Abstract
Tumor necrosis factor-α-induced protein 8 (TNFAIP8) expression has been linked to tumor progression in various cancer types, but the detailed mechanisms of TNFAIP8 are not fully elucidated. Here we define the role of TNFAIP8 in early events associated with development of hepatocellular carcinoma (HCC). Increased TNFAIP8 levels in HCC cells enhanced cell survival by blocking apoptosis, rendering HCC cells more resistant to the anticancer drugs, sorafenib and regorafenib. TNFAIP8 also induced autophagy and steatosis in liver cancer cells. Consistent with these observations, TNFAIP8 blocked AKT/mTOR signaling and showed direct interaction with ATG3-ATG7 proteins. TNFAIP8 also exhibited binding with fatty acids and modulated expression of lipid/fatty-acid metabolizing enzymes. Chronic feeding of mice with alcohol increased hepatic levels of TNFAIP8, autophagy, and steatosis but not in high-fat-fed obese mice. Similarly, higher TNFAIP8 expression was associated with steatotic livers of human patients with a history of alcohol use but not in steatotic patients with no history of alcohol use. Our data indicate a novel role of TNFAIP8 in modulation of drug resistance, autophagy, and hepatic steatosis, all key early events in HCC progression.
Highlights
Tumor necrosis factor-α-induced protein 8 (TNFAIP8)is a member of the TNFAIP8/TIPE family, which includes TIPE1, TIPE2 and TIPE31–4
We found that TNFAIP8 promoted liver cancer cell survival/drug resistance and increased cell/hepatic steatosis in alcoholic fatty liver diseases (AFLD) suggesting that TNFAIP8–autophagy may contribute to early liver cancer progression by modulation of hepatic steatosis in mice and in human patients
(see figure on previous page) Fig. 1 Higher TNFAIP8 expression is associated with liver cancer progression. a Representative images of tumor microarray (TMA) of TNFAIP8 expression in different stages of liver cancer. b Expression levels of TNFAIP8 protein in normal livers, stage I, stage II, and stage III hepatocellular carcinoma (HCC) tumors were quantified from Tissue microarray (TMA)
Summary
Tumor necrosis factor-α-induced protein 8 (TNFAIP8)is a member of the TNFAIP8/TIPE family, which includes TIPE1, TIPE2 and TIPE31–4. Expression of TNFAIP8 is associated with cell survival and drug resistance[2,5]. TNFAIP8 promotes cancer cell proliferation and drug resistance[7,8,9,10,11,12]. Depletion of TNFAIP8 has been shown to increase the expression of genes associated with anti-proliferation and apoptosis (IL-24, FAT3, LPHN2, EPHA3), fatty-acid oxidation (ACADL), and decrease the expression of several oncogenes such as NFAT5, MALAT1, MET, FOXA1, KRAS, S100P, OSTF15. In HCC cells, expression of TNFAIP8 induces cell proliferation, migration, invasion, and xenograft tumor growth[13]. TNFAIP8 modulates the Hippo pathway by inhibition of YAP phosphorylation and by the interaction with LATS1 protein. TNFAIP8-LATS1 interaction increases nuclear localization and stabilization of YAP protein, resulting in increased cell proliferation
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