title: Nuclear receptor retinoid-related orphan receptor alpha promotes apoptosis but is reduced in human gastric cancer.
abstract: 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.
authors.affiliation: Department of Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, P.R. China.
authors.forename: Zhengguang
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Laboratory of Molecular Biology and Department of Biochemistry, Anhui Medical University, Hefei, Anhui, P.R. China.
authors.forename: Fangyuan
authors.initials: F
authors.lastname: Xiong
authors.affiliation: Department of Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, P.R. China.
authors.forename: Xiaoshan
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, P.R. China.
authors.forename: Yijun
authors.initials: Y
authors.lastname: Qi
authors.affiliation: Department of Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, P.R. China.
authors.forename: Haoyuan
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, P.R. China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Laboratory of Molecular Biology and Department of Biochemistry, Anhui Medical University, Hefei, Anhui, P.R. China.
authors.forename: Huaqing
authors.initials: H
authors.lastname: Zhu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012265:Ribonucleotides / Q000494:pharmacology; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D012265:Ribonucleotides; D025521:Tumor Suppressor Proteins; D000620:Aminoimidazole Carboxamide; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide
keywords: AMPK; RORα; apoptosis; chemotherapy resistance; gastric carcinoma