lncRNA-AT作为ceRNA参与TRAIL调控PD-1促进胃癌增殖的机制

Recent study reported that PD-1 was expressed in melanoma cells, and ligand PD-L1 binding PD-1 promoted cancer cell proliferation. However, whether PD-1 is expressed in gastric cancer cells and its function is yet unknown. Our original results demonstrated that TRAIL, as an apoptosis-inducing factor, increased PD-1 expression and promoted cell proliferation in gastric cancer cells. TRAIL also increased lncRNA-AT expression. The inhibition of lncRNA-AT expression induced PD-1 downregulation. In addition, miR-1291, as the regulator of PD-1 expression, could inhibit lncRNA-AT-mediated PD-1 upregulation by binding lncRNA-AT. Moreover, TRAIL induced NF-κB activation. The inhibition of NF-κB expression induced lncRNA-AT downregulation. The aim of our study is to prove that TRAIL upregulates lncRNA-AT expression through TRAIL-induced NF-κB activation. Then lncRNA-AT, as ceRNA, inhibits miR-1291-mediated PD-1 downregulation by competitively binding miR-1291, which finally results in PD-1 overexpression, cell proliferation and the inhibition of TRAIL-induced apoptosis in gastric cancer cells. This study might provide a scientific basis for elucidating the mechanism of the PD-1/PD-L1 pathway in promoting cell proliferation and inhibiting TRAIL-induced apoptosis in gastric cancer.

最新文献报告，黑色素瘤细胞表达PD-1，结合配体PD-L1后促进肿瘤增殖。但胃癌细胞是否表达PD-1及其功能不明。我们原创性研究证实：①TRAIL作为凋亡诱导因子，却能上调胃癌细胞PD-1表达，促进胃癌增殖；②TRAIL同时上调lncRNA-AT的表达，抑制lncRNA-AT表达则PD-1下调，并且调控PD-1的miR-1291能通过与lncRNA-AT结合，抑制lncRNA-AT介导的PD-1上调；③ TRAIL活化NF-κB，抑制NF-κB则lncRNA-AT下调。本研究旨在证明，TRAIL通过激活NF-κB上调lncRNA-AT的表达；lncRNA-AT作为ceRNA竞争性结合miR-1291，从而解除miR-1291对PD-1的抑制，提高PD-1的表达，促进胃癌增殖并拮抗TRAIL诱导的凋亡。研究结果将为阐明PD-1/PD-L1通路促进胃癌增殖、拮抗TRAIL诱导凋亡提供科学依据。

胃癌是我国常见的消化系统恶性肿瘤。生物靶向药，肿瘤坏死因子相关凋亡诱导配体（TRAIL），已进入临床试验，但胃癌对TRAIL并不敏感。我们原创性研究证实：TRAIL作为凋亡诱导因子，却能上调胃癌细胞PD-1表达，促进胃癌增殖；TRAIL同时上调lncRNA-AT的表达，抑制lncRNA-AT表达则PD-1下调，并且调控PD-1的miR-1291能通过与lncRNA-AT结合，抑制lncRNA-AT介导的PD-1上调；TRAIL活化NF-κB，抑制NF-κB则lncRNA-AT下调。本研究证明，TRAIL通过激活NF-κB上调lncRNA-AT的表达；lncRNA-AT作为ceRNA竞争性结合miR-1291，从而解除miR-1291对PD-1的抑制，提高PD-1的表达，促进胃癌增殖并拮抗TRAIL诱导的凋亡。在研究中我们还发现，miR-429高表达是胃癌患者预后良好指标。miR-429通过抑制PD-L1表达及PD-L1和EGFR的结合，抑制下游Akt和mTOR增殖通路，提高胃癌细胞对TRAIL的敏感性。在耐药的胃癌细胞中，DR5-Cbl-b/c-Cbl-TRAF2复合物能促进TRAF2介导的caspase-8泛素化，进而抑制TRAIL诱导的胃癌细胞凋亡。而miR-200a靶向抑制A20的表达和RIP1的泛素化，促进了caspase-8的裂解，增强TRAIL诱导的胃癌细胞凋亡。抑制耐药胃癌细胞中IGF-1R/Caveolin-1/Src三聚复合物的形成，同样能提高TRAIL的敏感性。此外，我们还发现传统中药β-榄香烯，通过促进脂质筏内DISC形成和caspase-8活化，能提高胃癌细胞对TRAIL的敏感性。我们的研究结果为阐明PD-1/PD-L1通路促进胃癌增殖、拮抗TRAIL诱导凋亡提供科学依据。本研究也为阐明胃癌对TRAIL的耐药机理以及TRAIL的临床应用提供新的策略。