ALBERT

Description: Hepatocellular carcinoma is one of the most common cancer types worldwide. In cases of advanced-stage disease, sorafenib is considered the treatment of choice. However, resistance to sorafenib remains a major obstacle for effective clinical application. Based on integrated phosphoproteomic and The Cancer Genome Atlas (TCGA) data, we identified a transcription factor, Y-box binding protein-1 (YB-1), with elevated phosphorylation of Ser102 in sorafenib-resistant HuH-7R cells. Phosphoinositide-3-kinase (PI3K) and protein kinase B (AKT) were activated by sorafenib, which, in turn, increased the phosphorylation level of YB-1. In functional analyses, knockdown of YB-1 led to decreased cell migration and invasion in vitro. At the molecular level, inhibition of YB-1 induced suppression of zinc-finger protein SNAI1 (Snail), twist-related protein 1 (Twist1), zinc-finger E-box-binding homeobox 1 (Zeb1), matrix metalloproteinase-2 (MMP-2) and vimentin levels, implying a role of YB-1 in the epithelial-mesenchymal transition (EMT) process in HuH-7R cells. Additionally, YB-1 contributes to morphological alterations resulting from F-actin rearrangement through Cdc42 activation. Mutation analyses revealed that phosphorylation at S102 affects the migratory and invasive potential of HuH-7R cells. Our collective findings suggest that sorafenib promotes YB-1 phosphorylation through effect from the EGFR/PI3K/AKT pathway, leading to significant enhancement of hepatocellular carcinoma (HCC) cell metastasis. Elucidation of the specific mechanisms of action of YB-1 may aid in the development of effective strategies to suppress metastasis and overcome resistance.

Description: Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death worldwide. Chronic liver inflammation due to hepatitis virus infection and other major effectors is a major risk factor of HCC. Indoleamine 2,3-dioxygenase 1 (IDO1), a heme enzyme highly expressed upon stimulation with proinflammatory cytokines such as interferon-γ (IFN-γ), is activated to modulate the tumor microenvironment and potentially crucial in the development of certain cancer types. Earlier studies have majorly reported an immunomodulatory function of IDO1. However, the specific role of IDO1 in cancer cells, particularly HCC, remains to be clarified. Analysis of The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA LIHC) dataset in the current study revealed a significant correlation between IDO1 expression and HCC. We further established inducible IDO1-expressing cell models by coupling lentivirus-mediated knockdown and IFN-γ induction of IDO1 in normal and HCC cells. In functional assays, proliferation and motility-related functions of HCC cells were compromised upon suppression of IDO1, which may partially be rescued by its enzymatic product, kynurenine (KYN), while normal hepatocytes were not affected. Aryl hydrocarbon receptor (AhR), a reported endogenous KYN receptor, is suggested to participate in tumorigenesis. In mechanistic studies, IDO1 activation promoted both AhR and β-catenin activity and nuclear translocation. Immunofluorescence staining and co-immunoprecipitation assays further disclosed interactions between AhR and β-catenin. In addition, we identified a Src-PTEN-PI3K/Akt-GSK-3β axis involved in β-catenin stabilization and activation following IDO1-mediated AhR activation. IDO1-induced AhR and β-catenin modulated the expression of proliferation- and EMT-related genes to facilitate growth and metastasis of HCC cells. Our collective findings provide a mechanistic basis for the design of more efficacious IDO1-targeted therapy for HCC.