Elevated FBXL6 activates both wild-type KRAS and mutant KRASG12D and drives HCC tumorigenesis via the ERK/mTOR/PRELID2/ROS axis in mice

• Published in: Military medical research 2023-12, Vol.10 (1), p.1-68, Article 68
• Main Authors: Xiong, Hao-Jun, Yu, Hong-Qiang, Zhang, Jie, Fang, Lei, Wu, Di, Lin, Xiao-Tong, Xie, Chuan-Ming
• Format: Article
• Language: English
• Subjects: Antibodies; Cancer therapies; Extracellular signal-regulated kinase (ERK); F-box and leucine-rich repeat 6 (FBXL6); Hepatitis; Kinases; Kirsten rat sarcoma (KRAS); Laboratory animals; Liver cancer; Mutagenesis; Mutation; Plasmids; PRELID2; Proteins; Reactive oxygen species; Sarcoma; Tumorigenesis; Tumors; Ubiquitination
• ISSN: 2054-9369; 2095-7467; 2054-9369
• DOI: 10.1186/s40779-023-00501-8

BackgroundKirsten rat sarcoma (KRAS) and mutant KRASG12D have been implicated in human cancers, but it remains unclear whether their activation requires ubiquitination. This study aimed to investigate whether and how F-box and leucine-rich repeat 6 (FBXL6) regulates KRAS and KRASG12D activity in hepatocellular carcinoma (HCC).MethodsWe constructed transgenic mouse strains LC (LSL-Fbxl6KI/+;Alb-Cre, n = 13), KC (LSL-KrasG12D/+;Alb-Cre, n = 10) and KLC (LSL-KrasG12D/+;LSL-Fbxl6KI/+;Alb-Cre, n = 12) mice, and then monitored HCC for 320 d. Multiomics approaches and pharmacological inhibitors were used to determine oncogenic signaling in the context of elevated FBXL6 and KRAS activation. Co‑immunoprecipitation (Co-IP), Western blotting, ubiquitination assay and RAS activity detection assay were employed to investigate the underlying molecular mechanism by which FBXL6 activates KRAS. The pathological relevance of the FBXL6/KRAS/extracellular signal-regulated kinase (ERK)/mammalian target of rapamycin (mTOR)/proteins of relevant evolutionary and lymphoid interest domain 2 (PRELID2) axis was evaluated in 129 paired samples from HCC patients.ResultsFBXL6 is highly expressed in HCC as well as other human cancers (P