Article

RUNX3 protein is overexpressed in human basal cell carcinomas. Oncogene

National Skin Centre, Tumasik, 00, Singapore
Oncogene (Impact Factor: 8.46). 01/2007; 25(58):7646-9. DOI: 10.1038/sj.onc.1209739
Source: PubMed

ABSTRACT

Basal cell carcinomas (BCC), which are the most common form of skin malignancy, are invariably associated with the deregulation of the Sonic Hedgehog (Shh) signalling pathway. As such, BCC represent a unique model for the study of interactions of the Shh pathway with other genes and pathways. We constructed a tissue microarray (TMA) of 75 paired BCC and normal skin and analysed the expression of beta-catenin and RUNX3, nuclear effectors of the wingless-Int (Wnt) and bone morphogenetic protein/transforming growth factor-beta pathways, respectively. In line with previous reports, we observed varying subcellular expression pattern of beta-catenin in BCC, with 31 cases (41%) showing nuclear accumulation. In contrast, all the BCC cases tested by the TMA showed RUNX3 protein uniformly overexpressed in the nuclei of the cancer cells. Analysis by Western blotting and DNA sequencing indicates that the overexpressed protein is normal and full-length, containing no mutation in the coding region, implicating RUNX3 as an oncogene in certain human cancers. Our results indicate that although the deregulation of Wnt signalling could contribute to the pathogenesis of a subset of BCC, RUNX3 appears to be a universal downstream mediator of a constitutively active Shh pathway in BCC.

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Available from: Richie Soong, Apr 13, 2014
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    • "Equally significant, this scenario was not implicated by any, not even a single one, of the 286 published papers that based their research on the correctness of Li et al and went on to postulate loss of Runx3 expression in normal GIT Ep to explain the pathogenesis of various types of cancer. On the contrary, in several epithelial cancers an upregulation of RUNX3 expression was observed and in these cases RUNX3 is considered an oncogene (Carvalho et al, 2005; Lee et al, 2011; Nevadunsky et al, 2009; Salto-Tellez et al, 2006). "
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    ABSTRACT: The Runx3 transcription factor regulates cell fate decisions during embryonic development and in adults. It was previously reported that Runx3 is strongly expressed in embryonic and adult gastrointestinal tract (GIT) epithelium (Ep) and that its loss causes gastric cancer. More than 280 publications have based their research on these findings and concluded that Runx3 is indeed a tumour suppressor (TS). In stark contrast, using various measures, we found that Runx3 expression is undetectable in GIT Ep. Employing a variety of biochemical and genetic techniques, including analysis of Runx3-GFP and R26LacZ/Runx3(Cre) or R26tdTomato/Runx3(Cre) reporter strains, we readily detected Runx3 in GIT-embedded leukocytes, dorsal root ganglia, skeletal elements and hair follicles. However, none of these approaches revealed detectable Runx3 levels in GIT Ep. Moreover, our analysis of the original Runx3(LacZ/LacZ) mice used in the previously reported study failed to reproduce the GIT expression of Runx3. The lack of evidence for Runx3 expression in normal GIT Ep creates a serious challenge to the published data and undermines the notion that Runx3 is a TS involved in cancer pathogenesis.
    Full-text · Article · Oct 2011 · EMBO Molecular Medicine
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    • "The Runt-related transcription factor 3 (RUNX3) gene plays a role in the transforming growth factor-beta (TGF-β)induced tumor suppression pathway. Although RUNX3 has been considered as a TSG in some studies (Bae et al. 1995; Li et al. 2002), it has been shown that the expression level of RUNX3 in HNSCC tissues are higher than that in normal oral epithelial tissues due to demethylation (Ginos et al. 2004; Salto-Tellez et al. 2006). Therefore, it has been suggested that RUNX3 may have an oncogenic role in HNSCC and its expression may predict malignant behavior and the effect of chemotherapeutic drugs in HNSCC as a potential biomarker (Tsunematsu et al. 2009). "
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    ABSTRACT: Head and neck cancer (HNC) is a heterogenous and complex entity including diverse anatomical sites and a variety of tumor types displaying unique characteristics and different etilogies. Both environmental and genetic factors play a role in the development of the disease, but the underlying mechanism is still far from clear. Previous studies suggest that alterations in the genes acting in cellular signal pathways may contribute to head and neck carcinogenesis. In cancer, DNA methylation patterns display specific aberrations even in the early and precancerous stages and may confer susceptibility to further genetic or epigenetic changes. Silencing of the genes by hypermethylation or induction of oncogenes by promoter hypomethylation are frequent mechanisms in different types of cancer and achieve increasing diagnostic and therapeutic importance since the changes are reversible. Therefore, methylation analysis may provide promising clinical applications, including the development of new biomarkers and prediction of the therapeutic response or prognosis. In this review, we aimed to analyze the available information indicating a role for the epigenetic changes in HNC.
    Full-text · Article · Aug 2011 · Clinical Epigenetics
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    ABSTRACT: Aberrant methylation of cytosine in promoter CpG islands is a recognized contributory process to carcinogenesis. This study explores the methylation profile of RUNX3 in combination with p16, RASSF1A, CDH1 and hMLH1 in nasopharyngeal carcinoma (NPC) patients. Genomic DNA was extracted from 19 fresh frozen NPC biopsies, which were then subjected to bisulfite conversion and methylation-specific PCR for analysis of promoter hypermethylation for the five respective genes. Three cell lines, SNU1, RKO and LS174T, were used as controls. The incidences of promoter methylation were as follows: RUNX3 0/19 (0%), p16 6/19 (32%), RASSF1A 13/19 (68%), CDH1 9/19 (47%) and hMLH1 4/19 (21%). Ninety-five percent of the tumor specimens displayed aberrant methylation in at least one of these genes. No significant correlation between methylation status of these genes and clinical parameters was found. Methylation of multiple genes is involved in critical pathways for cancer development in NPC. Promoter hypermethylation for RUNX3 was, however, not present.
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