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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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miR-4723 expression is widely attenuated in prostate cancer.(A) Quantitative RT-PCR analysis of relative miR-4723 expression levels in laser capture microdissected (LCM) PCa tissues (n = 57) and patient matched adjacent normal regions. Data were normalized to RNU48 control. Table summarizes the relative miR-4723 expression levels in these specimens. (B) Correlation of miR-4723 expression with clinicopathological characteristics of prostate cancer patients including Gleason grade, pathological stage and biochemical recurrence.
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pone-0078023-g001: miR-4723 expression is widely attenuated in prostate cancer.(A) Quantitative RT-PCR analysis of relative miR-4723 expression levels in laser capture microdissected (LCM) PCa tissues (n = 57) and patient matched adjacent normal regions. Data were normalized to RNU48 control. Table summarizes the relative miR-4723 expression levels in these specimens. (B) Correlation of miR-4723 expression with clinicopathological characteristics of prostate cancer patients including Gleason grade, pathological stage and biochemical recurrence.

Mentions: To evaluate the role of miR-4723 in prostate cancer, miR-4723 expression was assayed in human human clinical prostate samples (Fig. 1A). Clinicopathological characteristics of the patients are summarized in Table S1. We examined the expression levels of miR-4723 in laser capture microdissected (LCM) prostate cancer tissues (n = 57) and matched adjacent normal regions by real-time PCR. While the expression of miR-4723 was unaltered in 6/57 cases (10%) and higher in 9/57 cases (16%), a major fraction of tissue samples (42/57, ∼74%) showed lower miR-4723 levels relative to matched normal tissues. The differences were statistically significant with the Wilcoxon Signed Rank test (p<0.0001). This suggests that miR-4723 is widely downregulated in prostate cancer and is a potential prostate cancer tumor suppressor.


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)

miR-4723 expression is widely attenuated in prostate cancer.(A) Quantitative RT-PCR analysis of relative miR-4723 expression levels in laser capture microdissected (LCM) PCa tissues (n = 57) and patient matched adjacent normal regions. Data were normalized to RNU48 control. Table summarizes the relative miR-4723 expression levels in these specimens. (B) Correlation of miR-4723 expression with clinicopathological characteristics of prostate cancer patients including Gleason grade, pathological stage and biochemical recurrence.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0078023-g001: miR-4723 expression is widely attenuated in prostate cancer.(A) Quantitative RT-PCR analysis of relative miR-4723 expression levels in laser capture microdissected (LCM) PCa tissues (n = 57) and patient matched adjacent normal regions. Data were normalized to RNU48 control. Table summarizes the relative miR-4723 expression levels in these specimens. (B) Correlation of miR-4723 expression with clinicopathological characteristics of prostate cancer patients including Gleason grade, pathological stage and biochemical recurrence.
Mentions: To evaluate the role of miR-4723 in prostate cancer, miR-4723 expression was assayed in human human clinical prostate samples (Fig. 1A). Clinicopathological characteristics of the patients are summarized in Table S1. We examined the expression levels of miR-4723 in laser capture microdissected (LCM) prostate cancer tissues (n = 57) and matched adjacent normal regions by real-time PCR. While the expression of miR-4723 was unaltered in 6/57 cases (10%) and higher in 9/57 cases (16%), a major fraction of tissue samples (42/57, ∼74%) showed lower miR-4723 levels relative to matched normal tissues. The differences were statistically significant with the Wilcoxon Signed Rank test (p<0.0001). This suggests that miR-4723 is widely downregulated in prostate cancer and is a potential prostate cancer tumor suppressor.

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