The feedback loop between miR-124 and TGF-β pathway plays a significant role in non-small cell lung cancer metastasis.

Abstract

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-β (TGF-β) 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-β 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-β 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-β 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.

• Authors: Lidong Zu, Yunjing Xue, Jinglong Wang, Yujie Fu, Xiumin Wang, Gang Xiao, Mingang Hao, Xueqing Sun, Yingying Wang, Guohui Fu, Jianhua Wang
• Journal: Carcinogenesis (Carcinogenesis) Vol. 37 Issue 3 Pg. 333-343 (Mar 2016) ISSN: 1460-2180 [Electronic] England
• PMID: 26818357 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• MIRN124 microRNA, human
• MicroRNAs
• Transforming Growth Factor beta

Topics

• Animals
• Blotting, Western
• Carcinoma, Non-Small-Cell Lung (genetics, metabolism, pathology)
• Cell Movement (genetics)
• Chromatin Immunoprecipitation
• Feedback, Physiological
• Heterografts
• Humans
• Immunohistochemistry
• Lung Neoplasms (genetics, metabolism, pathology)
• Mice
• Mice, Inbred BALB C
• MicroRNAs (metabolism)
• Neoplasm Invasiveness (genetics)
• Real-Time Polymerase Chain Reaction
• Signal Transduction
• Transforming Growth Factor beta (metabolism)