title: miR-199a-3p inhibits hepatocyte growth factor/c-Met signaling in renal cancer carcinoma.
abstract: MicroRNAs (miRNAs) are a class of small non-coding RNAs that bind protein-coding mRNAs and negatively regulate protein expression by translation repression or mRNA cleavage. Accumulating evidence suggests that miRNAs are involved in cancer development and progression, acting as either tumor suppressors or oncogenes. It has been shown that miR-199a-3p was significantly down-regulated in several types of cancers. However, its role and relevance in renal cell carcinoma (RCC) are still largely unknown. Here, we show that miR-199a-3p is significantly down-regulated in human RCC primary tumors and cell lines compared to their non-tumor counterparts. Moreover, the down-regulation of miR-199a-3p is correlated with the histological grade and TNM (tumor-lymph node-metastasis) stage of RCC. Reintroducing miR-199a-3p in RCC cell lines 769-P and Caki-1 inhibited cell proliferation and caused G1 phase arrest. We found that c-Met was up-regulated in RCC cell lines and its expression could be repressed by miR-199a-3p. Moreover, c-Met was up-regulated in RCC primary tumors and reversely correlated with miR-199a-3p expression in the same paired RCC tissues. Reintroducing miR-199a-3p inhibited c-Met expression and led to attenuated activation of c-Met downstream signaling pathways including STAT3, mTOR and ERK1/2. We found that the concentrations of serum hepatocyte growth factor (HGF), the ligand of c-Met receptor, were significantly elevated in RCC patients compared to healthy persons. In addition, HGF treatment could promote proliferation of RCC cells, and the increased cell proliferation was abrogated by miR-199a-3p. Our findings indicated that miR-199a-3p target HGF/c-Met signaling pathway which is crucial for RCC development and suggest that miR-199a-3p may serve as a potential target miRNA for RCC therapy.
authors.affiliation: Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 168 Pujian Road, Pudong District, Shanghai, 200127, China.
authors.forename: Jiwei
authors.initials: J
authors.lastname: Huang
authors.forename: BaiJun
authors.initials: B
authors.lastname: Dong
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.forename: Wen
authors.initials: W
authors.lastname: Kong
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Chen
authors.forename: Wei
authors.initials: W
authors.lastname: Xue
authors.forename: Dongming
authors.initials: D
authors.lastname: Liu
authors.forename: Yiran
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000328:Adult; D000368:Aged; D002292:Carcinoma, Renal Cell / Q000473:pathology* / Q000628:therapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors* / Q000502:physiology; D006801:Humans; D007680:Kidney Neoplasms / Q000473:pathology* / Q000628:therapy; D008297:Male; D035683:MicroRNAs / Q000502:physiology*; D008875:Middle Aged; D019859:Proto-Oncogene Proteins c-met / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D035683:MicroRNAs; C531408:mirn199 microRNA, human; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met