title: Down-Regulated miR-30a in Clear Cell Renal Cell Carcinoma Correlated with Tumor Hematogenous Metastasis by Targeting Angiogenesis-Specific DLL4.
abstract: Endothelial DLL4 plays an important role in controlling of tumor angiogenesis, which is required for tumor invasive growth and metastasis. However, the regulation of DLL4 in clear cell renal cell carcinoma (ccRCC) has not yet been systematically elucidated.
  
  
  
  We performed bioinformatical analysis to explore miRNAs targeting DLL4. miR-30a was selected as a representative to validate its functional association in endothelial cell. Then, the expressions of DLL4 and mature miR-30a from 90 cases of ccRCC and 28 cases of nonmatched adjacent non-tumor tissues were measured by quantitative real-time PCR. Finally, the expression of miR-30a was correlated with DLL4 expression, tumor features (metastatic condition and microvessel density), and patient metastasis-free survival. The univariate and multivariate analyses were performed to select the risk factors associated with hematogenous metastasis, respectively.
  
  
  
  miR-30a negatively regulated DLL4 and inhibited the proliferation and migration of endothelial cells. DLL4 was up-regulated in ccRCC and further increased in hematogenous metastatic cases, while miR-30a was down-regulated in tumor tissues and further decreased in hematogenous metastatic ccRCC (student t test, all p<0.05). Additionally, expression of miR-30a was inversely correlated with expression of DLL4 and microvessel density (linear correlation analysis, both p<0.05). Low-level miR-30a also indicated a higher probability of developing metastasis (log-rank test, p = 0.010). Most importantly, miR-30a expression was an independent predictor of ccRCC hematogenous metastasis by the univariate analysis and binary logistic regression model (both p<0.05).
  
  
  
  Down-regulated miR-30a in ccRCC was associated with tumor hematogenous metastasis through increasing microvessel density by targeting angiogenesis-specific DLL4.
authors.affiliation: Department of Urology/State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital/PLA Medical School, Beijing, China.
authors.forename: Qing Bo
authors.initials: QB
authors.lastname: Huang
authors.forename: Xin
authors.initials: X
authors.lastname: Ma
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
authors.forename: Shang Wen
authors.initials: SW
authors.lastname: Liu
authors.forename: Qing
authors.initials: Q
authors.lastname: Ai
authors.forename: Tao Ping
authors.initials: TP
authors.lastname: Shi
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yu
authors.initials: Y
authors.lastname: Gao
authors.forename: Yang
authors.initials: Y
authors.lastname: Fan
authors.forename: Dong
authors.initials: D
authors.lastname: Ni
authors.forename: Bao Jun
authors.initials: BJ
authors.lastname: Wang
authors.forename: Hong Zhao
authors.initials: HZ
authors.lastname: Li
authors.forename: Tao
authors.initials: T
authors.lastname: Zheng
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D014408:Biomarkers, Tumor / Q000378:metabolism; D002135:Calcium-Binding Proteins; D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D019295:Computational Biology; D018572:Disease-Free Survival; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D055806:Microvessels / Q000378:metabolism; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000473:pathology / Q000503:physiopathology; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D002135:Calcium-Binding Proteins; C424126:DLL4 protein, human; D036341:Intercellular Signaling Peptides and Proteins; C546086:MIRN30b microRNA, human; D035683:MicroRNAs