Elevated FBXL18 promotes RPS15A ubiquitination and SMAD3 activation to drive HCC

作者全名："Yu, Hong-Qiang; Li, Feng; Xiong, HaoJun; Fang, Lei; Zhang, Jie; Bie, Ping; Xie, Chuan-Ming"

作者地址："[Yu, Hong-Qiang; Xiong, HaoJun; Fang, Lei; Zhang, Jie; Xie, Chuan-Ming] Army Med Univ, Mil Med Univ 3, Southwest Hosp, Inst Hepatobiliary Surg,Key Lab Hepatobiliary & Pa, Chongqing, Peoples R China; [Li, Feng; Bie, Ping] Chongqing Med Univ, Dept Hepatobiliary Surg, Affiliated Hosp 3, Chongqing, Peoples R China; [Xie, Chuan-Ming] Army Med Univ, Southwest Hosp, Inst Hepatobiliary Surg, Chongqing 400038, Peoples R China"

通信作者："Xie, CM (通讯作者)，Army Med Univ, Southwest Hosp, Inst Hepatobiliary Surg, Chongqing 400038, Peoples R China."

来源：HEPATOLOGY COMMUNICATIONS

ESI学科分类：　

WOS号：WOS:001018185400001

JCR分区：Q1

影响因子：5.6

年份：2023

卷号：7

期号：7

开始页：　

结束页：　

文献类型：Article

关键词：　

摘要："Background:F-box and leucine-rich repeat protein 18 (FBXL18) is an E3 ubiquitin ligase that is reported to be involved in the tumorigenesis of various types of cancer. However, it remains unknown whether FBXL18 is correlated with hepatocarcinogenesis. Methods and results:In the current study, we found that FBXL18 was highly expressed in HCC tissues and positively associated with poor overall survival of HCC patients. FBXL18 was an independent risk factor for HCC patients. We observed that FBXL18 drove HCC in FBXL18 transgenic mice. Mechanistically, FBXL18 promoted the K63-linked ubiquitination of small-subunit ribosomal protein S15A (RPS15A) and enhanced its stability, increasing SMAD family member 3 (SMAD3) levels and translocation to the nucleus and promoting HCC cell proliferation. Moreover, the knockdown of RPS15A or SMAD3 significantly suppressed FBXL18-mediated HCC proliferation. In clinical samples, elevated FBXL18 expression was positively associated with RPS15A expression. Conclusion:FBXL18 promotes RPS15A ubiquitination and upregulates SMAD3 expression, leading to hepatocellular carcinogenesis, and this study provides a novel therapeutic strategy for HCC treatment by targeting the FBXL18/RPS15A/SMAD3 pathway."

基金机构："National Natural Science Foundation of China [32071294, 31900449]; Third Military Medical University [4174C6]"

基金资助正文："& nbsp;This research was supported by the National Natural Science Foundation of China (Grant no. 32071294 and 31900449), Third Military Medical University (4174C6).& nbsp;"