Transcriptional intermediary factor 1 gamma (TIF1c) may play either a potential tumor-suppressor or -promoter role in cancer. Here we report on a critical role of TIF1c in the progression of hepatocellular carcinoma (HCC). Reduced expression of TIF1c was detected in HCC, especially in advanced HCC tissues, compared to adjacent noncancerous tissues. HCC patients with low TIF1c expression had shorter overall survival times and higher recurrence rates than those with high TIF1c expression. Reduced TIF1c expression was an independent and significant risk factor for recurrence and survival after curative resection. In HCC cells, TIF1c played a dual role: It promoted tumor growth in early-stage HCC, but not in advanced-stage HCC, whereas it inhibited invasion and metastasis in both early-and advanced-stage HCC. Mechanistically, we confirmed that TIF1c inhibited transforming growth factor-b/ Drosophila mothers against decapentaplegic protein (TGF-b/Smad) signaling through monoubiquitination of Smad4 and suppressed the formation of Smad2/3/4 complex in HCC cells. TGF-binducing cytostasis and metastasis were both inhibited by TIF1c in HCC. We further proved that TIF1c suppressed cyotstasis-related TGF-b/Smad downstream c-myc downregulation, as well as p21/cip1 and p15/ink4b up-regulation in early-stage HCC. Meanwhile, TGF-b inducible epithelial-mesenchymal transition and TGF-b/Smad downstream metastatic cascades, including phosphatase and tensin homolog deleted on chromosome ten down-regulation, chemokine (CXC motif ) receptor 4 and matrix metalloproteinase 1 induction, and epidermal growth factor receptor-and protein kinase B-signaling transactivation, were inhibited by TIF1c. In addition, we found that the downregulation of TIF1c in HCC was caused by hypermethylation of CpG islands in the TIF1c promoter, and demonstrated that the combination of TIF1c and phosphorylated Smad2 was a more powerful predictor of poor prognosis. Conclusion: TIF1c regulates tumor growth and metastasis through inhibition of TGF-b/Smad signaling and may serve as a novel prognostic biomarker in HCC. (HEPATOLOGY 2014;60:1620-1636 H epatocellular carcinoma (HCC) is one of the most common cancers and the third leading cause of cancer-related mortality worldwide. Recurrence and metastasis contribute predominantly to the high mortality of HCC patients after curative resection. 1 However, the molecular mechanisms underlying the metastasis of HCC is still largely elusive.Transcriptional intermediary factor 1 gamma (TIF1c), also termed tripartite motif 33 (TRIM33) or ectodermin, is a member of the tripartite motif/RING finger,

The ACE2 G8790A polymorphism in T2DM patients was correlated with CS, and the A allele might be a risk factor of T2DM combined with CS.

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