Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fujian Medical University, Fuzhou, China.
Key Laboratory of Ministry of Education for Gastrointestinal Cancer and Key Laboratory of Tumor Microbiology, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China.
Biosci Rep. 2019 Apr 12;39(4). doi: 10.1042/BSR20182266. Print 2019 Apr 30.
Gallbladder cancer (GBC) is a demanding fatal disease with no ideal treatment for inoperable patients. Recent reports have determined TNF-α associated lymphatic metastasis in GBC, while its resistance to TNF-α-killing remains largely unexplored. In this assay, we first found cellular inhibitor of apoptosis (cIAP1) overexpressed in GBC tissues and the roles in promoting the proliferation and migration of GBC as its homology cIAP2 does. Then how GBC cell survives TNF-α toxicity and TNF-α-induced apoptosis first prevail as follows. The reduction in cIAP1 does not give rise to apoptosis even with the stimulation of TNF-α. Importantly, the loss of cIAP1 enhanced TNF-α/cycloheximide-induced apoptosis in higher activation statuses of Caspase-8, Caspase-3 without the induction of Complex Ⅱ. In response to TNF-α, the reduction in cIAP1 caused the suppression in nuclear factor-κB (NF-κB) pathway and inhibition of transcription of cell death regulator cellular FLICE-like Inhibitory Protein (c-FLIP) instead. To conclude, cIAP1 is an oncological protein abundant in GBC tissues, which enhances proliferation and immigration and blocks TNF-α from apoptosis through NF-κB pathway .
胆囊癌（GBC）是一种难以治疗的致命疾病，对于无法手术的患者目前尚无理想的治疗方法。最近的报告确定了 TNF-α 相关的淋巴转移与 GBC 有关，而其对 TNF-α 的耐药性在很大程度上仍未得到探索。在本研究中，我们首先发现细胞凋亡抑制剂 1（cIAP1）在 GBC 组织中过度表达，并发现其与同源物 cIAP2 一样，促进 GBC 的增殖和迁移。那么 GBC 细胞如何在 TNF-α 毒性和 TNF-α 诱导的凋亡中存活，首先要弄清楚以下几点。即使受到 TNF-α 的刺激，cIAP1 的减少也不会引起细胞凋亡。重要的是，cIAP1 的缺失增强了 Caspase-8、Caspase-3 的更高激活状态下 TNF-α/环已酰亚胺诱导的凋亡，而不会诱导复合物 Ⅱ的形成。对 TNF-α 的反应，cIAP1 的减少导致核因子-κB（NF-κB）通路的抑制，并抑制细胞死亡调节因子细胞 FLICE 样抑制蛋白（c-FLIP）的转录。总之，cIAP1 是 GBC 组织中丰富的癌蛋白，通过 NF-κB 通路增强增殖和迁移，并阻止 TNF-α 诱导的细胞凋亡。
