Dysregulation of Type I Interferon (IFN-I) Signaling: A Potential Contributor to Racial Disparity in Hepatocellular Carcinoma (HCC)

SIMPLE SUMMARY: Hepatocellular carcinoma (HCC) is the most common primary liver cancer arising from the liver cells, hepatocytes. Chronic liver inflammation plays a key role in the development of HCC. HCC is a highly fatal disease where race/ethnicity plays a vital role in determining incidence, mortality and survival rates. There is a knowledge gap in our understanding of the molecular mechanism underlying the HCC racial disparity between African-American (AA)/Black and White patients. Global gene expression analysis between AA/Black and White HCC patients identified the activation of a key inflammatory pathway in AA/Black tumors. Ginger extract (GE) is known for its anti-inflammatory properties. GE inhibited proliferation of HCC cells, and our data suggest that HCC cell lines from AA/Black patients responded better to GE compared to those from White and Asian patients. These findings suggest that AA/Black HCC patients might benefit from holistic dietary approach which includes ginger. ABSTRACT: African-American (AA)/Black hepatocellular carcinoma (HCC) patients have increased incidence and decreased survival rates compared to non-Hispanic (White) patients, the underlying molecular mechanism of which is not clear. Analysis of existing RNA-sequencing (RNA-seq) data in The Cancer Genome Atlas (TCGA) and in-house RNA-sequencing of 14 White and 18 AA/Black HCC patients revealed statistically significant activation of type I interferon (IFN-I) signaling pathway in AA/Black patients. A four-gene signature of IFN-stimulated genes (ISGs) showed increased expression in AA/Black HCC tumors versus White. HCC is a disease of chronic inflammation, and IFN-Is function as pro-inflammatory cytokines. We tested efficacy of ginger extract (GE), a dietary compound known for anti-inflammatory properties, on HCC cell lines derived from White (HepG2), AA/Black (Hep3B and O/20) and Asian (HuH-7) patients. GE exhibited a significantly lower IC(50) on Hep3B and O/20 cells than on HepG2 and HuH-7 cells. The GE treatment inhibited the activation of downstream mediators of IFN-I signaling pathways and expression of ISGs in all four HCC cells. Our data suggest that ginger can potentially attenuate IFN-I-mediated signaling pathways in HCC, and cells from AA/Black HCC patients may be more sensitive to ginger. AA/Black HCC patients might benefit from a holistic diet containing ginger.