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MicroRNA-4723 inhibits prostate cancer growth through inactivation of the Abelson family of nonreceptor protein tyrosine kinases.

Arora S, Saini S, Fukuhara S, Majid S, Shahryari V, Yamamura S, Chiyomaru T, Deng G, Tanaka Y, Dahiya R - PLoS ONE (2013)

Bottom Line: However, the mechanism of regulation of c-Abl is not known.Analysis of putative miR-4723 targets showed that miR-4723 targets integrin alpha 3 and Methyl CpG binding protein in addition to Abl1 and Abl2 kinases.In conclusion, we have identified a novel microRNA that mediates regulation of Abl kinases in prostate cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, Veterans Affairs Medical Center, San Francisco and University of California San Francisco, San Francisco, California, United States of America.

ABSTRACT
The Abelson (c-Abl) proto-oncogene encodes a highly conserved nonreceptor protein tyrosine kinase that plays a role in cell proliferation, differentiation, apoptosis and cell adhesion. c-Abl represents a specific anti-cancer target in prostate cancer as aberrant activity of this kinase has been implicated in the stimulation of prostate cancer growth and progression. However, the mechanism of regulation of c-Abl is not known. Here we report that Abl kinases are regulated by a novel microRNA, miR-4723, in prostate cancer. Expression profiling of miR-4723 expression in a cohort of prostate cancer clinical specimens showed that miR-4723 expression is widely attenuated in prostate cancer. Low miR-4723 expression was significantly correlated with poor survival outcome and our analyses suggest that miR-4723 has significant potential as a disease biomarker for diagnosis and prognosis in prostate cancer. To evaluate the functional significance of decreased miR-4723 expression in prostate cancer, miR-4723 was overexpressed in prostate cancer cell lines followed by functional assays. miR-4723 overexpression led to significant decreases in cell growth, clonability, invasion and migration. Importantly, miR-4723 expression led to dramatic induction of apoptosis in prostate cancer cell lines suggesting that miR-4723 is a pro-apoptotic miRNA regulating prostate carcinogenesis. Analysis of putative miR-4723 targets showed that miR-4723 targets integrin alpha 3 and Methyl CpG binding protein in addition to Abl1 and Abl2 kinases. Further, we found that the expression of Abl kinase is inversely correlated with miR-4723 expression in prostate cancer clinical specimens. Also, Abl1 knockdown partially phenocopies miR-4723 reexpression in prostate cancer cells suggesting that Abl is a functionally relevant target of miR-4723 in prostate cancer. In conclusion, we have identified a novel microRNA that mediates regulation of Abl kinases in prostate cancer. This study suggests that miR-4723 may be an attractive target for therapeutic intervention in prostate cancer.

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Expression of Abl kinase is inversely correlated with miR-4723 expression in prostate cancer.We examined the correlation between miR-4723 and Abl expression in a subset of our clinical cohort by performing immunohistochemical staining for Abl in PCa tissues (n = 12). Relative expression levels of Abl (as scored by IHC) and miR-4723 (as determined by RT-PCR) for the samples analysed are represented in the bar graph.
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pone-0078023-g008: Expression of Abl kinase is inversely correlated with miR-4723 expression in prostate cancer.We examined the correlation between miR-4723 and Abl expression in a subset of our clinical cohort by performing immunohistochemical staining for Abl in PCa tissues (n = 12). Relative expression levels of Abl (as scored by IHC) and miR-4723 (as determined by RT-PCR) for the samples analysed are represented in the bar graph.

Mentions: To further confirm Abl as a pathologically relevant target of miR-4723 in vivo, we examined the correlation between miR-4723 and Abl expression in a subset of our clinical cohort. We performed immunohistochemical staining for Abl in PCa tissues (n = 12) and observed a negative correlation between Abl and miR-4723 expression (Fig. 8). Clinical samples with low miR-4723 expression (relative to adjacent normal tissue) showed high levels of Abl expression (Fig. 8).


