title: Nuclear Receptor Expression and Function in Human Lung Cancer Pathogenesis.
abstract: Lung cancer is caused by combinations of diverse genetic mutations. Here, to understand the relevance of nuclear receptors (NRs) in the oncogene-associated lung cancer pathogenesis, we investigated the expression profile of the entire 48 NR members by using QPCR analysis in a panel of human bronchial epithelial cells (HBECs) that included precancerous and tumorigenic HBECs harboring oncogenic K-rasV12 and/or p53 alterations. The analysis of the profile revealed that oncogenic alterations accompanied transcriptional changes in the expression of 19 NRs in precancerous HBECs and 15 NRs according to the malignant progression of HBECs. Amongst these, peroxisome proliferator-activated receptor gamma (PPARγ), a NR chosen as a proof-of-principle study, showed increased expression in precancerous HBECs, which was surprisingly reversed when these HBECs acquired full in vivo tumorigenicity. Notably, PPARγ activation by thiazolidinedione (TZD) treatment reversed the increased expression of pro-inflammatory cyclooxygenase 2 (COX2) in precancerous HBECs. In fully tumorigenic HBECs with inducible expression of PPARγ, TZD treatments inhibited tumor cell growth, clonogenecity, and cell migration in a PPARγ-sumoylation dependent manner. Mechanistically, the sumoylation of liganded-PPARγ decreased COX2 expression and increased 15-hydroxyprostaglandin dehydrogenase expression. This suggests that ligand-mediated sumoylation of PPARγ plays an important role in lung cancer pathogenesis by modulating prostaglandin metabolism.
authors.affiliation: Department of Biochemistry, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do, Republic of Korea; Institute of Lifestyle Medicine, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do, Republic of Korea; Nuclear Receptor Research Consortium, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do, Republic of Korea.
authors.forename: Jihye
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Sato
authors.affiliation: Department of Biochemistry, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do, Republic of Korea.
authors.forename: Jong-Whan
authors.initials: JW
authors.lastname: Choi
authors.affiliation: Department of Biochemistry, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do, Republic of Korea.
authors.forename: Hyun-Won
authors.initials: HW
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do, Republic of Korea.
authors.forename: Byung-Il
authors.initials: BI
authors.lastname: Yeh
authors.affiliation: The Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Jill E
authors.initials: JE
authors.lastname: Larsen
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America; Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America; The Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: John D
authors.initials: JD
authors.lastname: Minna
authors.affiliation: Department of Oral Biology, Oral Cancer Research Institute, Oral Science Research Center, BK21 Project, Research Center for Orofacial Hard Tissue Regeneration, Yonsei University College of Dentistry, Seoul, Republic of Korea.
authors.forename: Jeong-Heon
authors.initials: JH
authors.lastname: Cha
authors.affiliation: Department of Biochemistry, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do, Republic of Korea; Institute of Lifestyle Medicine, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do, Republic of Korea; Nuclear Receptor Research Consortium, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do, Republic of Korea.
authors.forename: Yangsik
authors.initials: Y
authors.lastname: Jeong
mesh_terms: D001980:Bronchi / Q000166:cytology; D002461:Cell Line, Transformed; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism*; D020869:Gene Expression Profiling / Q000379:methods*; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D058207:Sumoylation; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: D047495:PPAR gamma; D018160:Receptors, Cytoplasmic and Nuclear; D045162:Thiazolidinediones; C089946:2,4-thiazolidinedione; D051546:Cyclooxygenase 2