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

ABSTRACT:

Background

Kirsten rat sarcoma (KRAS) and mutant KRAS^G12D 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^G12D activity in hepatocellular carcinoma (HCC).

Methods

We constructed transgenic mouse strains LC (LSL-Fbxl6^KI/+;Alb-Cre, n = 13), KC (LSL-Kras^G12D/+;Alb-Cre, n = 10) and KLC (LSL-Kras^G12D/+;LSL-Fbxl6^KI/+;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 (

SUBMITTER: Xiong HJ 

PROVIDER: S-EPMC10731709 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature