Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Hepatology. 2014 Nov;60(5):1620-36. doi: 10.1002/hep.27273. Epub 2014 Sep 25.
Transcriptional intermediary factor 1 gamma (TIF1γ) may play either a potential tumor-suppressor or -promoter role in cancer. Here we report on a critical role of TIF1γ in the progression of hepatocellular carcinoma (HCC). Reduced expression of TIF1γ was detected in HCC, especially in advanced HCC tissues, compared to adjacent noncancerous tissues. HCC patients with low TIF1γ expression had shorter overall survival times and higher recurrence rates than those with high TIF1γ expression. Reduced TIF1γ expression was an independent and significant risk factor for recurrence and survival after curative resection. In HCC cells, TIF1γ 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 TIF1γ inhibited transforming growth factor-β/ Drosophila mothers against decapentaplegic protein (TGF-β/Smad) signaling through monoubiquitination of Smad4 and suppressed the formation of Smad2/3/4 complex in HCC cells. TGF-β-inducing cytostasis and metastasis were both inhibited by TIF1γ in HCC. We further proved that TIF1γ suppressed cyotstasis-related TGF-β/Smad downstream c-myc down-regulation, as well as p21/cip1 and p15/ink4b up-regulation in early-stage HCC. Meanwhile, TGF-β inducible epithelial-mesenchymal transition and TGF-β/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 TIF1γ. In addition, we found that the down-regulation of TIF1γ in HCC was caused by hypermethylation of CpG islands in the TIF1γ promoter, and demonstrated that the combination of TIF1γ and phosphorylated Smad2 was a more powerful predictor of poor prognosis.
TIF1γ regulates tumor growth and metastasis through inhibition of TGF-β/Smad signaling and may serve as a novel prognostic biomarker in HCC.
转录中介因子 1 伽马（TIF1γ）在癌症中可能发挥潜在的肿瘤抑制或促进作用。在这里，我们报告了 TIF1γ 在肝细胞癌（HCC）进展中的关键作用。与相邻的非癌组织相比，TIF1γ 在 HCC 中表达降低，特别是在晚期 HCC 组织中。TIF1γ 低表达的 HCC 患者总生存时间较短，复发率较高。TIF1γ 表达降低是根治性切除术后复发和生存的独立且重要的危险因素。在 HCC 细胞中，TIF1γ 发挥双重作用：它促进早期 HCC 的肿瘤生长，但不促进晚期 HCC 的肿瘤生长，而在早期和晚期 HCC 中均抑制侵袭和转移。在机制上，我们证实 TIF1γ 通过 Smad4 的单泛素化抑制转化生长因子-β/果蝇抗 decapentaplegic 蛋白（TGF-β/Smad）信号，并抑制 HCC 细胞中 Smad2/3/4 复合物的形成。TIF1γ 在 HCC 中抑制 TGF-β诱导的细胞停滞和转移。我们进一步证明，TIF1γ 抑制细胞停滞相关的 TGF-β/Smad 下游 c-myc 下调，以及早期 HCC 中的 p21/cip1 和 p15/ink4b 上调。同时，TIF1γ 抑制 TGF-β诱导的上皮-间充质转化和 TGF-β/Smad 下游转移级联，包括磷酸酶和张力蛋白同源物缺失于染色体 10 下调、趋化因子（CXC 基序）受体 4 和基质金属蛋白酶 1 诱导以及表皮生长因子受体和蛋白激酶 B 信号转导的反式激活。此外，我们发现 HCC 中 TIF1γ 的下调是由于 TIF1γ 启动子中 CpG 岛的高甲基化所致，并证明 TIF1γ 与磷酸化 Smad2 的结合是预后不良的更有力预测因子。
TIF1γ 通过抑制 TGF-β/Smad 信号调节肿瘤生长和转移，可能成为 HCC 的新型预后生物标志物。
