CCDC178 promotes hepatocellular carcinoma metastasis through modulation of anoikis
CCDC178 promotes hepatocellular carcinoma metastasis through modulation of anoikis
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CCDC178通过调节失巢凋亡促进肝细胞癌转移
作者：
Hu, X.;Zhao, Y.;Wu, J.
肝细胞癌（Hepatocellular carcinoma，HCC）是世界上最常见的恶性肿瘤之一，复发转移率高。卷曲螺旋结构域蛋白178（CCDC178）在肝细胞癌（HCC）中存在突变，但其在生理和病理过程中的作用尚不清楚。在此，我们发现CCDC178在HCC组织中上调，并且其过表达与病理分期相关（P= 0.003）。CCDC178缺陷可降低肝癌细胞的贴壁生长能力和抗失巢凋亡能力，抑制肝癌细胞的体内转移。在机制上，CCDC178与BRCA 1相关蛋白2（BRAP2）（细胞外信号调节激酶（ERK）通路的负调节因子）相关，并促进其降解。此外，CCDC178缺陷损害了依赖于BRAP2的ERK活化。综上所述，我们确定CCDC178作为一个新的候选癌基因参与失巢凋亡抵抗和肝癌转移，并提出CCDC178可能是一个新的治疗肝癌的目标。
Hepatocellular carcinoma (HCC) is one of the most malignant tumors with high rate of recurrence and metastasis. Coiled-coil domain-containing protein 178 (CCDC178) has been reported to be mutated in HCC, whereas its role in physiological and pathologic process, including in human cancer, remains largely unknown. Here, we found that CCDC178 is upregulated in HCC tissues and its overexpression is correlated with pathological stage (P= 0.003). CCDC178 deficiency reduced the anchorage-independent growth and anoikis resistance of HCC cells, and inhibited the HCC metastasis in vivo. Mechanistically, CCDC178 associated with BRCA1-associated protein 2 (BRAP2), a negative regulator of extracellular signal-regulated kinase (ERK) pathway, and promoted its degradation. Moreover, CCDC178 deficiency impaired the ERK activation, which is dependent on BRAP2. In conclusion, we identify CCDC178 as a novel candidate oncogene involved in anoikis resistance and HCC metastasis, and raise the possibility that CCDC178 may be a new therapeutic target for HCC.