miR-23b represses proto-oncogene Src kinase and functions as methylation-silenced tumor suppressor with diagnostic and prognostic significance in prostate cancer.
The miRNAs have great potential as biomarkers and therapeutic agents owing to their ability to control multiple genes and potential to influence cellular behavior. Here, we identified that miR-23b is a methylation-silenced tumor suppressor in prostate cancer. We showed that miR-23b expression is controlled by promoter methylation and has great promise as a diagnostic and prognostic biomarker in prostate cancer. High levels of miR-23b expression are positively correlated with higher overall and recurrence-free survival in patients with prostate cancer. Furthermore, we elucidated the tumor suppressor role of miR-23b using in vitro and in vivo models. We showed that proto-oncogene Src kinase and Akt are direct targets of miR-23b. Increased expression of miR-23b inhibited proliferation, colony formation, migration/invasion, and triggered G(0)-G(1) cell-cycle arrest and apoptosis in prostate cancer. Overexpression of miR-23b inhibited epithelial-to-mesenchymal transition (EMT) causing a decline in mesenchymal markers Vimentin and Snail and increasing the epithelial marker, E-cadherin. Depletion of Src by RNA interference conferred similar functional effects as that of miR-23b reconstitution. miR-23b expression caused a dramatic decrease in tumor growth in nude mice and attenuated Src expression in excised tumors compared with a control miR. These findings suggest that miR-23b is a methylation-silenced tumor suppressor that may be a useful biomarker in prostate cancer. Loss of miR-23b may confer proliferative advantage and promote prostate cancer migration and invasion, and reexpression of miR-23b may contribute to the epigenetic therapy for prostate cancer.
Department of Urology, VA Medical Center and UCSF, San Francisco, California 94121, USA.
Shahana
S
Majid
Altaf A
AA
Dar
Sharanjot
S
Saini
Sumit
S
Arora
Varahram
V
Shahryari
Mohd Saif
MS
Zaman
Inik
I
Chang
Soichiro
S
Yamamura
Yuichiro
Y
Tanaka
Guoren
G
Deng
Rajvir
R
Dahiya
D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000502:physiology; D002277:Carcinoma / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology / Q000628:therapy; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000235:genetics*; D063185:Epigenetic Repression / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor / Q000502:physiology; D016391:Genes, src / Q000235:genetics*; D015316:Genetic Therapy; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology / Q000628:therapy; D000090063:Proto-Oncogene Mas; D023041:Xenograft Model Antitumor Assays
D014408:Biomarkers, Tumor; C000715470:MAS1 protein, human; C552430:MIRN23a microRNA, human; D035683:MicroRNAs; D000090063:Proto-Oncogene Mas