title: Bile acids regulate nuclear receptor (Nur77) expression and intracellular location to control proliferation and apoptosis.
abstract: Bile acids (BA) are endogenous agents capable of causing cancer throughout the gastrointestinal (GI) tract. To uncover the mechanism by which BAs exert carcinogenic effects, both human liver and colon cancer cells as well as mouse primary hepatocytes were treated with BAs and assayed for viability, genotoxic stress, and transcriptional response. BAs induced both Nur77 (NR4A1) and proinflammatory gene expression. The intracellular location of BA-induced Nur77 was time dependent; short-term (1-3 hours) exposure induced nuclear Nur77, whereas longer (1-2 days) exposure also increased cytosolic Nur77 expression and apoptosis. Inhibiting Nur77 nuclear export with leptomycin B decreased lithocholic acid (LCA)-induced apoptosis. Extended (7 days) treatment with BA generated resistance to BA with increased nuclear Nur77, viability, and mobility. While, knockdown of Nur77 in BA-resistant cells increased cellular susceptibility to LCA-induced apoptosis. Moreover, in vivo mouse xenograft experiments demonstrated that BA-resistant cells form larger tumors with elevated Nur77 expression compared with parental controls. DNA-binding and gene expression assays identified multiple survival genes (CDK4, CCND2, MAP4K5, STAT5A, and RBBP8) and a proapoptosis gene (BID) as Nur77 targets. Consistently, BA-induced upregulation of the aforementioned genes was abrogated by a lack of Nur77. Importantly, Nur77 was overexpressed in high percentage of human colon and liver cancer specimens, and the intracellular location of Nur77 correlated with elevated serum total BA levels in patients with colon cancer. These data show for the first time that BAs via Nur77 have a dual role in modulating cell survival and death.
  
  
  CONCLUSIONS
  These findings establish a direct link between Nur77 and the carcinogenic effect of BAs.
authors.affiliation: Department of Medical Pathology and Laboratory Medicine, University of California, Davis Health Systems, Sacramento, California.
authors.forename: Ying
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Medical Pathology and Laboratory Medicine, University of California, Davis Health Systems, Sacramento, California.
authors.forename: Thinh
authors.initials: T
authors.lastname: Chau
authors.affiliation: Department of Medical Pathology and Laboratory Medicine, University of California, Davis Health Systems, Sacramento, California.
authors.forename: Hui-Xin
authors.initials: HX
authors.lastname: Liu
authors.affiliation: Department of Pathology, Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
authors.forename: Degui
authors.initials: D
authors.lastname: Liao
authors.affiliation: Department of Medical Pathology and Laboratory Medicine, University of California, Davis Health Systems, Sacramento, California.
authors.forename: Ryan
authors.initials: R
authors.lastname: Keane
authors.affiliation: Department of Gastroenterology, First Municipal's People Hospital of Guangzhou, Guangzhou Medical University, Guangzhou, China.
authors.forename: Yuqiang
authors.initials: Y
authors.lastname: Nie
authors.affiliation: Department of Gastroenterology, Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China. yjywan@ucdavis.edu yanghui030454@gmail.com.
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Medical Pathology and Laboratory Medicine, University of California, Davis Health Systems, Sacramento, California. Department of Gastroenterology, First Municipal's People Hospital of Guangzhou, Guangzhou Medical University, Guangzhou, China. yjywan@ucdavis.edu yanghui030454@gmail.com.
authors.forename: Yu-Jui Yvonne
authors.initials: YJ
authors.lastname: Wan
mesh_terms: D000818:Animals; D017209:Apoptosis; D001647:Bile Acids and Salts / Q000097:blood / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045325:HCT116 Cells; D019073:HT29 Cells; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D009368:Neoplasm Transplantation; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D001647:Bile Acids and Salts; C539821:NR4A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1