase polymorphisms and susceptibility to osteosarcoma. PLoS ONE. 2012;7(7):e41610.
Minde DP, Anvarian Z, Rudiger SG, Maurice MM. Messing up disorder: how do missense mutations in the tumor suppressor protein APC lead to cancer? Mol Cancer. 2011;10:101.
Bojesen SE, Tybjaerg-Hansen A, Nordestgaard BG. Integrin beta3 Leu33Pro homozygosity and risk of cancer. J Natl Cancer Inst. 2003;95(15):1150–7.
Choma DP, Milano V, Pumiglia KM, DiPersio CM. Integrin alpha3beta1-dependent activation of FAK/Src regulates Rac1-mediated keratinocyte polarization on laminin-5. J Invest Dermatol. 2007;127(1):31–40.
Raymond K, Cagnet S, Kreft M, Janssen H, Sonnenberg A, Glukhova MA. Control of mammary myoepithelial cell contractile function by alpha3beta1 integrin signalling. EMBO J. 2011;30(10):1896–906.
Schwartz MA, Ginsberg MH. Networks and crosstalk: integrin signalling spreads. Nat Cell Biol. 2002;4(4):E65–8.
Playford MP, Schaller MD. The interplay between Src and integrins in normal and tumor biology. Oncogene. 2004;23(48):7928–46.
Brunton VG, Frame MC. Src and focal adhesion kinase as therapeutic targets in cancer. Curr Opin Pharmacol. 2008;8(4):427–32.
McCawley LJ, Matrisian LM. Tumor progression: defining the soil round the tumor seed. Curr Biol. 2001;11(1):R25–7.
Coussens LM, Tinkle CL, Hanahan D, Werb Z. MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis. Cell. 2000;103(3):481–90.
Beliveau A, Mott JD, Lo A, Chen EI, Koller AA, Yaswen P, et al. Raf-induced MMP9 disrupts tissue architecture of human breast cells in three-dimensional culture and is necessary for tumor growth in vivo. Genes Dev. 2010;24(24):2800–11.
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This research was supported by the National Natural Science Foundation of China (Grant No. 81160323) and the Guangxi Innovative Program of Graduate Education (Grant No. YCSZ2013035).
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Yang, W., He, M., Zhao, J. et al. Association of ITGA3 gene polymorphisms with susceptibility and clinicopathological characteristics of osteosarcoma. Med Oncol 31, 826 (2014). https://doi.org/10.1007/s12032-013-0826-y
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DOI: https://doi.org/10.1007/s12032-013-0826-y