Down-regulation of micro-RNA-1 (miR-1) in lung cancer. Suppression of tumorigenic property of lung cancer cells and their sensitization to doxorubicin-induced apoptosis by miR-1. J Biol Chem 2008 Nov 28;283(48):33394-405
Date
09/27/2008Pubmed ID
18818206Pubmed Central ID
PMC2586284DOI
10.1074/jbc.M804788200Scopus ID
2-s2.0-57749089758 (requires institutional sign-in at Scopus site) 335 CitationsAbstract
Micro-RNAs are approximately 21-25-nucleotide-long noncoding RNAs that regulate gene expression primarily at the post-transcriptional level in animals. Here, we report that micro-RNA-1 (miR-1), abundant in the cardiac and smooth muscles, is expressed in the lung and is down-regulated in human primary lung cancer tissues and cell lines. In situ hybridization demonstrated localization of miR-1 in bronchial epithelial cells. The tumor suppressor C/EBPalpha, frequently suppressed in lung cancer, reactivated miR-1 expression in the lung cancer cells. Repressed miR-1 was also activated in lung cancer cells upon treatment with a histone deacetylase inhibitor. These observations led us to examine the antitumorigenic potential of miR-1 in lung cancer cells. Expression of miR-1 in nonexpressing A549 and H1299 cells reversed their tumorigenic properties, such as growth, replication potential, motility/migration, clonogenic survival, and tumor formation in nude mice. Exogenous miR-1 significantly reduced expression of oncogenic targets, such as MET, a receptor tyrosine kinase, and Pim-1, a Ser/Thr kinase, frequently up-regulated in lung cancer. Similarly, the levels of two additional targets, FoxP1, a transcription factor with oncogeneic property, and HDAC4 that represses differentiation-promoting genes, were reduced in miR-1-expressing cells. Conversely, depletion of miR-1 facilitated N417 cell growth with concomitant elevation of these targets. Further, ectopic miR-1 induced apoptosis in A549 cells in response to the potent anticancer drug doxorubicin. Enhanced activation of caspases 3 and 7, cleavage of their substrate PARP-1, and depletion of anti-apoptotic Mcl-1 contributed to the sensitivity of miR-1-expressing cells to doxorubicin. Thus, miR-1 has potential therapeutic application against lung cancers.
Author List
Nasser MW, Datta J, Nuovo G, Kutay H, Motiwala T, Majumder S, Wang B, Suster S, Jacob ST, Ghoshal KMESH terms used to index this publication - Major topics in bold
AnimalsAntibiotics, Antineoplastic
Apoptosis
Caspase 3
Caspase 7
Cell Line, Tumor
Cell Movement
Cell Survival
Down-Regulation
Doxorubicin
Forkhead Transcription Factors
Gene Expression Regulation, Neoplastic
Histone Deacetylases
Humans
Lung Neoplasms
Mice
Mice, Nude
MicroRNAs
Myeloid Cell Leukemia Sequence 1 Protein
Poly (ADP-Ribose) Polymerase-1
Poly(ADP-ribose) Polymerases
Proto-Oncogene Proteins
Proto-Oncogene Proteins c-bcl-2
Proto-Oncogene Proteins c-met
Proto-Oncogene Proteins c-pim-1
RNA, Neoplasm
Receptors, Growth Factor
Repressor Proteins