Wang Zhengguang, Xiong Fangyuan, Wang Xiaoshan, Qi Yijun, Yu Haoyuan, Zhu Yong, Zhu Huaqing
Department of Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, P.R. China.
Laboratory of Molecular Biology and Department of Biochemistry, Anhui Medical University, Hefei, Anhui, P.R. China.
Oncotarget. 2017 Feb 14;8(7):11105-11113. doi: 10.18632/oncotarget.14364.
Retinoid-related orphan receptor α (RORα) is a nuclear receptor, which regulates inflammation and immune responses, lipid metabolism and circadian rhythm. Although RORα suppresses breast tumor invasion, it is unknown whether RORα is dysregulated in gastric cancer leading to cellular survival. Therefore, we hypothesize that RORα is dysfunctional in gastric carcinoma and this causes decreased apoptosis in gastric cancer cells. To test this hypothesis, we employed human gastric cancer tissues with different stages to determine RORα expression, as well as in vitro human gastric cancer cells to determine how RORα is reduced during apoptosis. We found that the expression of RORα was reduced in gastric tissues with cancer, and this correlated with increased TNM stages. The mechanisms underlying RORα reduction is due to the reduced activation of AMP-activated protein kinase (AMPK), as a selective AMPK activator AICAR increased RORα activation and level in human gastric cancer cells. Furthermore, AICAR treatment increased RORα recruitment on the promoters of tumor suppressor genes (i.e., FBXM7, SEMA3F and p21) leading to apoptosis in human gastric cancer cells. Taken together, RORα reduction occurs in gastric cancer leading to the survival of tumor cells, which is attenuated by AMPK. Therefore, both RORα and AMPK are potential targets for the intervention and therapy in gastric carcinoma.
维甲酸相关孤儿受体α（RORα）是一种核受体，可调节炎症和免疫反应、脂质代谢以及昼夜节律。尽管RORα可抑制乳腺肿瘤侵袭，但尚不清楚RORα在胃癌中是否失调并导致细胞存活。因此，我们推测RORα在胃癌中功能失调，这会导致胃癌细胞凋亡减少。为了验证这一假设，我们使用不同阶段的人胃癌组织来确定RORα的表达，并使用体外人胃癌细胞来确定RORα在凋亡过程中是如何减少的。我们发现，RORα在胃癌组织中的表达降低，这与TNM分期增加相关。RORα减少的机制是由于AMP激活的蛋白激酶（AMPK）的激活减少，因为选择性AMPK激活剂AICAR增加了人胃癌细胞中RORα的激活和水平。此外，AICAR处理增加了RORα在肿瘤抑制基因（即FBXM7、SEMA3F和p21）启动子上的募集，从而导致人胃癌细胞凋亡。综上所述，RORα在胃癌中减少导致肿瘤细胞存活，而AMPK可减弱这种作用。因此，RORα和AMPK都是胃癌干预和治疗的潜在靶点。