MicroRNA-4723 inhibits prostate cancer growth through inactivation of the Abelson family of nonreceptor protein tyrosine kinases.

Arora S, Saini S, Fukuhara S, Majid S, Shahryari V, Yamamura S, Chiyomaru T, Deng G, Tanaka Y, Dahiya R - PLoS ONE (2013)

Expression of Abl kinase is inversely correlated with miR-4723 expression in prostate cancer.We examined the correlation between miR-4723 and Abl expression in a subset of our clinical cohort by performing immunohistochemical staining for Abl in PCa tissues (n = 12). Relative expression levels of Abl (as scored by IHC) and miR-4723 (as determined by RT-PCR) for the samples analysed are represented in the bar graph.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3815229&req=5

pone-0078023-g008: Expression of Abl kinase is inversely correlated with miR-4723 expression in prostate cancer.We examined the correlation between miR-4723 and Abl expression in a subset of our clinical cohort by performing immunohistochemical staining for Abl in PCa tissues (n = 12). Relative expression levels of Abl (as scored by IHC) and miR-4723 (as determined by RT-PCR) for the samples analysed are represented in the bar graph.
Mentions: To further confirm Abl as a pathologically relevant target of miR-4723 in vivo, we examined the correlation between miR-4723 and Abl expression in a subset of our clinical cohort. We performed immunohistochemical staining for Abl in PCa tissues (n = 12) and observed a negative correlation between Abl and miR-4723 expression (Fig. 8). Clinical samples with low miR-4723 expression (relative to adjacent normal tissue) showed high levels of Abl expression (Fig. 8).

Bottom Line: However, the mechanism of regulation of c-Abl is not known.Analysis of putative miR-4723 targets showed that miR-4723 targets integrin alpha 3 and Methyl CpG binding protein in addition to Abl1 and Abl2 kinases.In conclusion, we have identified a novel microRNA that mediates regulation of Abl kinases in prostate cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, Veterans Affairs Medical Center, San Francisco and University of California San Francisco, San Francisco, California, United States of America.

ABSTRACT
The Abelson (c-Abl) proto-oncogene encodes a highly conserved nonreceptor protein tyrosine kinase that plays a role in cell proliferation, differentiation, apoptosis and cell adhesion. c-Abl represents a specific anti-cancer target in prostate cancer as aberrant activity of this kinase has been implicated in the stimulation of prostate cancer growth and progression. However, the mechanism of regulation of c-Abl is not known. Here we report that Abl kinases are regulated by a novel microRNA, miR-4723, in prostate cancer. Expression profiling of miR-4723 expression in a cohort of prostate cancer clinical specimens showed that miR-4723 expression is widely attenuated in prostate cancer. Low miR-4723 expression was significantly correlated with poor survival outcome and our analyses suggest that miR-4723 has significant potential as a disease biomarker for diagnosis and prognosis in prostate cancer. To evaluate the functional significance of decreased miR-4723 expression in prostate cancer, miR-4723 was overexpressed in prostate cancer cell lines followed by functional assays. miR-4723 overexpression led to significant decreases in cell growth, clonability, invasion and migration. Importantly, miR-4723 expression led to dramatic induction of apoptosis in prostate cancer cell lines suggesting that miR-4723 is a pro-apoptotic miRNA regulating prostate carcinogenesis. Analysis of putative miR-4723 targets showed that miR-4723 targets integrin alpha 3 and Methyl CpG binding protein in addition to Abl1 and Abl2 kinases. Further, we found that the expression of Abl kinase is inversely correlated with miR-4723 expression in prostate cancer clinical specimens. Also, Abl1 knockdown partially phenocopies miR-4723 reexpression in prostate cancer cells suggesting that Abl is a functionally relevant target of miR-4723 in prostate cancer. In conclusion, we have identified a novel microRNA that mediates regulation of Abl kinases in prostate cancer. This study suggests that miR-4723 may be an attractive target for therapeutic intervention in prostate cancer.

Show MeSH
Related in: MedlinePlus