FBXW10-S6K1 promotes ANXA2 polyubiquitination and KRAS activation to drive hepatocellular carcinoma development in males
作者全名："Liu, Ze-Yu; Lin, Xiao-Tong; Zhang, Yu -Jun; Gu, Yong-Peng; Yu, Hong-Qiang; Fang, Lei; Li, Chun -Ming; Wu, Di; Zhang, Lei -Da; Xie, Chuan-Ming"
作者地址："[Liu, Ze-Yu; Lin, Xiao-Tong; Zhang, Yu -Jun; Gu, Yong-Peng; Yu, Hong-Qiang; Fang, Lei; Wu, Di; Zhang, Lei -Da; Xie, Chuan-Ming] Third Mil Med Univ, Army Med Univ, Southwest Hosp, Inst Hepatobiliary Surg,Key Lab Hepatobiliary & Pa, Chongqing 400038, Peoples R China; [Li, Chun -Ming] Chongqing Med Univ, Dept Hepatobiliary Surg, Affiliated Hosp 2, Chongqing, Peoples R China"
通信作者："Zhang, LD; Xie, CM (通讯作者)，Third Mil Med Univ, Army Med Univ, Southwest Hosp, Inst Hepatobiliary Surg,Key Lab Hepatobiliary & Pa, Chongqing 400038, Peoples R China."
关键词：FBXW10; ANXA2; KRAS; Ubiquitination; HCC
摘要："The incidence rate of human hepatocellular carcinoma (HCC) is approximately three times higher in males than in females. A better understanding of the mechanisms underlying HCC development in males could lead to more effective therapies for HCC. Our previous study found that FBXW10 played a critical role in promoting HCC development in male mice and patients, but the mechanism remains unknown. Here, we found that FBXW10 promoted K63-linked ANXA2 polyubiquitination and activation in HCC tissues from males, and this process was required for S6K1-mediated phosphorylation. Activated ANXA2 further translocated from the cytoplasm to the cell membrane to bind KRAS and then activated the MEK/ERK pathway, leading to HCC proliferation and lung metastasis. Interfering with ANXA2 significantly blocked FBXW10-driven HCC growth and lung metastasis in vitro and in vivo. Notably, membrane ANXA2 was upregulated and positively correlated with FBXW10 expression in male HCC patients. These findings offer new insights into the regulation and function of FBXW10 signaling in HCC tumorigenesis and metastasis and suggest that the FBXW10-S6K1-ANXA2-KRAS-ERK axis may serve as a potential biomarker and therapeutic target in male HCC patients with high FBXW10 expression."
基金机构：National Natural Science Foundation of China ; Third Military Medical University (Army Medical University) [2019XQY10]
基金资助正文："This work was supported by National Natural Science Foundation of China (NSFC, 32071294) and direct grant from the Third Military Medical University (Army Medical University) (2019XQY10) to C.M.X."