State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, the Fourth Military Medical Univeristy, Xi'an, China State Key Laboratory of Cancer Biology and Department of Pathology, Xijing Hospital, the Fourth Military Medical University, Xi'an, China.
FEBS J. 2012 Oct;279(19):3652-3664. doi: 10.1111/j.1742-4658.2012.08726.x. Epub 2012 Aug 31.
Gastric cancer is one of the leading causes of malignancy-related mortality in the world, and malignant growth is a crucial characteristic in gastric cancer. In our previous study, we found that growth arrest-specific gene 1 (GAS1) suppression was involved in making gastric cancer cells multidrug-resistant by protecting them from drug-induced apoptosis. In the present study, we investigated the potential role of GAS1 in the growth and proliferation of gastric cancer. We demonstrated that GAS1 expression was decreased in gastric cancer, and patients without GAS1 expression showed shorter survival times than those with GAS1 expression. Both gain-of-function (by overexpression of GAS1) and loss-of-function (by GAS1-specific small interfering RNA knockdown) studies showed that increased GAS1 expression significantly reduced the colony-forming ability of gastric cancer cells in vitro and reduced cell growth in vivo, whereas decreased GAS1 expression had the opposite effects. Moreover, upregulation of GAS1 induced cell apoptosis, and downregulation of GAS1 inhibited apoptosis. Furthermore, we demonstrated that GAS1 could induce gastric cancer cell apoptosis, at least in part through modulating the Bcl-2/Bax ratio and the activity of caspase-3. Taken together, our results strongly indicate that GAS1 expression was decreased in gastric cancer and was predictive of a poor prognosis. Restoration of GAS1 expression inhibited cell growth and promoted apoptosis of gastric cancer cells, at least in part through modulating the Bcl-2/Bax ratio and activating caspase-3, suggesting that GAS1 might be used as a novel therapeutic candidate for gastric cancer.
胃癌是全球导致恶性肿瘤相关死亡率的主要原因之一，而恶性生长是胃癌的一个关键特征。在我们之前的研究中，我们发现生长停滞特异性基因 1（GAS1）的抑制通过保护胃癌细胞免受药物诱导的细胞凋亡而使胃癌细胞产生多药耐药。在本研究中，我们研究了 GAS1 在胃癌生长和增殖中的潜在作用。我们表明，GAS1 在胃癌中表达降低，并且没有 GAS1 表达的患者的存活时间短于有 GAS1 表达的患者。功能获得（通过过表达 GAS1）和功能丧失（通过 GAS1 特异性小干扰 RNA 敲低）研究均表明，GAS1 表达的增加显著降低了胃癌细胞在体外的集落形成能力，并减少了体内细胞生长，而 GAS1 表达的降低则产生相反的效果。此外，GAS1 的上调诱导细胞凋亡，而下调 GAS1 则抑制细胞凋亡。此外，我们证明 GAS1 可以诱导胃癌细胞凋亡，至少部分通过调节 Bcl-2/Bax 比值和 caspase-3 的活性。总之，我们的结果强烈表明 GAS1 在胃癌中表达降低，并且与预后不良相关。恢复 GAS1 表达抑制了胃癌细胞的生长并促进了细胞凋亡，至少部分通过调节 Bcl-2/Bax 比值和激活 caspase-3，这表明 GAS1 可能被用作胃癌的新型治疗候选物。
