The State Key Laboratory of Genetic Engineering, Zhongshan Hospital and School of Life Science, Fudan University, Shanghai, People's Republic of China.
Department of Oncology, The 401 Hospital of PLA, Qingdao, People's Republic of China.
Oncogene. 2017 Jul 13;36(28):4047-4059. doi: 10.1038/onc.2017.10. Epub 2017 Mar 20.
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.
肝细胞癌（HCC）是一种恶性程度较高的肿瘤，复发和转移率较高。卷曲螺旋结构域蛋白 178（CCDC178）已被报道在 HCC 中发生突变，但其在生理和病理过程中的作用，包括在人类癌症中的作用，仍知之甚少。在这里，我们发现 CCDC178 在 HCC 组织中上调，其过表达与病理分期相关（P=0.003）。CCDC178 缺失降低了 HCC 细胞的锚定非依赖性生长和抗失巢凋亡能力，并抑制了 HCC 的体内转移。在机制上，CCDC178 与 BRCA1 相关蛋白 2（BRAP2）相关，BRAP2 是细胞外信号调节激酶（ERK）通路的负调节剂，并促进其降解。此外，CCDC178 缺失会损害 ERK 的激活，而这依赖于 BRAP2。总之，我们将 CCDC178 鉴定为一种参与抗失巢凋亡和 HCC 转移的新型候选癌基因，并提出 CCDC178 可能是 HCC 的一个新的治疗靶点的可能性。
