Analysis of integrin α7 mutations in prostate cancer, liver cancer, glioblastoma multiforme, and leiomyosarcoma
Analysis of integrin α7 mutations in prostate cancer, liver cancer, glioblastoma multiforme, and leiomyosarcoma
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DOI：
10.1093/jnci/djk199
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发表时间：
2007-06-06
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影响因子：
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通讯作者：
Luo, Jian-Hua
中科院分区：
文献类型：
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作者：
Ren, Baoguo;Yu, Yan P.;Luo, Jian-Hua
背景整合素是哺乳动物细胞中主要的粘附分子。每种整合素亚型在细胞分化和胚胎发育中起着独特的作用。然而，整合素参与致癌作用还没有得到很好的defined.Methods我们确定了整合素α 7基因组DNA和cDNA序列从122个标本，包括62个原发性人类肿瘤样本，4个细胞系，和56个匹配的正常组织中的突变。我们通过在PC-3和Du 145前列腺癌细胞和SK-UT-1平滑肌肉瘤细胞中强制表达整合素α 7，用集落形成、软琼脂集落生长和细胞迁移试验评估其肿瘤抑制活性。在严重联合免疫缺陷小鼠中具有增加的整合素0水平的PC-3和Du 145异种移植肿瘤用于评估整合素α 7对肿瘤生长和转移的影响。免疫染色用于定位和测量整合素α 7的水平在701和141标本的前列腺和平滑肌，分别。对来自四项研究的整合素α 7 mRNA微阵列数据进行荟萃分析。Kaplan-Meier分析用于评估生存率。结果在28例前列腺癌标本中有16例发现了整合素α 7突变，导致截短（57%，95%置信区间[Cl] = 37%-76%），24例肝细胞癌中有5例（21%，95%CI = 7%-42%），6例多形性胶质母细胞瘤中的5例（83%，95%CI = 36%-99%），4例平滑肌瘤中的1例（25%，95%CI = 0.6%-81%）。整合素α 7突变与人前列腺癌复发增加相关（13例整合素α 7突变患者中9例复发，8例无此类突变患者中1例复发;比值比[OR] = 14，95% CI = 1.15至782，P =.024）和肝细胞癌（8例整合素0突变患者中5例复发，16例无此类突变患者中1例复发，OR = 21，95%CI = 1.6至1245; P = 0.007）。前列腺癌和平滑肌肉瘤细胞系中正常整合素α 7的强制表达在体外和体内均抑制肿瘤生长和转移。在人前列腺癌和软组织平滑肌肉瘤中，整合素α 7的局灶性表达或无表达与无转移生存率的降低相关（例如，对于局灶性表达或无表达的前列腺癌，5年无转移生存率为32%，95%CI = 24.4%至46.3%，而对于至少弱表达的前列腺癌，5年无转移生存率为85%，95% CI = 79%至91%; P
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