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MicroRNA let-7c is downregulated in prostate cancer and suppresses prostate cancer growth.

Nadiminty N, Tummala R, Lou W, Zhu Y, Shi XB, Zou JX, Chen H, Zhang J, Chen X, Luo J, deVere White RW, Kung HJ, Evans CP, Gao AC - PLoS ONE (2012)

Bottom Line: Lentiviral-mediated re-expression of let-7c was utilized to assess the effects on human PCa xenografts.Overexpression of let-7c decreased while downregulation of let-7c increased cell proliferation, clonogenicity and anchorage-independent growth of PCa cells in vitro.Furthermore, let-7c expression is downregulated in clinical PCa specimens compared to their matched benign tissues, while the expression of Lin28, a master regulator of let-7 miRNA processing, is upregulated in clinical PCa specimens.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, University of California Davis, Sacramento, California, United States of America. nnadiminty@ucdavis.edu

ABSTRACT

Purpose: Prostate cancer (PCa) is characterized by deregulated expression of several tumor suppressor or oncogenic miRNAs. The objective of this study was the identification and characterization of miR-let-7c as a potential tumor suppressor in PCa.

Experimental design: Levels of expression of miR-let-7c were examined in human PCa cell lines and tissues using qRT-PCR and in situ hybridization. Let-7c was overexpressed or suppressed to assess the effects on the growth of human PCa cell lines. Lentiviral-mediated re-expression of let-7c was utilized to assess the effects on human PCa xenografts.

Results: We identified miR-let-7c as a potential tumor suppressor in PCa. Expression of let-7c is downregulated in castration-resistant prostate cancer (CRPC) cells. Overexpression of let-7c decreased while downregulation of let-7c increased cell proliferation, clonogenicity and anchorage-independent growth of PCa cells in vitro. Suppression of let-7c expression enhanced the ability of androgen-sensitive PCa cells to grow in androgen-deprived conditions in vitro. Reconstitution of Let-7c by lentiviral-mediated intratumoral delivery significantly reduced tumor burden in xenografts of human PCa cells. Furthermore, let-7c expression is downregulated in clinical PCa specimens compared to their matched benign tissues, while the expression of Lin28, a master regulator of let-7 miRNA processing, is upregulated in clinical PCa specimens.

Conclusions: These results demonstrate that microRNA let-7c is downregulated in PCa and functions as a tumor suppressor, and is a potential therapeutic target for PCa.

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Let-7c expression is downregulated in human PCa.A) Relative expression levels of let-7c were measured by qRT-PCR in total RNAs extracted from 10 paired benign and tumor human prostate samples. B) Let-7c levels were measured using in situ hybridization in TMAs containing 160 cores each from unmatched benign and cancerous prostate biopsies. Representative images are shown for benign and cancer cores. Expression of let-7c was higher in benign prostates compared to cancerous prostates. C) Relative expression levels of Lin28 in the 10 paired benign and tumor human prostate samples. Expression levels of Lin28 were correlated inversely with those of let-7c. Error bars denote ± SD (*p < 0.05).
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pone-0032832-g002: Let-7c expression is downregulated in human PCa.A) Relative expression levels of let-7c were measured by qRT-PCR in total RNAs extracted from 10 paired benign and tumor human prostate samples. B) Let-7c levels were measured using in situ hybridization in TMAs containing 160 cores each from unmatched benign and cancerous prostate biopsies. Representative images are shown for benign and cancer cores. Expression of let-7c was higher in benign prostates compared to cancerous prostates. C) Relative expression levels of Lin28 in the 10 paired benign and tumor human prostate samples. Expression levels of Lin28 were correlated inversely with those of let-7c. Error bars denote ± SD (*p < 0.05).

Mentions: To determine whether the levels of let-7c expression are downregulated in clinical PCa, we analyzed RNAs from 10 paired benign and tumor human PCa specimens by quantitative RT-PCR. RNAs were isolated from human tissues, reverse transcribed and subjected to qRT-PCR using LNA-conjugated let-7c primers (Exiqon). The levels of let-7c were significantly decreased in 8/10 tumors compared to their matched benign prostate tissues (Fig. 2A). We also analyzed two tissue microarrays containing benign and cancerous prostate biopsies respectively by in situ hybridization using LNA-conjugated mature let-7c-specific probe (Exiqon). The images were analyzed using an Olympus IX81 microscope and DP Controller Software. Our results showed that let-7c was highly expressed in benign PCa, while its expression was downregulated in the cancerous prostate (Fig. 2B). Collectively, these results suggest that loss of let-7c expression may be associated with prostate tumorigenesis.


