MicroRNA-1826 directly targets beta-catenin (CTNNB1) and MEK1 (MAP2K1) in VHL-inactivated renal cancer. Carcinogenesis

Department of Urology, San Francisco Veterans Affairs Medical Center and University of California at San Francisco, San Francisco, CA 94121, USA.
Carcinogenesis (Impact Factor: 5.33). 12/2011; 33(3):501-8. DOI: 10.1093/carcin/bgr302
Source: PubMed


The aim of this project is to identify new therapeutic microRNAs (miRNAs) for von Hippel-Lindau (VHL)-inactivated renal cancer cells. We initially identified several potential miRNAs targeting CTNNB1 and MEK1 using several targets scan algorithms. Only miR-1826 was found to target CTNNB1 and MEK1. Therefore, we focused on miRNA-1826 and performed 3' untranslated region (UTR) luciferase assay, functional analyses and association study between miR-1826 expression and renal cancer patient outcomes. miR-1826 expression was significantly lower in renal cancer tissues compared with non-neoplastic areas and lower expression was significantly associated with overall shorter survival and earlier recurrence after radical nephrectomy. Following miR-1826 transfection, 3' UTR luciferase activity and protein expression of beta-catenin and MEK1 were significantly downregulated in renal cancer cells. Introduction of miR-1826 also inhibited renal cancer cell proliferation, invasion and migration. Additionally, miR-1826 promoted apoptosis and G(1) arrest in VHL-inactivated renal cancer cells. Knockdowns of CTNNB1 and MEK1 by small interfering RNAs reproduced the tumor-suppressive effect of miR-1826. Our data suggest that the miR-1826 plays an important role as a tumor suppressor by downregulating beta-catenin and MEK1 in VHL-inactivated renal cancers.

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    • "Several studies profiling miRNA expression in RCC have identified a number of differentially expressed miRNAs though no consensus has been reached [7-11]. In addition, a series of miRNAs (including miR-34a, miR-145, miR-205, miR-708, miR-1285 and miR-1826) have been shown to modulate the viability, proliferation, invasion and metastasis of RCC cells [12-17]. "
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    ABSTRACT: Background Emerging evidence has suggested that dysregulation of miR-182-5p may contribute to tumor development and progression in several types of human cancers. However, its role in renal cell carcinoma (RCC) is still unknown. Methods Quantitative RT-PCR was used to quantify miR-182-5p expression in RCC clinical tissues. Bisulfite sequencing PCR was used for DNA methylation analysis. The CCK-8, colony formation, flow cytometry, and a xenograft model were performed. Immunohistochemistry was conducted using the peroxidase and DAB methods. A miR-182-5p target was determined by luciferase reporter assays, quantitative RT-PCR, and Western blotting. Results miR-182-5p is frequently down-regulated in human RCC tissues. Epigenetic modulation may be involved in the regulation of miR-182-5p expression. Enforced expression of miR-182-5p in RCC cells significantly inhibited the proliferation and tumorigenicity in vitro and in vivo. Additionally, overexpression of miR-182-5p induced G1-phase arrest via inhibition of AKT/FOXO3a signaling. Moreover, FLOT1 was confirmed as a target of miR-182-5p. Silencing FLOT1 by small interfering RNAs phenocopied the effects of miR-182-5p overexpression, whereas restoration of FLOT1 in miR-182-5p -overexpressed RCC cells partly reversed the suppressive effects of miR-182-5p. Conclusions These findings highlight an important role for miR-182-5p in the pathogenesis of RCC, and restoration of miR-182-5p could be considered as a potential therapeutic strategy for RCC therapy.
    Molecular Cancer 05/2014; 13(1):109. DOI:10.1186/1476-4598-13-109 · 4.26 Impact Factor
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    • "In the present study, we for the first time demonstrated that miR-320a was a negative regulator of b-catenin expression in a posttranscriptional level. Recent studies from other groups have also shown that several other microRNAs, including miR-200a, miR1826 and miR-483-3p can also directly bind to the b-catenin 3 0 UTR and inhibit its expression in different types of cancer, suggesting that microRNA-mediated post-transcriptional silencing mechanisms play a critical role in regulating the expression of b-catenin in cancer cells [35] [36] [37]. Taken together, our present study demonstrates miR-320a as a growth-suppressive miRNA in human colon cancer, at least, partially through repression of b-catenin. "
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    ABSTRACT: Recent profile studies of microRNA (miRNA) expression have documented a deregulation of miRNA (miR-320a) in human colorectal carcinoma. However, its expression pattern and underlying mechanisms in the development and progression of colorectal carcinoma has not been elucidated clearly. Here, we performed real-time PCR to examine the expression levels of miR-320a in colon cancer cell lines and tumor tissues. And then, we investigated its biological functions in colon cancer cells by a gain of functional strategy. Further more, by the combinational approaches of bioinformatics and experimental validation, we confirmed target associations of miR-320a in colorectal carcinoma. Our results showed that miR-320a was frequently downregulated in cancer cell lines and colon cancer tissues. And we demonstrated that miR-320a restoration inhibited colon cancer cell proliferation and β-catenin, a functionally oncogenic molecule was a direct target gene of miR-320a. Finally, the data of real-time PCR showed the reciprocal relationship between miR-320a and β-catenin's downstream genes in colon cancer tissues. These findings indicate that miR-320a suppresses the growth of colon cancer cells by directly targeting β-catenin, suggesting its application in prognosis prediction and cancer treatment.
    Biochemical and Biophysical Research Communications 03/2012; 420(4):787-92. DOI:10.1016/j.bbrc.2012.03.075 · 2.30 Impact Factor
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    ABSTRACT: Introduction: The results of cancer-associated miRNA research have yielded surprising insights into the pathogenesis of a range of different cancers. Many of the dysregulated miRNAs are involved in the regulation of genes that are essential for carcinogenesis. Areas covered: This review discusses the latest discovery of miRNAs acting as oncogenes and tumor suppressor genes, as well as the potential applications of miRNA regulations in cancer therapy. Several translational studies have demonstrated the feasibility of targeting oncogenic miRNAs and restoring tumor-suppressive miRNAs for cancer therapy using in vivo model systems. Expert opinion: miRNAs are extensive regulators of cancer progression. With increasing understanding of the miRNA target genes and the cellular behaviors influenced by them, modulating the miRNA activities may provide exciting opportunities for cancer therapy. Despite the hurdles incurred in acquiring effective systemic drug delivery systems, in vivo delivery of miRNAs for therapeutic purposes in preclinical animal models is rapidly developing. Accumulating evidences indicate that using miRNA expression alterations to influence molecular pathways has the potential of being translated into clinical applications.
    Expert Opinion on Therapeutic Targets 06/2012; 16(8):747-59. DOI:10.1517/14728222.2012.696102 · 5.14 Impact Factor
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