miR-23b represses proto-oncogene Src kinase and functions as methylation-silenced tumor suppressor with diagnostic and prognostic significance in prostate cancer

Shahana Majid, Altaf A. Dar, Sharanjot Saini, Sumit Arora, Varahram Shahryari, Mohd Saif Zaman, Inik Chang, Soichiro Yamamura, Yuichiro Tanaka, Guoren Deng, Rajvir Dahiya

Research output: Contribution to journalArticle

Abstract

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 G0-G1 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.

Original languageEnglish (US)
Pages (from-to)6435-6446
Number of pages12
JournalCancer Research
Volume72
Issue number24
DOIs
StatePublished - Dec 15 2012
Externally publishedYes

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Proto-Oncogenes
src-Family Kinases
Methylation
Prostatic Neoplasms
Neoplasms
Biomarkers
G1 Phase Cell Cycle Checkpoints
Epithelial-Mesenchymal Transition
Vimentin
Cadherins
RNA Interference
MicroRNAs
Epigenomics
Nude Mice
Apoptosis
Recurrence
Survival
Therapeutics
Growth
Genes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

miR-23b represses proto-oncogene Src kinase and functions as methylation-silenced tumor suppressor with diagnostic and prognostic significance in prostate cancer. / Majid, Shahana; Dar, Altaf A.; Saini, Sharanjot; Arora, Sumit; Shahryari, Varahram; Zaman, Mohd Saif; Chang, Inik; Yamamura, Soichiro; Tanaka, Yuichiro; Deng, Guoren; Dahiya, Rajvir.

In: Cancer Research, Vol. 72, No. 24, 15.12.2012, p. 6435-6446.

Research output: Contribution to journalArticle

Majid, S, Dar, AA, Saini, S, Arora, S, Shahryari, V, Zaman, MS, Chang, I, Yamamura, S, Tanaka, Y, Deng, G & Dahiya, R 2012, 'miR-23b represses proto-oncogene Src kinase and functions as methylation-silenced tumor suppressor with diagnostic and prognostic significance in prostate cancer', Cancer Research, vol. 72, no. 24, pp. 6435-6446. https://doi.org/10.1158/0008-5472.CAN-12-2181
Majid, Shahana ; Dar, Altaf A. ; Saini, Sharanjot ; Arora, Sumit ; Shahryari, Varahram ; Zaman, Mohd Saif ; Chang, Inik ; Yamamura, Soichiro ; Tanaka, Yuichiro ; Deng, Guoren ; Dahiya, Rajvir. / miR-23b represses proto-oncogene Src kinase and functions as methylation-silenced tumor suppressor with diagnostic and prognostic significance in prostate cancer. In: Cancer Research. 2012 ; Vol. 72, No. 24. pp. 6435-6446.
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AU - Dar, Altaf A.

AU - Saini, Sharanjot

AU - Arora, Sumit

AU - Shahryari, Varahram

AU - Zaman, Mohd Saif

AU - Chang, Inik

AU - Yamamura, Soichiro

AU - Tanaka, Yuichiro

AU - Deng, Guoren

AU - Dahiya, Rajvir

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N2 - 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 G0-G1 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.

AB - 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 G0-G1 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.

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