Nuclear receptor expression and function in human lung cancer pathogenesis

Jihye Kim, Mitsuo Sato, Jong Whan Choi, Hyun Won Kim, Byung Ii Yeh, Jill E. Larsen, John D. Minna, Jeong Heon Cha, Yangsik Jeong

Research output: Contribution to journalArticle

9 Scopus citations

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.

Original languageEnglish (US)
Article numbere0134842
JournalPloS one
Volume10
Issue number8
DOIs
StatePublished - Aug 5 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Kim, J., Sato, M., Choi, J. W., Kim, H. W., Yeh, B. I., Larsen, J. E., Minna, J. D., Cha, J. H., & Jeong, Y. (2015). Nuclear receptor expression and function in human lung cancer pathogenesis. PloS one, 10(8), [e0134842]. https://doi.org/10.1371/journal.pone.0134842