Tumor necrosis factor α-induced protein 1 as a novel tumor suppressor through selective downregulation of CSNK2B blocks nuclear factor-κB activation in hepatocellular carcinoma.

Tumor necrosis factor α-induced protein 1 (TNFAIP1) is frequently downregulated in cancer cell lines and promotes cancer cell apoptosis. However, its role, clinical significance and molecular mechanisms in hepatocellular carcinoma (HCC) are unknown. The expression of TNFAIP1 in HCC tumor tissues and cell lines was measured by Western blot and immunohistochemistry. The effects of TNFAIP1 on HCC proliferation, apoptosis, metastasis, angiogenesis and tumor formation were evaluated by Cell Counting Kit-8 (CCK8), Terminal deoxynucleotidyl transferase dUTP Nick-End Labeling (TUNEL), transwell, tube formation assay in vitro and nude mice experiments in vivo. The interaction between TNFAIP1 and CSNK2B was validated by liquid chromatography-tandem mass spectrometry (LC-MS/MS), Co-immunoprecipitation and Western blot. The mechanism of how TNFAIP1 regulated nuclear factor-kappaB (NF-κB) pathway was analyzed by dual-luciferase reporter, immunofluorescence, quantitative Real-time polymerase chain reaction (RT-qPCR) and Western blot. The TNFAIP1 expression is significantly decreased in HCC tissues and cell lines, and negatively correlated with the increased HCC histological grade. Overexpression of TNFAIP1 inhibits HCC cell proliferation, metastasis, angiogenesis and promotes cancer cell apoptosis both in vitro and in vivo, whereas the knockdown of TNFAIP1 in HCC cell displays opposite effects. Mechanistically, TNFAIP1 interacts with CSNK2B and promotes its ubiquitin-mediated degradation with Cul3, causing attenuation of CSNK2B-dependent NF-κB trans-activation in HCC cell. Moreover, the enforced expression of CSNK2B counteracts the inhibitory effects of TNFAIP1 on HCC cell proliferation, migration, and angiogenesis in vitro and in vivo. Our results support that TNFAIP1 can act as a tumor suppressor of HCC by modulating TNFAIP1/CSNK2B/NF-κB pathway, implying that TNFAIP1 may represent a potential marker and a promising therapeutic target for HCC.

Xiao Y ，Huang S ，Qiu F ，Ding X ，Sun Y ，Wei C ，Hu X ，Wei K ，Long S ，Xie L ，Xun Y ，Chen W ，Zhang Z ，Liu N ，Xiang S ... -  《EBioMedicine》

EYA4 inhibits hepatocellular carcinoma growth and invasion by suppressing NF-κB-dependent RAP1 transactivation.

Mo SJ ，Hou X ，Hao XY ，Cai JP ，Liu X ，Chen W ，Chen D ，Yin XY ... -  《Cancer Communications》

Reciprocal activation between ATPase inhibitory factor 1 and NF-κB drives hepatocellular carcinoma angiogenesis and metastasis.

Hepatocellular carcinoma (HCC) is a highly vascularized tumor with frequent extrahepatic metastasis. Active angiogenesis and metastasis are responsible for rapid recurrence and poor survival of HCC. However, the mechanisms that contribute to tumor metastasis remain unclear. Here we evaluate the effects of ATPase inhibitory factor 1 (IF1), an inhibitor of the mitochondrial H(+)-adenosine triphosphate (ATP) synthase, on HCC angiogenesis and metastasis. We found that increased expression of IF1 in human HCC predicts poor survival and disease recurrence after surgery. Patients with HCC who have large tumors, with vascular invasion and metastasis, expressed high levels of IF1. Invasive tumors overexpressing IF1 were featured by active epithelial-mesenchymal transition (EMT) and increased angiogenesis, whereas silencing IF1 expression attenuated EMT and invasion of HCC cells. Mechanistically, IF1 promoted Snai1 and vascular endothelial growth factor (VEGF) expression by way of activating nuclear factor kappa B (NF-κB) signaling, which depended on the binding of tumor necrosis factor (TNF) receptor-associated factor 1 (TRAF1) to NF-κB-inducing kinase (NIK) and the disruption of NIK association with the TRAF2-cIAP2 complex. Suppression of the NF-κB pathway interfered with IF1-mediated EMT and invasion. Chromatin immunoprecipitation assay showed that NF-κB can bind to the Snai1 promoter and trigger its transcription. IF1 was directly transcribed by NF-κB, thus forming a positive feedback signaling loop. There was a significant correlation between IF1 expression and pp65 levels in a cohort of HCC biopsies, and the combination of these two parameters was a more powerful predictor of poor prognosis. IF1 promotes HCC angiogenesis and metastasis by up-regulation of Snai1 and VEGF transcription, thereby providing new insight into HCC progression and IF1 function. (Hepatology 2014;60:1659-1673).

Song R ，Song H ，Liang Y ，Yin D ，Zhang H ，Zheng T ，Wang J ，Lu Z ，Song X ，Pei T ，Qin Y ，Li Y ，Xie C ，Sun B ，Shi H ，Li S ，Meng X ，Yang G ，Pan S ，Zhu J ，Qi S ，Jiang H ，Zhang Z ，Liu L ... -  《-》

URG4/URGCP enhances the angiogenic capacity of human hepatocellular carcinoma cells in vitro via activation of the NF-κB signaling pathway.

Xing S ，Zhang B ，Hua R ，Tai WC ，Zeng Z ，Xie B ，Huang C ，Xue J ，Xiong S ，Yang J ，Liu S ，Li H ... -  《BMC CANCER》

The zinc finger protein GATA4 induces mesenchymal-to-epithelial transition and cellular senescence through the nuclear factor-κB pathway in hepatocellular carcinoma.

The high mortality and poor prognosis of hepatocellular carcinoma (HCC) have raised the public attention. Gene therapy is considered as a promising treatment option for cancer; thus, finding a new therapeutic target for HCC is urgently needed. GATA4 is a tumor suppressor gene in multiple cancers, but its role in HCC is unclear. In this study, we explored the function of GATA4 in HCC. Reverse transcription-polymerase chain reaction and quantitative polymerase chain reaction were used to detect the mRNA expression of GATA4 in HCC cells and tissues. Cell viability, transwell, colony formation, and flow cytometry assays were applied to examine different aspects of biological effects of GATA4 in vitro. Xenografts, immunohistochemistry, and terminal deoxynucleotidyl transferase-mediated digoxigenin-dUTP nick-end labeling assays were performed to evaluate the effect of GATA4 on tumorigenicity in vivo. Western blotting, immunofluorescence, and β-galactosidase staining were used to investigate the mechanism underlying the function of GATA4. We found that GATA4 was silenced in 15/19 (79%) HCC tissues. Restoring the expression of GATA4 induced G0 /G1 phase arrest, promoted apoptosis, suppressed HCC proliferation in vitro, and inhibited HCC tumor growth in vivo. Our data further showed that the ectopic expression of GATA4 induced cellular senescence through regulating nuclear factor-κB and inducing mesenchymal-to-epithelial transition. Our data demonstrated that by inducing cellular senescence and mesenchymal-to-epithelial transition, GATA4 plays a crucial role as a tumor suppressor in HCC. It may thus be a potential cancer therapeutic target for HCC.

Xiang Q ，Zhou D ，He X ，Fan J ，Tang J ，Qiu Z ，Zhang Y ，Qiu J ，Xu Y ，Lai G ... -  《-》