Genetic and epigenetic control of UNC5C expression in human renal cell carcinoma
Genetic and epigenetic control of UNC5C expression in human renal cell carcinoma
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人肾细胞癌UNC5C表达的遗传和表观遗传控制
DOI：
10.1016/j.ejca.2011.04.021
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发表时间：
2011-09-01
影响因子：
8.4
通讯作者：
Zhang, Jun
中科院分区：
文献类型：
--
作者：
Lv, Dan;Zhao, Wei;Zhang, Jun
不适当的基因沉默和随后的混杂活性定义了包括肾细胞癌（RCC）在内的许多实体瘤的转化。在此，我们报告 Netrin-1 受体之一 UNC5C 在肾细胞癌细胞系和原发性肿瘤中经常失活。 UNC5C 蛋白在人肾的近曲小管中表达，这是透明细胞肾细胞癌 (ccRCC) 和乳头状肾细胞癌 (pRCC) 的推测起源。与配对的邻近非恶性组织相比，RCC 中 UNC5C mRNA 和蛋白表达均显着下调。免疫组化分析显示，94.3%的样本中UNC5C失活，且UNC5C的丢失发生在RCC早期。甲基化特异性PCR显示UNC5C启动子在两种肾癌细胞系中被甲基化。单独的药理去甲基化或与去乙酰化抑制相结合可显着诱导 UNC5C 表达。此外，亚硫酸氢盐基因组测序（BGS）证实UNC5C启动子中存在密集甲基化。在配对肿瘤样本中，44 名患者中有 12 名 (27.3%) 观察到 UNC5C 甲基化。此外，我们分析了肾细胞癌中UNC5C杂合性丢失（LOH），44名患者中有27名（61.4%）观察到LOH。最后，UNC5C表达的恢复抑制了肾癌细胞的集落形成。此外，UNC5C 抑制肿瘤细胞增殖、迁移并增强对顺铂和依托泊苷的化疗敏感性。因此，UNC5C 在 RCC 中充当肿瘤抑制因子，并且在 RCC 中下调。杂合性丢失和 DNA 甲基化导致肾细胞癌中 UNC5C 失活。 (C) 2011 Elsevier Ltd. 保留所有权利。
Inappropriate gene silencing and subsequent promiscuous activity define the transformation of many solid tumours including renal cell carcinoma (RCC). Here, we report that UNC5C, one of the Netrin-1 receptors, was frequently inactivated in RCC cell lines and primary tumours. UNC5C protein was expressed in the proximal convoluted tubules of the human kidney, the presumed origin of clear cell RCC (ccRCC) and papillary RCC (pRCC). Compared to paired adjacent non-malignant tissues, both UNC5C mRNA and protein expression were significantly down-regulated in RCC. Immunohistochemical analysis showed that UNC5C was inactivated in 94.3% of the samples and the loss of UNC5C occurred at the early stage of RCC. Methylation specific PCR showed that UNC5C promoter was methylated in two renal carcinoma cell lines. Pharmacologic demethylation alone or in combination with inhibition of deacetylation dramatically induced UNC5C expression. Furthermore, bisulfite genomic sequencing (BGS) confirmed that dense methylation existed in UNC5C promoter. In paired tumour samples, UNC5C methylation was observed in 12 out of 44 patients (27.3%). Moreover, we analysed the loss of heterozygosity (LOH) of UNC5C in renal cell carcinoma, the LOH was observed in 27 out of 44 patients (61.4%). Finally, restoration of UNC5C expression suppressed the colony formation of renal carcinoma cells. In addition, UNC5C inhibited tumour cell proliferation, migration and enhanced chemosensitivity to cisplatin and etoposide. Therefore, UNC5C acts as a tumour suppressor in RCC and is down-regulated in RCC. Loss of heterozygosity and DNA methylation contribute to the inactivation of UNC5C in renal cell carcinoma. (C) 2011 Elsevier Ltd. All rights reserved.