The expression of metastasis suppressor MIM/MTSS1 is regulated by DNA methylation

Department of Dermatology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany.
International Journal of Cancer (Impact Factor: 5.09). 11/2006; 119(10):2287-93. DOI: 10.1002/ijc.22106
Source: PubMed


MIM/MTSS1 was initially described as a gene missing in invasive bladder cancer cell lines. Functional analysis revealed that MIM is an actin binding protein involved in the regulation of actin cytoskeleton dynamics. MIM was shown to be sonic hedgehog (Shh) signaling dependent and synergizes with the effects of Gli transcription factors. Overexpression of MIM in cell lines leads to the inhibition of cell proliferation. In this study, we showed that the inhibition of cell growth by MIM is anchorage independent. We identified and cloned the promoter region of MIM and located the main promoter activity to 276 bp of 5' flanking sequence sited within a CpG island. Analysis of DNA methylation using bisulphite sequencing revealed that MIM promoter is methylated in its 5' region in cells and tissue samples with reduced endogenous MIM expression. Using luciferase reporter assay, we demonstrated that nonmethylated MIM promoter has a similar activity in cell lines with different endogenous MIM expression. Inhibition of DNA methylation by 5-Aza-2'-deoxycytidine led to upregulation of MIM expression in a low expressing cell line. In conclusion, we clearly demonstrate here that the expression of metastasis suppressor MIM is regulated by DNA methylation of a CpG island within its promoter region.

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Available from: Jochen Utikal, Sep 05, 2014
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    • "Interestingly several of these have previously been shown to be altered in other types of cancers. MTSS1 and DSP are known tumor suppressor genes and are together with PPP1R14A, also methylated in lung-, colorectal- and gastric cancer [27], [31]–[33]. However, this is, to the best of our knowledge, the first time DSP, FZD8, KCNH2, MTSS1, and PPP1R14A have been reported to be methylated in lymphoma. "
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    ABSTRACT: Epigenetic alterations of gene expression are important in the development of cancer. In this study, we identified genes which are epigenetically altered in major lymphoma types. We used DNA microarray technology to assess changes in gene expression after treatment of 11 lymphoma cell lines with epigenetic drugs. We identified 233 genes with upregulated expression in treated cell lines and with downregulated expression in B-cell lymphoma patient samples (n = 480) when compared to normal B cells (n = 5). The top 30 genes were further analyzed by methylation specific PCR (MSP) in 18 lymphoma cell lines. Seven of the genes were methylated in more than 70% of the cell lines and were further subjected to quantitative MSP in 37 B-cell lymphoma patient samples (diffuse large B-cell lymphoma (activated B-cell like and germinal center B-cell like subtypes), follicular lymphoma and Burkitt`s lymphoma) and normal B lymphocytes from 10 healthy donors. The promoters of DSP, FZD8, KCNH2, and PPP1R14A were methylated in 28%, 67%, 22%, and 78% of the 36 tumor samples, respectively, but not in control samples. Validation using a second series of healthy donor controls (n = 42; normal B cells, peripheral blood mononuclear cells, bone marrow, tonsils and follicular hyperplasia) and fresh-frozen lymphoma biopsies (n = 25), confirmed the results. The DNA methylation biomarker panel consisting of DSP, FZD8, KCNH2, and PPP1R14A was positive in 89% (54/61) of all lymphomas. Receiver operating characteristic analysis to determine the discriminative power between lymphoma and healthy control samples showed a c-statistic of 0.96, indicating a possible role for the biomarker panel in monitoring of lymphoma patients.
    PLoS ONE 11/2013; 8(11):e79602. DOI:10.1371/journal.pone.0079602 · 3.23 Impact Factor
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    • "Since the study of MTSS1 has been restricted to a limited number of cancer types and available data seem to be controversial, whether or not MTSS1 serves as a metastasis suppressor has not been clearly defined to date. Several lines of evidence have indicated that the expression of MTSS1 could be down-regulated in solid tumours [2,12,15,16], whereas up-regulation of MTSS1 expression has also been observed in one other tumour type [3]. Thus. the role of MTSS1 in cancer and cancer metastasis remains somewhat open. "
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    ABSTRACT: Metastasis suppressor-1 (MTSS1) has been proposed to function as a cytoskeletal protein with a role in cancer metastasis. Recent studies have demonstrated the clinical significance of MTSS1 in certain type of cancers, yet the clinical relevance of MTSS1 in oesophageal squamous cell carcinoma (ESCC) has not been reported. In this study, we assessed the expression levels of MTSS1 in tumours and its matched adjacent non-tumour tissues obtained from 105 ESCC patients. We also used ESCC cells with differing MTSS1 expression and assessed the influence of MTSS1 on ESCC cells. Down-regulation of MTSS1 expression was observed both in oesophageal tumour tissues and ESCC cancer cell lines. We also reported that MTSS1 expression was associated with tumour grade (p = 0.024), lymph node metastasis (p = 0.010) and overall survival (p = 0.035). Patients with high levels of MTSS1 transcripts had a favorable prognosis in comparison with those who had reduced or absent expression levels. Using over-expression and knockdown approach, we created sublines from ESCC cells and further demonstrated that MTSS1 expression in ESCC cells significantly influenced the aggressiveness of the oesophageal cancer cells, by reducing their cellular migration and in vitro invasiveness. MTSS1 serves as a potential prognostic indicator in human ESCC and may be an important target for cancer therapy.
    Journal of Translational Medicine 06/2011; 9(1):95. DOI:10.1186/1479-5876-9-95 · 3.93 Impact Factor
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    • "Preliminary analysis by Northern blotting demonstrated that MTSS1 is widely expressed but is most abundant in spleen, thymus, testis, and prostate, with low levels also detected in uterus and colon [8]. Since this pioneering article, other reports have indicated that MTSS1 played a role as a metastasis suppressor in prostate cancer [11,12], bladder cancer [8,11,13] and benign lesions, but up-regulated in basal cell carcinomas [14]. However, other evidences showed that MTSS1 is unlikely to be a metastasis suppressor. "
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    ABSTRACT: The putative tumor metastasis suppressor 1(MTSS1) is an actin-binding scaffold protein that has been implicated to play an important role in carcinogenesis and cancer metastasis, yet its role in the development of gastric cancer has not been well illustrated. In this study, we detected MTSS1 expression and explored its clinical significance in gastric cancer. Immunohistochemistry was performed using tissue microarrays containing gastric adenocarcinoma specimens from 1,072 Chinese patients with normal adjacent mucosa, primary gastric cancer and lymph node (LN) metastasis and specific antibody against MTSS1. MTSS1 mRNA and protein expression were detected by reverse transcription-polymerase chain reaction and Western blotting. The clinical follow-up was done in the 669 patients living in Shanghai that was chose from the 1072 cases. Complete loss of MTSS1 expression was observed in 751 cases (70.1%) of the 1,072 primary tumors and 103 (88%) of 117 nodal metastases; and loss of MTSS1 expression was significantly associated with poorly differentiated tumors, large tumor size, deep invasion level, the presence of nodal metastases and advanced disease stage. Moreover, multivariate analysis demonstrated that loss of MTSS1 expression correlated significantly with poor survival rates (RR = 0.194, 95% CI = 0.144-0.261, P < 0.001). MTSS1 expression decreased significantly as gastric cancer progressed and metastasized, suggesting MTSS1 may serve as a useful biomarker for the prediction of outcome of gastric cancer.
    BMC Cancer 08/2010; 10(1):428. DOI:10.1186/1471-2407-10-428 · 3.36 Impact Factor
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