MicroRNA let-7c Suppresses Androgen Receptor Expression and Activity via Regulation of Myc Expression in Prostate Cancer Cells

Department of Urology, University of California at Davis, Sacramento, California 95817, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 11/2011; 287(2):1527-37. DOI: 10.1074/jbc.M111.278705
Source: PubMed


Castration-resistant prostate cancer continues to rely on androgen receptor (AR) expression. AR plays a central role in the development of prostate cancer and progression to castration resistance during and after androgen deprivation therapy. Here, we identified miR-let-7c as a key regulator of expression of AR. miR-let-7c suppresses AR expression and activity in human prostate cancer cells by targeting its transcription via c-Myc. Suppression of AR by let-7c leads to decreased cell proliferation of human prostate cancer cells. Down-regulation of Let-7c in prostate cancer specimens is inversely correlated with AR expression, whereas the expression of Lin28 (a repressor of let-7) is correlated positively with AR expression. Our study demonstrates that the miRNA let-7c plays an important role in the regulation of androgen signaling in prostate cancer by down-regulating AR expression. These results suggest that reconstitution of miR-let-7c may aid in targeting enhanced and hypersensitive AR in advanced prostate cancer.

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    • "Among downregulated microRNAs correlating with PCa cancer progression , let-7b and let-7c were demonstrated to be lost in patients with shorter disease-free survival time [62]. This result is in agreement with the demonstrated biological role of let-7c in suppressing the expression of androgen receptor (AR) in prostate cancer cells [63]. Interestingly, the let-7c/AR interaction was not mediated by the canonical mechanism of miR-mediated control of gene expression, but rather through the targeting of v-myc avian myelocytomatosis viral oncogene homolog (MYC), a recognized transcription factor for the AR. "
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    ABSTRACT: Prostate cancer (PCa) is one of the leading causes of cancer-related death in men. Despite considerable advances in prostate cancer early detection and clinical management, validation of new biomarkers able to predict the natural history of tumor progression is still necessary in order to reduce overtreatment and to guide therapeutic decisions. MicroRNAs are endogenous noncoding RNAs which offer a fast fine-tuning and energy-saving mechanism for posttranscriptional control of protein expression. Growing evidence indicate that these RNAs are able to regulate basic cell functions and their aberrant expression has been significantly correlated with cancer development. Therefore, detection of microRNAs in tumor tissues and body fluids represents a new tool for early diagnosis and patient prognosis prediction. In this review, we summarize current knowledge about microRNA deregulation in prostate cancer mainly focusing on the different clinical aspects of the disease. We also highlight the potential roles of microRNAs in PCa management, while also discussing several current challenges and needed future research.
    BioMed Research International 09/2014; 2014:146170. DOI:10.1155/2014/146170 · 2.71 Impact Factor
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    • "The c-Myc protein regulates the biogenesis of let-7 by stimulating Lin28 [46], Lin28 in turn blocks the maturation of let-7 [47]. Additionally, c-Myc stimulates the expression of HMGA1 [48], AR [12], and IL6 [49]. NRAS is suggested to have an impact on HMGA2 biogenesis [45]. "
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    ABSTRACT: Prostate cancer is worldwide the sixth leading cause of cancer related death in men thus early detection and successful treatment are still of major interest. The commonly performed screening of the prostate-specific antigen (PSA) is controversially discussed, as in many patients the prostate-specific antigen levels are chronically elevated in the absence of cancer. Due to the unsatisfying efficiency of available prostate cancer screening markers and the current treatment outcome of the aggressive hormone refractory prostate cancer, the evaluation of novel molecular markers and targets is considered an issue of high importance. MicroRNAs are relatively stable in body fluids orchestrating simultaneously the expression of many genes. These molecules are currently discussed to bear a greater diagnostic potential than protein-coding genes, being additionally promising therapeutic drugs and/or targets. Herein we review the potential impact of the microRNA let-7 family on prostate cancer and show how deregulation of several of its target genes could influence the cellular equilibrium in the prostate gland, promoting cancer development as they do in a variety of other human malignant neoplasias.
    BioMed Research International 09/2014; 2014:376326. DOI:10.1155/2014/376326 · 2.71 Impact Factor
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    • "Using coimmunoprecipitation assays and Western blot analysis, miR-203/205 was demonstrated to directly target several components of mitogen-activated protein kinase (MAPK), IL-6 and AR signaling pathways, several AR coregulators, Harvey rat sarcoma viral oncogene homolog (HRAS) and Argonaute 2 (AGO2). Both pathways are crucial for the development of primary tumor, and in particular, the progression to incurable castration-resistant form (37,38) (Table 1). We therefore, propose that these miRNAs jointly act as tumor suppressors in PCa, and could interfere with progression to castration resistance. "
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    ABSTRACT: Prostate cancer (PCa) is the second most commonly occurring malignant tumor in Europe and America. Normal and neoplastic growth of prostate gland are dependent on androgen receptor (AR) expression and function. PCa is driven by androgen and its receptor, and they continue to be the key drivers of castration-resistant prostate cancer (CRPC). CRPC is the terminal stage of PCa and seriously jeopardizes the patient's quality of life and lifespan. miRNAs are small noncoding RNAs, 18-25 nt in length that destabilize mRNA or repress protein synthesis by interacting with the 3'-untranslated regions (3'-UTR) of target mRNAs. miRNAs can regulate AR or be regulated by AR and then affect various signaling pathways related to cellular functions and tumor processes. In this review, we focus on the relationship between miRNAs and AR in PCa and elucidate their roles in the induction of malignant changes in PCa. © 2014 IUBMB Life, 2014.
    International Union of Biochemistry and Molecular Biology Life 06/2014; 66(6). DOI:10.1002/iub.1281 · 3.14 Impact Factor
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