Abstract
TIFA (TNF receptor associated factor (TRAF)-interacting protein with a Forkhead-associated (FHA) domain), also called T2BP, was first identified using a yeast two-hybrid screening. TIFA contains a FHA domain, which directly binds phosphothreonine and phosphoserine, and a consensus TRAF6-binding motif. TIFA-mediated oligomerization and poly-ubiquitinylation of TRAF6 mediates signaling downstream of the Tumor necrosis factor alpha receptor 1 (TNFaR-I) and interleukin-1/Toll-like receptor 4 (TLR4) pathways. Examining TIFA expression in hepatocellular carcinoma (HCC) tissues microarrays, we noted marked decreases TIFA reactivity in tumor versus control samples. In agreement, we found that HCC cell lines show reduced TIFA expression levels versus normal liver controls. Reconstituting TIFA expression in HCC cell lines promoted two independent apoptosis signaling pathways: the induction of p53 and cell cycle arrest, and the activation of caspase-8 and caspase-3. In contrast, the expression of a non-oligomerizing mutant of TIFA impacted cells minimally, and suppression of TIFA expression protected cells from apoptosis. Mice bearing TIFA overexpression hepatocellular xenografts develop smaller tumors versus TIFA mutant tumors; terminal deoxynucleotidyl transferase dUTP nick end labeling staining demonstrates increased cell apoptosis, and decreased proliferation, reflecting cell cycle arrest. Interestingly, p53 has a greater role in decreased proliferation than cell death, as it appeared dispensable for TIFA-induced cell killing. The findings demonstrate a novel suppressive role of TIFA in HCC progression via promotion of cell death independent of p53.
Highlights
Chronic liver inflammation is associated with increased incidence of liver cancer
As shown (Figure 1a), a relatively robust expression of TIFA was detectable in normal liver tissues, whereas in contrast, TIFA expression was weakly detected in frank carcinoma
As TIFA has a role in promoting inflammation, which fosters Hepatocellular carcinoma (HCC), this result was somewhat unexpected
Summary
Chronic liver inflammation is associated with increased incidence of liver cancer. Hepatocellular carcinoma (HCC), the most common liver cancer, is an end product of chronic liver disease typically requiring decades to evolve. HCC is the fifth most common cancer worldwide, with a doubling incidence in the United States alone during the last two decades. An increased incidence of inflammatory mediators, such as ATF4,1,2 TLR4,3,4 TREM-1,5,6 have been linked to the development of HCC; other proteins, such as TIFA (TRAF-interacting protein with a Forkhead-associated (FHA) domain), are upregulated in response to hypoxia or other acute stress.. The most frequent cause for chronic hepatic inflammation in humans is infection with hepatitis B virus or hepatitis C virus, which currently persist in approximately 500 million people worldwide, and fosters an increasing. Effective means to eradicate these chronic viral infections have been elusive, new treatments for hepatitis C virus are poised to make a significant impact if economic barriers can be overcome
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