Expression of miRNAs involved in angiogenesis, tumor cell proliferation, tumor suppressor inhibition, epithelial-mesenchymal transition and activation of metastasis in bladder cancer.
OBJECTIVE
miRNAs are noncoding RNAs that posttranscriptionally regulate gene expression. Altered expression and function have been observed in bladder cancer. We analyzed the expression profile of a group of miRNAs involved in bladder cancer angiogenesis, tumor cell proliferation, tumor suppressor inhibition, epithelial-mesenchymal transition and metastasis activation. Prognostic and diagnostic value, and validated targets were further examined.


METHODS
Using quantitative real-time polymerase chain reaction 77 bladder cancer cases and 77 matched tumor associated normal samples were investigated to determine the expression of miR-10b, 19a, 19b, 21, 126, 145, 205, 210, 221, 296-5p and 378. The relationship between miRNA expression, patient survival and tumor pathological features was also examined.


RESULTS
miR-10b, 19a, 126, 145, 221, 296-5p and 378 were significantly down-regulated in bladder cancer compared to adjacent normal urothelium. miR-145 was the most down-regulated microRNA of this group. miR-19b, 21, 205 and 210 showed no significant difference between the 2 tissue types. High miR-21 expression correlated with worse overall patient survival (p = 0.0099). Multivariate analysis revealed that miR-21, 210 and 378 may serve as independent prognostic factors for overall patient survival (p = 0.005, 0.033 and 0.012, respectively). miR-21 and 378 may serve as independent prognostic factors for recurrence (p = 0.030 and 0.031, respectively). miR-145, 221, 296-5p and 378 showed the best combined ROC curves for specificity and sensitivity. miRWalk analysis was used to identify validated miRNA target genes. Further Gene Ontology enrichment revealed the main classes of biological functions of these validated targets.


CONCLUSIONS
Most miRNAs analyzed are down-regulated in bladder cancer. They may serve as candidate biomarkers for diagnostic and prognostic purposes in the future.
Laboratory of Virology, Medical School, University of Crete, Heraklion, Greece.
Apostolos
A
Zaravinos
Jelena
J
Radojicic
George I
GI
Lambrou
Dimitrios
D
Volanis
Dimitris
D
Delakas
Efstathios N
EN
Stathopoulos
Demetrios A
DA
Spandidos
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics; D002295:Carcinoma, Transitional Cell / Q000098:blood supply / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000556:secondary*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D015536:Down-Regulation / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D016147:Genes, Tumor Suppressor; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D060888:Real-Time Polymerase Chain Reaction; D013223:Statistics as Topic; D016019:Survival Analysis; D015996:Survival Rate; D020506:Untranslated Regions / Q000235:genetics; D001749:Urinary Bladder Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000401:mortality / Q000473:pathology
D014408:Biomarkers, Tumor; D035683:MicroRNAs; D020506:Untranslated Regions