Analysis of the VHL Tumor Suppressor Gene in Kidney Cancer

肾癌VHL抑癌基因分析

• 批准号: 13671662
• 负责人: YAO Masahiro
• 金额: $ 2.18万
• 依托单位: Yokohama City Unviersity
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671662/
• 关键词: Renal cell carcinoma; VHL gene; Tumor suppressor; Microarray; Cyclin D1

Somatic alteration of the VHL tumor suppressor gene is one of the most common genetic changes observed in the sporadic, clear-cell subtype of renal cell carcinoma (RCC). A total of 187 Japanese patients with clear-cell RCC who underwent nephrectomy were examined for somatic VHL gene alteration and clinicopathologic and prognostic data were also collected. A VHL mutation was detected in 108 (57%) samples. VHL alterations were strongly associated with better prognosis for 134 patients with stage I-III clear-cell RCC treated by radical nephrectomy for cancer-free survival and cancer-specific survival (logrank P =.024 and.023, respectively). These associations with cancer-free survival and cancer-specific survival were more statistically significant among patients with relatively advanced-stage tumors (stage III[P =.014 and.010, respectively] or stage II+III [P =.002 and.009]) or higher-grade tumors (【greater than or equal】G3 [P =.013 and.032] or 【greater than or equal】G2 [P =.013 and.018] … More ) or patients who presented with symptoms (P =.005 and.012). The VHL alteration was determined to be an independent prognostic factor, after adjustment for sex, age, stage, grading, and symptomatic presentation. However, VHL alterations were not associated with cancer-specific survival for the 53 patients with stage IV tumors treated with palliative or adjunctive nephrectomy (logrank P =.760). We compared the gene expression profile between VHL-deflcient renal carcinoma 786-O cells and those infected with an adenovirus vector encoding VHL to identify the target gene of pVHL. We found cyclin D1 as a new target of pVHL at a high cell density. Consequently, the phosporylation level of the Rb protein remained high in these cells whereas there was no phosporylated Rb in VHL (+) cells under the contact inhibition. The abnormal expression of cyclin D1 at a high cell density was observed even in VHL (+) cells under the hypoxic state. Moreover, ectopic expression of a HIF mutant resistant to pVHL-mediated proteolysis causes the abnormal cyclin D1 expression in VHL (+) cells. Taken together, these observations indicate that VHL is required for the down-regulation of cyclin D1 at a high cell density through HIF. Less

VHL 肿瘤抑制基因的体细胞改变是在散发性透明细胞亚型肾细胞癌 (RCC) 中观察到的最常见的遗传变化之一。对 187 名接受肾切除术的日本透明细胞 RCC 患者进行了检查。还收集了 108 个（57%）样本中的体细胞 VHL 基因改变以及临床病理和预后数据。VHL 改变与更好的预后密切相关。 134 名 I-III 期透明细胞肾细胞癌患者接受根治性肾切除术治疗，获得无癌生存期和癌症特异性生存期（对数秩 P 分别 = 0.024 和 023）。在晚期相对分期肿瘤（III 期[分别为 P = .014 和 .010] 或 II+III 期 [P = .002 和 .009]）或更高级别肿瘤的患者中更为显着（【大于或等于】G3 [P =.013 和.032] 或【大于或等于】G2 [P =.013 和.018] … 更多）或出现症状的患者（P =.005 和. 012)。在调整性别、年龄、分期、分级和症状表现后，VHL 改变被确定为独立的预后因素。然而，VHL 改变与癌症特异性生存无关。我们对 53 名接受姑息性或辅助性肾切除术治疗的 IV 期肿瘤患者进行了比较（logrank P =.760）。我们发现细胞周期蛋白 D1 在高细胞密度下作为 pVHL 的新靶点，其中 Rb 蛋白的磷酸化水平仍然很高。在接触抑制下，VHL（+）细胞中没有磷酸化的Rb。即使在缺氧状态下，VHL（+）细胞中也观察到高细胞密度的细胞周期蛋白D1的异常表达。对 pVHL 介导的蛋白水解具有抗性的突变体导致 VHL (+) 细胞中细胞周期蛋白 D1 表达异常。 综上所述，这些观察结果表明 VHL 是下调通过 HIF 减少高细胞密度的细胞周期蛋白 D1。

项目成果

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Baba M、Hiral S、Yamada-Okabe H、Hamada K、Tabuchi H、Kobayashi K、Kondo K、Yoshida M、Yamashita A、Kishida T、Nakaikawa N、Nagashima Y、Kubota Y、Yao M、Ohno S.：“损失

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