Analysis of integrin α7 mutations in prostate cancer, liver cancer, glioblastoma multiforme, and leiomyosarcoma

Background Integrins are the major adhesive molecules in mammalian cells. Each integrin subtype plays a unique role in cell differentiation and embryo development. However, integrin involvement in carcinogenesis has not been well defined. Methods We identified mutations in integrin alpha 7 by sequencing genomic DNAs and cDNAs from 122 specimens, including 62 primary human tumor samples, four cell lines, and 56 matched normal tissues. We evaluated the tumor suppressor activity of integrin alpha 7 with colony formation, soft agar colony growth, and cell migration assays by forcing its expression in PC-3 and Du145 prostate cancer cells and SK-UT-1 leiomyosarcoma cells. PC-3 and Du145 xenograft tumors with increased levels of integrin 0 in severe combined immune deficient mice were used to assess the effect of integrin alpha 7 on tumor growth and metastasis. Immunostaining was used to localize and to measure the level of integrin alpha 7 in 701 and 141 specimens of prostate and smooth muscle, respectively. A meta-analysis of integrin alpha 7 mRNA microarray data from four studies was performed. Kaplan-Meier analyses were used to assess survival. All statistical tests were two-sided. Results Integrin alpha 7 mutations that generate truncations were found in specimens of 16 of 28 prostate cancers (57%, 95% confidence interval [Cl] = 37% to 76%), five of 24 hepatocellular carcinomas (21%, 95% Cl = 7% to 42%), five of six glioblastomas multiforme (83%, 95% Cl = 36% to 99%), and one of four leiomyosarcomas (25%, 95% Cl = 0.6% to 81%). Integrin alpha 7 mutations were associated with increased recurrence of human prostate cancer (nine recurrences among 13 patients with integrin alpha 7 mutations versus one among eight without such mutations; odds ratio [OR] = 14, 95% Cl = 1.15 to 782, P =.024) and hepatocellular carcinoma (five recurrences among eight patients with integrin 0 mutations versus one among 16 without such mutations, OR = 21, 95% Cl = 1.6 to 1245; P =.007). Forced expression of normal integrin alpha 7 in prostate cancer and leiomyosarcoma cell lines suppressed tumor growth and metastasis both in vitro and in vivo. Focal or no integrin alpha 7 expression in human prostate cancer and soft tissue leiomyosarcoma was associated with a reduction of metastasis-free survival (for example, for prostate cancer with focal or no expression, 5-year metastasis-free survival was 32%, 95% Cl = 24.4% to 46.3%, and for prostate cancer with at least weak expression, it was 85%, 95% Cl = 79% to 91%; P<.001). Microarray analysis indicated that cyclin D kinase inhibitor 3 and GTPase-activating protein may be possible targets for integrin alpha 7-mediated tumor suppressor activity and inhibition of cell motility. Conclusion Integrin alpha 7 appears to be a tumor suppressor that operates by suppressing tumor growth and retarding migration.