MicroRNA let-7c is downregulated in prostate cancer and suppresses prostate cancer growth.

Nadiminty N, Tummala R, Lou W, Zhu Y, Shi XB, Zou JX, Chen H, Zhang J, Chen X, Luo J, deVere White RW, Kung HJ, Evans CP, Gao AC - PLoS ONE (2012)

Let-7c expression is downregulated in human PCa.A) Relative expression levels of let-7c were measured by qRT-PCR in total RNAs extracted from 10 paired benign and tumor human prostate samples. B) Let-7c levels were measured using in situ hybridization in TMAs containing 160 cores each from unmatched benign and cancerous prostate biopsies. Representative images are shown for benign and cancer cores. Expression of let-7c was higher in benign prostates compared to cancerous prostates. C) Relative expression levels of Lin28 in the 10 paired benign and tumor human prostate samples. Expression levels of Lin28 were correlated inversely with those of let-7c. Error bars denote ± SD (*p < 0.05).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3316551&req=5

pone-0032832-g002: Let-7c expression is downregulated in human PCa.A) Relative expression levels of let-7c were measured by qRT-PCR in total RNAs extracted from 10 paired benign and tumor human prostate samples. B) Let-7c levels were measured using in situ hybridization in TMAs containing 160 cores each from unmatched benign and cancerous prostate biopsies. Representative images are shown for benign and cancer cores. Expression of let-7c was higher in benign prostates compared to cancerous prostates. C) Relative expression levels of Lin28 in the 10 paired benign and tumor human prostate samples. Expression levels of Lin28 were correlated inversely with those of let-7c. Error bars denote ± SD (*p < 0.05).
Mentions: To determine whether the levels of let-7c expression are downregulated in clinical PCa, we analyzed RNAs from 10 paired benign and tumor human PCa specimens by quantitative RT-PCR. RNAs were isolated from human tissues, reverse transcribed and subjected to qRT-PCR using LNA-conjugated let-7c primers (Exiqon). The levels of let-7c were significantly decreased in 8/10 tumors compared to their matched benign prostate tissues (Fig. 2A). We also analyzed two tissue microarrays containing benign and cancerous prostate biopsies respectively by in situ hybridization using LNA-conjugated mature let-7c-specific probe (Exiqon). The images were analyzed using an Olympus IX81 microscope and DP Controller Software. Our results showed that let-7c was highly expressed in benign PCa, while its expression was downregulated in the cancerous prostate (Fig. 2B). Collectively, these results suggest that loss of let-7c expression may be associated with prostate tumorigenesis.

Bottom Line: Lentiviral-mediated re-expression of let-7c was utilized to assess the effects on human PCa xenografts.Overexpression of let-7c decreased while downregulation of let-7c increased cell proliferation, clonogenicity and anchorage-independent growth of PCa cells in vitro.Furthermore, let-7c expression is downregulated in clinical PCa specimens compared to their matched benign tissues, while the expression of Lin28, a master regulator of let-7 miRNA processing, is upregulated in clinical PCa specimens.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, University of California Davis, Sacramento, California, United States of America. nnadiminty@ucdavis.edu

ABSTRACT

Purpose: Prostate cancer (PCa) is characterized by deregulated expression of several tumor suppressor or oncogenic miRNAs. The objective of this study was the identification and characterization of miR-let-7c as a potential tumor suppressor in PCa.

Experimental design: Levels of expression of miR-let-7c were examined in human PCa cell lines and tissues using qRT-PCR and in situ hybridization. Let-7c was overexpressed or suppressed to assess the effects on the growth of human PCa cell lines. Lentiviral-mediated re-expression of let-7c was utilized to assess the effects on human PCa xenografts.

Results: We identified miR-let-7c as a potential tumor suppressor in PCa. Expression of let-7c is downregulated in castration-resistant prostate cancer (CRPC) cells. Overexpression of let-7c decreased while downregulation of let-7c increased cell proliferation, clonogenicity and anchorage-independent growth of PCa cells in vitro. Suppression of let-7c expression enhanced the ability of androgen-sensitive PCa cells to grow in androgen-deprived conditions in vitro. Reconstitution of Let-7c by lentiviral-mediated intratumoral delivery significantly reduced tumor burden in xenografts of human PCa cells. Furthermore, let-7c expression is downregulated in clinical PCa specimens compared to their matched benign tissues, while the expression of Lin28, a master regulator of let-7 miRNA processing, is upregulated in clinical PCa specimens.

Conclusions: These results demonstrate that microRNA let-7c is downregulated in PCa and functions as a tumor suppressor, and is a potential therapeutic target for PCa.

Show MeSH
Related in: MedlinePlus