Department of Immunology, School of Medicine, Nankai University, Tianjin, China.
International Joint Center for Biomedical Research of the Ministry of Education, Tianjin, China.
Signal Transduct Target Ther. 2016 Jul 22;1:16013. doi: 10.1038/sigtrans.2016.13. eCollection 2016.
TIFA, also called T2BP, was first identified using yeast two-hybrid screening. Our previous work showed that TIFA suppresses hepatocellular carcinoma (HCC) progression via apoptosis and cell cycle arrest. However, the mechanism by which this TIFA suppression occurs remains unclear. Here we demonstrated that TIFA-induced apoptosis demonstrates two distinct time patterns (i.e., at 48 h and >7 days) when TIFA reconstitution occurs. Moreover, we found that MALT1 (a competitor of TIFA) plays a crucial role in short-duration TIFA reconstitution. In this regard, MALT1 silencing with shRNA markedly enhances TIFA-induced apoptosis and . In addition, TIFA overexpression triggers JNK and p38 activation in long-duration TIFA reconstitution through TRAF6 binding. In particular, JNK activation leads to TIFA-induced apoptosis while p38 activation governs TIFA-induced cell cycle arrest by p53-p21 signaling and . Our data suggest a novel mechanism by which TIFA suppresses HCC progression via both MALT1-dependent and MALT1-independent signaling pathways. This may provide insights into a novel targets where HCC progression may be vulnerable to clinical treatment.
TIFA，也称为 T2BP，最初是通过酵母双杂交筛选鉴定出来的。我们之前的工作表明，TIFA 通过细胞凋亡和细胞周期阻滞来抑制肝细胞癌（HCC）的进展。然而，这种 TIFA 抑制发生的机制尚不清楚。在这里，我们证明了当 TIFA 重建发生时，TIFA 诱导的细胞凋亡表现出两种不同的时间模式（即 48 h 和>7 天）。此外，我们发现 MALT1（TIFA 的竞争者）在短时间 TIFA 重建中发挥关键作用。在这方面，shRNA 沉默 MALT1 可显著增强 TIFA 诱导的凋亡和细胞周期阻滞。此外，TIFA 过表达通过 TRAF6 结合在长时间 TIFA 重建中触发 JNK 和 p38 的激活。特别是，JNK 激活导致 TIFA 诱导的细胞凋亡，而 p38 激活通过 p53-p21 信号通路调控 TIFA 诱导的细胞周期阻滞。我们的数据表明，TIFA 通过 MALT1 依赖性和非依赖性信号通路抑制 HCC 进展的一种新机制。这可能为 HCC 进展可能容易受到临床治疗的新靶点提供见解。
