期刊
CARCINOGENESIS
卷 37, 期 3, 页码 333-343出版社
OXFORD UNIV PRESS
DOI: 10.1093/carcin/bgw011
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资金
- National Natural funding of China [81071747, 81272404]
- National key program (973) for Basic Research of China [2011CB510106, 2011CB504300]
- Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning
- Program of Shanghai Municipal Health Bureau Subject Chief Scientist [XBR20110052]
Our data disclose that the feedback loop between miR-124 and transforming growth factor-beta pathway may play a significant role in non-small cell lung cancer (NSCLC) metastasis. These findings suggest that targeting the loop may provide a more effective therapeutic strategy for NSCLC.Increasing evidence shows that micro RNAs (miRNAs) play a critical role in tumor development. However, the role of miRNAs in non-small cell lung cancer (NSCLC) metastasis remains largely unknown. Here, we found that miR-124 expression was significantly impaired in NSCLC tissues and associated with its metastasis. In vitro and in vivo experiments indicate that restoring miR-124 expression in NSCLC cells had a marked effect on reducing cell migration, invasion and metastasis. Mechanistic analyses show that Smad4, a cobinding protein in transforming growth factor-beta (TGF-beta) pathway, was identified as a new target gene of miR-124. Restoring Smad4 expression in miR-124-infected cells could partially rescue miR-124-induced abolition of cell migration and invasion. Notably, upon TGF-beta stimulation, phosphorylation of Smad2/3 was modulated by alteration of miR-124 or Smad4 expression, followed by inducing some special transcription of downstream genes including Snail, Slug and ZEB2, all of which may trigger epithelial-mesenchymal transition and be associated with NSCLC metastasis. Moreover, activation of TGF-beta pathway may enhance expression of DNMT3a, leading to hypermethylation on miR-124 promoter. Therefore, heavily loss of miR-124 expression further enhances Smad4 level by this feedback loop. Taken together, our data show for the first time that the feedback loop between miR-124 and TGF-beta pathway may play a significant role in NSCLC metastasis. Targeting the loop may prove beneficial to prevent metastasis and provide a more effective therapeutic strategy for NSCLC.
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