Yap promotes hepatocellular carcinoma metastasis and mobilization via governing cofilin/F-actin/lamellipodium axis by regulation of JNK/Bnip3/SERCA/CaMKII pathways

作     者：Shi, Chen Cai, Yong Li, Yongheng Li, Ye Hu, Nan Ma, Sai Hu, Shunying Zhu, Pingjun Wang, Weihu Zhou, Hao 

作者机构：Peking Univ Canc Hosp & Inst Dept Radiat Oncol Minist Educ Beijing Key Lab Carcinogenesis & Translat Res Beijing Peoples R China Peoples Liberat Army Gen Hosp Canc Ctr Dept Oncol Beijing Peoples R China Univ Wyoming Coll Hlth Sci Ctr Cardiovasc Res & Alternat Med Laramie WY 82071 USA Chinese Peoples Liberat Army Gen Hosp Dept Cardiol Beijing Peoples R China 

出 版 物：《REDOX BIOLOGY》 (氧化还原生物学)

年 卷 期：2018年第14卷

页      面：59-71页

核心收录：

学科分类：0710[理学-生物学] 071010[理学-生物化学与分子生物学] 07[理学] 

基　　金：Key laboratory of Carcinogenesis and Translational Research, Ministry of Education/Beijing National Natural Science Foundation of China People Liberation Army General Hospital [16KMZ02] 

主　　题：Yap JNK Bnip3 SERCA CaMKII F-actin Cofilin Lamellipodium Migration 

摘      要：Despite the increasingly important role of Hippo-Yap in hepatocellular carcinoma (HCC) development and progression, little insight is available at the time regarding the specifics interaction of Yap and cancer cells migration. Here, we identified the mechanism by which tumor-intrinsic Yap deletion resulted in HCC migratory inhibition. Yap was greatly upregulated in HCC and its expression promoted the cells migration. Functional studies found that knockdown of Yap induced JNK phosphorylation which closely bound to the Bnip3 promoter and contributed to Bnip3 expression. Higher Bnip3 employed excessive mitophagy leading to mitochondrial dysfunction and ATP shortage. The insufficient ATP inactivated SERCA and consequently triggered intracellular calcium overload. As the consequence of calcium oscillation, Ca/calmodulin-dependent protein kinases II (CaMKII) was signaled and subsequently inhibited cofilin activity via phosphorylated modification. The phosphorylated cofilin failed to manipulate F-actin polymerization and lamellipodium formation, resulting into the impairment of lamellipodium-based migration. Collectively, our results identified Hippo-Yap as the tumor promoter in hepatocellular carcinoma that mediated via activation of cofilin/F-actin/lamellipodium axis by limiting JNK-Bnip3-SERCA-CaMKII pathways, with potential application to HCC therapy involving cancer metastasis.