Abstract
We have recently identified and characterized a novel oncogene, maelstrom (MAEL) from 1q24, in the pathogenesis of hepatocellular carcinoma. In this study, MAEL was investigated for its oncogenic role in urothelial carcinoma of the bladder (UCB) tumorigenesis/aggressiveness and underlying molecular mechanisms. Here, we report that overexpression of MAEL in UCB is important in the acquisition of an aggressive and/or poor prognostic phenotype. In UCB cell lines, knockdown of MAEL by short hairpin RNA is sufficient to inhibit cell growth, invasiveness/metastasis and suppressed epithelial-mesenchymal transition (EMT), whereas ectopic overexpression of MAEL promoted cell growth, invasive and/or metastatic capacity and enhanced EMT both in vitro and in vivo. We further demonstrate that MAEL could induce UCB cell EMT by downregulating a critical downstream target, the metastasis suppressor 1 (MTSS1) gene, ultimately leading to an increased invasiveness of cancer cells. Notably, overexpression of MAEL in UCB cells substantially enhanced the enrichment of DNA methyltrans-ferase (DNMT)3B and histone deacetylase (HDAC)1/2 on the promoter of the MTSS1, and thereby epigenetically suppressing the MTSS1 transcription. Downregulation of MTSS1 by MAEL in UCB cells is partially dependent on DNMT3B. Furthermore, we identify that beside the gene amplification of MAEL, miR-186 is a key negative regulator of MAEL and downregulation of miR-186 is another important mechanism for MAEL overexpression in UCBs. These data suggest that overexpression of MAEL, caused by gene amplification and/or decreased miR-186, has a critical oncogenic role in UCB pathogenesis by downregulation of MTSS1, and MAEL could be used as a novel prognostic marker and/or effective therapeutic target for human UCB.
Highlights
Urothelial carcinoma of the bladder (UCB) is one among the most common and lethal urothelial malignancies in Western countries.[1]Patients with muscle-invasive UCB have a poor prognosis with a 5-year overall survival of 48–67% even after radical cystectomy for localized disease.[2]
MAEL expression in bladder tissues and cells examined by western blotting Of the eight bladder cell lines analyzed by western blot, endogenous MAEL was overexpressed in four UCB cell lines, whereas the human normal uroepithelial cell line SV-HUC-1 and the other three UCB lines had low levels of MAEL (Figure 1a)
The dual luciferase reporter assay showed that knocking down DNMT3B by specific siRNA partially blocked the inhibitory effect of MAEL on the metastasis suppressor 1 (MTSS1) transcription. These results indicate that MAEL transcriptionally downregulates MTSS1 expression via DNMT3B in UCB cells
Summary
Urothelial carcinoma of the bladder (UCB) is one among the most common and lethal urothelial malignancies in Western countries.[1]Patients with muscle-invasive UCB have a poor prognosis with a 5-year overall survival of 48–67% even after radical cystectomy for localized disease.[2]. It is necessary to elucidate the molecular mechanism(s) underlying tumorigenesis and/or metastasis of UCB, so as to find novel therapeutic targets and develop new modalities of treatment. Amplification of 1q is one of the most frequent chromosomal aberrations in human UCB4–6 and several types of other cancers including hepatocellular,[7] lung,[8] colorectal,[9] breast[10] and esophageal[11] carcinomas. These suggest that human chromosome 1q contains oncogenes related to tumorigenesis and/or progression of human cancers. We have recently identified a novel oncogene, maelstrom (MAEL) from 1q24, one of the most frequent chromosomal alterations in hepatocellular carcinoma (HCC).[12]
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