title: 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.affiliation: Pathology Center, Shanghai General Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.|Department of Biochemistry and Molecular & Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Lidong
authors.initials: L
authors.lastname: Zu
authors.affiliation: Pathology Center, Shanghai General Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine , Shanghai 200025 , China.
authors.forename: Yunjing
authors.initials: Y
authors.lastname: Xue
authors.affiliation: Pathology Center, Shanghai General Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine , Shanghai 200025 , China.
authors.forename: Jinglong
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Thoracic Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai 200127 , China.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Department of Biochemistry and Molecular & Cell Biology, Shanghai Jiao Tong University School of Medicine , Shanghai 200025 , China.
authors.forename: Xiumin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular & Cell Biology, Shanghai Jiao Tong University School of Medicine , Shanghai 200025 , China.
authors.forename: Gang
authors.initials: G
authors.lastname: Xiao
authors.affiliation: Department of Biochemistry and Molecular & Cell Biology, Shanghai Jiao Tong University School of Medicine , Shanghai 200025 , China.
authors.forename: Mingang
authors.initials: M
authors.lastname: Hao
authors.affiliation: Department of Biochemistry and Molecular & Cell Biology, Shanghai Jiao Tong University School of Medicine , Shanghai 200025 , China.
authors.forename: Xueqing
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Biochemistry and Molecular & Cell Biology, Shanghai Jiao Tong University School of Medicine , Shanghai 200025 , China.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Pathology Center, Shanghai General Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine , Shanghai 200025 , China.
authors.forename: Guohui
authors.initials: G
authors.lastname: Fu
authors.affiliation: Cancer institute, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, China and.|Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060, China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement / Q000235:genetics; D047369:Chromatin Immunoprecipitation; D025461:Feedback, Physiological; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: C509207:MIRN124 microRNA, human; D035683:MicroRNAs; D016212:Transforming Growth Factor beta