Abstract
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.
Highlights
Hepatocellular carcinoma (HCC) accounts for >80% of primary liver cancers worldwide [1]
We examined the translocation of Aryl hydrocarbon receptor (AhR) and β-catenin under modulation of IDO1 activity in
HCC, one of the most lethal malignancies worldwide, has been characterized as a chronic liver damage-induced disease resulting from hepatitis B virus (HBV) and hepatitis C virus (HCV) infection or other non-viral factors [34,35]
Summary
Hepatocellular carcinoma (HCC) accounts for >80% of primary liver cancers worldwide [1]. Liver cancer is the fourth most common cause of cancer-related death globally and ranks sixth in terms of incidence [2]. Based on projections by the World Health Organization, more than one-million deaths from liver cancer are estimated by 2030 [3]. 5-year survival rate of ~18%, liver cancer is the second most lethal tumor after pancreatic cancer in the US [4]. In Taiwan, liver cancer ranks fourth in incidence and second as a cause of cancer-related mortality. In view of the high mortality and incidence rates, comprehensive analysis of the mechanisms underlying pathogenesis and development of HCC is critical to improve patient survival
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