摘要
Alpha-fetoprotein (AFP) is the most widely used biomarker for the diagnosis of hepatocellular carcinoma (HCC). However, asubstantial proportion of HCC patients have either normal or marginally increased AFP levels in serum, and the underlyingmechanisms are not fully understood. In the present study, we provided in vitro and in vivo evidence that heat shock protein gp96promoted AFP expression at the transcriptional level in HCC. NR5A2 was identified as a key transcription factor for the AFP gene, andits stability was enhanced by gp96. A further mechanistic study by co-immunoprecipitation, GST pull-down, and molecular dockingshowed gp96 and the SUMO E3 ligase RanBP2 competitively binding to NR5A2 at the sites spanning from aa 507 to aa 539. Thebinding of gp96 inhibited SUMOylation, ubiquitination, and subsequent degradation of NR5A2. In addition, clinical analysis of HCCpatients indicated that gp96 expression in tumors was positively correlated with serum AFP levels. Therefore, our study uncovered anovel mechanism that gp96 regulates the stability of its client proteins by directly affecting their SUMOylation and ubiquitination.These findings will help in designing more accurate AFP-based HCC diagnosis and progression monitoring approaches.
基金
supported by the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB29040000)
the Industrial Innovation Team grant from Foshan Industrial Technology Research Institute,Chinese Academy of Sciences,the National Natural Science Foundation of China(32070163,81871297,and 81903142)
China ATOMIC Energy Authority,Foshan High-level Hospital Construction DengFeng Plan,and Guangdong Province Biomedical Innovation Platform Construction Project Tumor Immunobiotherapy.
作者简介
Correspondence to:Songdong Meng,E-mail:mengsd@im.ac.cn;Correspondence to:Changfei Li,E-mail:lichangfei2006@163.com。
