Department of Gastrointestinal Surgery, Affiliated Hospital, Zunyi Medical University, Zunyi, China.
Department of Cell Biology, Zunyi Medical University, Zunyi, China; Key Laboratory of Brain Science, Guizhou Key Laboratory of Anesthesia and Organ Protection, Zunyi Medical University, Zunyi, China.
Biochimie. 2018 Nov;154:119-126. doi: 10.1016/j.biochi.2018.08.006. Epub 2018 Aug 23.
Gastric cancer (GC) is one of the most common malignancies as well as the third leading cause for cancer-related death. Molecular basis of GC are essential and critical for its therapeutic treatment, but still remain poorly understood. T-cell intracellular antigen-1 (TIA1) extensively involves in cancer progression, whereas its role and regulation mechanism in GC have not been revealed. In the present study, we found that TIA-1 protein level was down-regulated in GC tissues and TIA1 inhibited proliferation and promoted apoptosis of GC cells. Then, we used bioinformatics to predict miR-487a as the upstream regulator of TIA1 and we also observed an inverse correlation between miR-487a level and TIA-1 protein level in GC tissues. Next, we demonstrated that miR-487a directly targeted TIA1 via binding to its 3'-untranslated region. Furthermore, we investigated the role of miR-487a-TIA1 pathway in the growth of GC cells both in vitro and in vivo. The repression of TIA-1 by miR-487a promoted cell proliferation and suppressed cell apoptosis in vitro, and the knockdown of miR-487a had the opposite effects. Finally, we demonstrated that miR-487a promoted the development of gastric tumor growth in xenograft mice by targeting TIA-1. These effects could be partially reversed by restoring the expression of TIA-1. Overall, our results reveal that TIA1 is a tumor suppressor gene and is directly regulated by miR-487a in GC, which may offer new therapeutic targets for GC treatment.
胃癌（GC）是最常见的恶性肿瘤之一，也是癌症相关死亡的第三大主要原因。GC 的分子基础对其治疗至关重要，但仍知之甚少。T 细胞内抗原-1（TIA1）广泛参与癌症的进展，但其在 GC 中的作用和调节机制尚未被揭示。在本研究中，我们发现 TIA-1 蛋白水平在 GC 组织中下调，TIA1 抑制 GC 细胞的增殖并促进其凋亡。然后，我们使用生物信息学方法预测 miR-487a 是 TIA1 的上游调节因子，并且还观察到 GC 组织中 miR-487a 水平与 TIA-1 蛋白水平呈负相关。接下来，我们证明 miR-487a 通过与 TIA1 的 3'-非翻译区结合而直接靶向 TIA1。此外，我们在体内和体外研究了 miR-487a-TIA1 通路在 GC 细胞生长中的作用。miR-487a 对 TIA-1 的抑制促进了体外细胞增殖并抑制了细胞凋亡，而 miR-487a 的敲低则产生了相反的效果。最后，我们证明 miR-487a 通过靶向 TIA1 促进了异种移植小鼠胃肿瘤生长的发展。通过恢复 TIA-1 的表达可以部分逆转这些影响。总的来说，我们的研究结果表明，TIA1 是一种肿瘤抑制基因，在 GC 中直接受到 miR-487a 的调控，这可能为 GC 的治疗提供新的治疗靶点。
