DNA and RNA sequencing identified a novel oncogene VPS35 in liver hepatocellular carcinoma
DNA and RNA sequencing identified a novel oncogene VPS35 in liver hepatocellular carcinoma
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DNA和RNA测序鉴定出肝癌中的一个新癌基因VPS35
DOI：
10.1038/s41388-020-1215-6
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发表时间：
2020-02-19
期刊：
影响因子：
8
通讯作者：
Ding, Keyue
中科院分区：
文献类型：
--
作者：
Zhang, Guiji;Tang, Xia;Ding, Keyue
肝细胞癌（LIHC）是全球癌症死亡的第二大原因。尽管到目前为止发现的癌症驱动基因被认为是饱和或接近饱和的，但由于肿瘤的显著异质性，在发现致癌的新基因方面仍然存在挑战。在此，在一个乙型肝炎病毒（HBV）相关LIHC的小队列中，我们使用全外显子组和RNA测序数据研究了肿瘤突变等位基因的转录模式。转录肿瘤突变等位基因的图聚类特征重叠功能簇，从而优先考虑潜在的新致癌基因。我们在体外和体内验证了潜在的新型致癌基因的功能。我们发现，反转录复合物的一个组成部分-液泡蛋白分选相关蛋白35 (VPS35)-通过PI3K/AKT信号通路促进肝癌细胞的增殖。在敲除VPS35的肝癌细胞中，膜成纤维细胞生长因子受体3 （FGFR3）的分布显著减少，表明VPS35对跨膜受体的分选和运输有影响。这项研究提供了对逆转录复合物在癌变中的作用的深入了解，并对LIHC的个性化治疗策略的发展具有重要意义。
Liver hepatocellular carcinoma (LIHC) is the second leading cause of cancer mortality worldwide. Although cancer driver genes identified so far have been considered to be saturated or nearly saturated, challenges remain in discovering novel genes underlying carcinogenesis due to significant tumor heterogeneity. Here, in a small cohort of hepatitis B virus (HBV)-associated LIHC, we investigated the transcriptional patterns of tumor-mutated alleles using both whole-exome and RNA sequencing data. A graph clustering of the transcribed tumor-mutated alleles characterized overlapped functional clusters, and thus prioritized potentially novel oncogenes. We validated the function of the potentially novel oncogenes in vitro and in vivo. We showed that a component of the retromer complex-the vacuolar protein sorting-associated protein 35 (VPS35)-promoted the proliferation of hepatoma cell through the PI3K/AKT signaling pathway. In VPS35-knockout hepatoma cells, a significantly reduced distribution of membrane fibroblast growth factor receptor 3 (FGFR3) demonstrated the effects of VPS35 on sorting and trafficking of transmembrane receptor. This study provides insight into the roles of the retromer complex on carcinogenesis and has important implications for the development of personalized therapeutic strategies for LIHC.