MicroRNA-15a/16 regulates apoptosis of lung epithelial cells after oxidative stress

Yong Cao, Duo Zhang, Hyung Geun Moon, Heedoo Lee, Jeffrey A. Haspel, Kebin Hu, Lixin Xie, Yang Jin

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Lung epithelial cell apoptosis is an important feature of hyperoxia-induced lung injury. The death receptor–associated extrinsic pathway and mitochondria-associated intrinsic pathway both mediate the development of lung epithelial cell apoptosis. Despite decades of research, molecular mechanisms of hyperoxia-induced epithelial cell apoptosis remain incompletely understood. Here, we report a novel regulatory paradigm in response to hyperoxia-associated oxidative stress. Hyperoxia markedly upregulated microRNA (miR)-15a/16 levels in lung epithelial cells, bronchoalveolar lavage fluid (BALF) and lung tissue. This effect was mediated by hyperoxia-induced reactive oxygen species. Functionally, miR-15a/16 inhibitors induced caspase-3–mediated lung epithelial cell apoptosis, in the presence of hyperoxia. MiR-15a/16 inhibitors robustly enhanced FADD level and downregulated Bcl-2 expression. Consistently, cleaved caspase-8 and -9 were highly induced in the miR-15a/16–deficient cells, after hyperoxia. Using airway epithelial cell–specific, miR-15a/16–/– mice, we found that Bcl-2 was significantly reduced in lung epithelial cells in vivo after hyperoxia. In contrast, caspase-3, caspase-8 and Bcl-2–associated death promoter (BAD) were highly elevated in the miR-15a/16–/– epithelial cells in vivo. Interestingly, in lung epithelial malignant cells, rather than benign cells, deletion of miR-15a/16 prevented apoptosis. Furthermore, deletion of miR-15a/16 in macrophages also prohibited apoptosis, which is the opposite of what we have found in normal lung epithelial cells. Taken together, our data suggested that miR-15a/16 may exert differential roles in different cell types. MiR-15a/16 deficiency results in lung epithelial cell apoptosis in response to hyperoxia, via modulating both intrinsic and extrinsic apoptosis pathways.

Original languageEnglish (US)
Pages (from-to)233-243
Number of pages11
JournalMolecular Medicine
Volume22
DOIs
StatePublished - 2016

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Fingerprint Dive into the research topics of 'MicroRNA-15a/16 regulates apoptosis of lung epithelial cells after oxidative stress'. Together they form a unique fingerprint.

Cite this