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Signal Transduct Target Ther. 2016 Jul 22;1:16013. doi: 10.1038/sigtrans.2016.13. eCollection 2016.

TIFA suppresses hepatocellular carcinoma progression via MALT1-dependent and -independent signaling pathways.

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Department of Immunology, School of Medicine, Nankai University, Tianjin, China.
International Joint Center for Biomedical Research of the Ministry of Education, Tianjin, China.
Department of Immunology, Institute of Basic Medical Science, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.
Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest University Medical Center, Winston-Salem, North Carolina, USA.
West China Hospital, Molecular Medicine Research Centre, State Key Lab Biotherapy, Sichuan University, Chengdu, China.


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 in vitro and in vivo. 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 in vitro and in vivo. 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.

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