Elevated FBXL6 activates both wild-type KRAS and mutant KRAS G12D and drives HCC tumorigenesis via the ERK/mTOR/PRELID2/ROS axis in mice

Kirsten rat sarcoma (KRAS) and mutant KRAS 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 KRAS activity in hepatocellular carcin...

Full description

Saved in:
Bibliographic Details
Published in:Military medical research 2023-12, Vol.10 (1), p.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:
Animals
Carcinogenesis
Carcinoma, Hepatocellular - genetics
Extracellular Signal-Regulated MAP Kinases - metabolism
Humans
Liver Neoplasms - genetics
Mammals - metabolism
Mice
Mitogen-Activated Protein Kinase Kinases - metabolism
Pancreatic Neoplasms - metabolism
Pancreatic Neoplasms - pathology
Proto-Oncogene Proteins p21(ras) - genetics
Proto-Oncogene Proteins p21(ras) - metabolism
Reactive Oxygen Species - metabolism
TOR Serine-Threonine Kinases - metabolism
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Kirsten rat sarcoma (KRAS) and mutant KRAS 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 KRAS activity in hepatocellular carcinoma (HCC). We constructed transgenic mouse strains LC (LSL-Fbxl6 ;Alb-Cre, n = 13), KC (LSL-Kras ;Alb-Cre, n = 10) and KLC (LSL-Kras ;LSL-Fbxl6 ;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. FBXL6 is highly expressed in HCC as well as other human cancers (P 
ISSN:2054-9369