Article

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

Department of Urology, San Francisco Veterans Affairs Medical Center and University of California at San Francisco, San Francisco, CA 94121, USA.
Carcinogenesis (Impact Factor: 5.27). 12/2011; 33(3):501-8. DOI: 10.1093/carcin/bgr302
Source: PubMed

ABSTRACT 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.

0 Followers
 · 
176 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cardiovascular diseases and cancers are the leading causes of morbidity and mortality in the world. MicroRNAs (miRNAs) are short non-coding RNAs that primarily repress target mRNAs. Here, miR-24, miR-125b, miR-195, and miR-214 were selected as representative cardio-miRs that are upregulated in human heart failure. To bridge the gap between miRNA studies in cardiology and oncology, the targets and functions of these miRNAs in cardiovascular diseases and cancers will be reviewed. ACVR1B, BCL2, BIM, eNOS, FGFR3, JPH2, MEN1, MYC, p16, and ST7L are miR-24 targets that have been experimentally validated in human cells. ARID3B, BAK1, BCL2, BMPR1B, ERBB2, FGFR2, IL6R, MUC1, SITR7, Smoothened, STAT3, TET2, and TP53 are representative miR-125b targets. ACVR2A, BCL2, CCND1, E2F3, GLUT3, MYB, RAF1, VEGF, WEE1, and WNT7A are representative miR-195 targets. BCL2L2, ß-catenin, BIM, CADM1, EZH2, FGFR1, NRAS, PTEN, TP53, and TWIST1 are representative miR-214 targets. miR-125b is a good cardio-miR that protects cardiomyocytes; miR-195 is a bad cardio-miR that elicits cardiomyopathy and heart failure; miR-24 and miR-214 are bi-functional cardio-miRs. By contrast, miR-24, miR-125b, miR-195, and miR-214 function as oncogenic or tumor suppressor miRNAs in a cancer (sub)type-dependent manner. Circulating miR-24 is elevated in diabetes, breast cancer and lung cancer. Circulating miR-195 is elevated in acute myocardial infarction, breast cancer, prostate cancer and colorectal adenoma. Circulating miR-125b and miR-214 are elevated in some cancers. Cardio-miRs and onco-miRs bear some similarities in functions and circulation profiles. miRNAs regulate WNT, FGF, Hedgehog and other signaling cascades that are involved in orchestration of embryogenesis and homeostasis as well as pathogenesis of human diseases. Because circulating miRNA profiles are modulated by genetic and environmental factors and are dysregulated by genetic and epigenetic alterations in somatic cells, circulating miRNA association studies (CMASs) within several thousands of cases each for common non-cancerous diseases and major cancers are necessary for miRNA-based diagnostics.
    Frontiers in Cell and Developmental Biology 10/2014; 2:61. DOI:10.3389/fcell.2014.00061
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Despite recent advances in the understanding of the biology of renal cell carcinoma (RCC), successful surgical treatment and implementation of novel‑targeted therapies, the prognosis for RCC patients remains poor. Late presentation, tumor heterogeneity and in particular the lack of molecular biomarkers for early detection, classification and the surveillance of RCC treatments are major obstacles. The increasing knowledge regarding the functional role of microRNAs (miRNAs) in pathophysiological processes may provide an important link to the identification of suitable therapeutic targets and diagnostic/prognostic biomarkers for RCC. The aim of this review was to provide new insight into the function of miRNAs in the pathogenesis of RCC and to emphasize their potential as diagnostic and prognostic markers, as well as therapeutic targets.
    Oncology Reports 02/2015; 33(4). DOI:10.3892/or.2015.3799 · 2.19 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cancer stem cells (CSCs) are rare, tumour-initiating cells that exhibit stem cell properties: capacity of self-renewal, pluripotency, highly tumorigenic potential, and resistance to therapy. Cancer stem cells have been characterised and isolated from many cancers, including breast cancer. Developmental pathways, such as the Wnt/β-catenin, Notch/γ-secretase/Jagged, Shh (sonic hedgehog), and BMP signalling pathways, which direct proliferation and differentiation of normal stem cells, have emerged as major signalling pathways that contribute to the self-renewal of stem and/or progenitor cells in a variety of organs and cancers. Deregulation of these signalling pathways is frequently linked to an epithelial-mesenchymal transition (EMT), and breast CSCs often possess properties of cells that have undergone the EMT process. Signalling networks mediated by microRNAs and EMT-inducing transcription factors tie the EMT process to regulatory networks that maintain "stemness". Recent studies have elucidated epigenetic mechanisms that control pluripotency and stemness, which allows an assessment on how embryonic and normal tissue stem cells are deregulated during cancerogenesis to give rise to CSCs. Epigenetic-based mechanisms are reversible, and the possibility of "resetting" the abnormal cancer epigenome by applying pharmacological compounds targeting epigenetic enzymes is a promising new therapeutic strategy. Chemoresistance of CSCs is frequently driven by various mechanisms, including aberrant expression/activity of ABC transporters, aldehyde dehydrogenase and anti-oncogenic proteins (i.e. BCL2, B-cell lymphoma-2), enhanced DNA damage response, activation of pro-survival signalling pathways, and epigenetic deregulations. Despite controversy surrounding the CSC hypothesis, there is substantial evidence for their role in cancer, and a number of drugs intended to specifically target CSCs have entered clinical trials.

Preview

Download
0 Downloads
Available from