Downregulation of WDR20 due to loss of 14q is involved in the malignant transformation of clear cell renal cell carcinoma.
Downregulation of WDR20 due to loss of 14q is involved in the malignant transformation of clear cell renal cell carcinoma.
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DOI：
10.1111/cas.12892
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发表时间：
2016-04
期刊：
影响因子：
5.7
通讯作者：
Moriyama M
中科院分区：
文献类型：
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作者：
Takahashi M;Tsukamoto Y;Kai T;Tokunaga A;Nakada C;Hijiya N;Uchida T;Daa T;Nomura T;Sato F;Mimata H;Matsuura K;Moriyama M
此前，我们报道了14q基因组缺失在高级别透明细胞肾细胞癌（ccRCC）中比在低级别透明细胞肾细胞癌（ccRCC）中更常见，并且对该区域基因的表达水平有显着影响，表明这些基因可能参与了ccRCC的恶性转化。在这里，我们发现位于 14q 丢失最小公共区域的六个基因由于拷贝数丢失而在高级别 ccRCC 中显着下调。使用癌症基因组图谱研究网络的数据集，我们发现这六个基因之一 WDR20 的下调与 ccRCC 患者的较差预后显着相关，表明 WDR20 下调可能与 ccRCC 的恶性转化有关。在功能测定中，外源 WDR20 显着抑制 RCC 细胞系的生长并诱导细胞凋亡。有趣的是，据报道，ERK 和蛋白激酶 B/AKT 的磷酸化水平与 RCC 细胞的恶性表型有关，但 WDR20 的外源表达明显降低了 ERK 和蛋白激酶 B/AKT 的磷酸化水平。因此，我们的数据表明，由于 14q 缺失而导致的 WDR20 下调可能与 ccRCC 的恶性转化有关，部分通过 ERK 和蛋白激酶 B/AKT 途径的激活来实现。
Previously, we reported that genomic loss of 14q occurs more frequently in high‐grade than in low‐grade clear cell renal cell carcinomas (ccRCCs), and has a significant impact on the levels of expression of genes located in this region, suggesting that such genes may be involved in the malignant transformation of ccRCCs. Here, we found that six of the genes located in the minimal common region of 14q loss were significantly downregulated in high‐grade ccRCCs due to copy number loss. Using a dataset from The Cancer Genome Atlas Research Network, we found that downregulation of one of these six genes, WDR20, was significantly associated with poorer outcome in patients with ccRCC, suggesting that WDR20 downregulation may be involved in the malignant transformation of ccRCCs. In functional assays, exogenous WDR20 significantly inhibited the growth of RCC cell lines and induced apoptosis. Interestingly, the phosphorylation levels of ERK and protein kinase B/AKT, which reportedly contribute to the malignant phenotype of RCC cells, were clearly reduced by exogenous expression of WDR20. Thus, our data suggest that downregulation of WDR20 due to 14q loss may be involved in the malignant transformation of ccRCCs, in part through activation of the ERK and protein kinase B/AKT pathways.