TBK1促进PTPRD介导的STAT1活化降低胃癌对TRAIL敏感性的机制研究

肿瘤坏死因子相关凋亡诱导配体(TRAIL)可以诱导多种肿瘤凋亡，但部分胃癌对其耐药，机制不明。我们原创性的研究证实：TRAIL作用于胃癌耐药细胞后，发生了转录因子STAT1活化和TRAIL通路负调控分子c-FLIP上调；TRAIL同时促进TBK1与PTPRD结合，使PTPRD泛素化降解，并与STAT1解离；STAT1解离后活化，进入细胞核，上调c-FLIP表达，而抑制STAT1/TBK1或者过表达PTPRD后，均能提高胃癌对TRAIL的敏感性。本研究旨在证明TRAIL在胃癌细胞中，可能通过促进TBK1与PTPRD结合介导PTPRD降解，解除其对STAT1的抑制，促进STAT1活化入核，进而通过转录上调c-FLIP表达，导致了TRAIL耐药。研究将为阐明TBK1/PTPRD/STAT1/c-FLIP是调控胃癌TRAIL耐药的关键机制，以及为建立TRAIL治疗胃癌的新策略提供新的科学依据。

Tumor necrosis factor-related apoptosis-inducing ligand(TRAIL) induces apoptosis in many kinds of tumors, but some gastric cancers show resistance to TRAIL and the mechanism is still unknown. Our original study have demonstrated that: TRAIL-induced the activation of transcription factor STAT1, then up-regulation the c-FLIP expression which is the negative regulation molecule of TRAIL pathway in drug-resistant gastric cancer cells; TRAIL also promoted the binding of TBK1 and PTPRD then induced the ubiquitin-degraded of PTPRD and the dissociated with STAT1; STAT1 was activated after dissociation with PTPRD and entered into the nucleus to up-regulate the expression of c-FLIP. While inhibition of STAT1/ TBK1 or over-expression of PTPRD could all improve the sensitivity to TRAIL in gastric cancer cells. The aim of this study is to clarify that TRAIL may promoted the binding of TBK1 and PTPRD to mediate the degradation of PTPRD, removed the inhibition on STAT1 by PTPRD, then induced STAT1 into the nucleus after activation to up-regulate the expression of c-FLIP at transcription level, eventually resulted the resistance to TRAIL in gastric cancer cells. This research will clarify that TBK1/PTPRD/STAT1/c-FLIP is the key mechanism for regulating the resistance to TRAIL in gastric cancer, and provide a new scientific basis and new strategy for the treatment of TRAIL on gastric cancer.