Kinase suppressor of Ras 1 (KSR1) promotes liver carcinogenesis via activation of the RAS/RAF/MEK/ERK signaling pathway.

Background & Aims: Mutations in the RAS and RAF genes are frequently observed in various human cancers, leading to persistent activation of the RAS/RAF/MEK/ERK signaling pathway and driving tumorigenesis. Intriguingly, hepatocellular carcinoma (HCC) reveals rare mutations in Methods: Gene expression data from human cancers were analyzed using publicly available databases. HCC cell lines stably expressing KSR1 were established to evaluate RAS/RAF/MEK/ERK signaling activity. Liver cancer was induced in C57BL/6 male mice via hydrodynamic tail vein injection. Tumor-bearing livers were formalin-fixed and processed for H&E staining and immunohistochemistry. Results: KSR1 expression was frequently upregulated in human HCC (n = 366, Conclusions: Overexpression of KSR1 activates the RAS/RAF/MEK/ERK signaling pathway and drives hepatic tumorigenesis in the absence of mutations in Impact and implications: Our findings identify kinase suppressor of Ras 1 (KSR1) as an oncogenic driver in the liver and a key activator of the RAS/RAF/MEK/ERK signaling pathway. This study enhances our understanding of the role that scaffold proteins play in promoting oncogenic signaling cascades. The successful use of a pharmacological inhibitor of KSR to suppress