Hypermethylation of the RECK gene predicts poor prognosis in oral squamous cell carcinomas. Oral Oncol

Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Gifu University, Gifu 501-1194, Japan.
Oral Oncology (Impact Factor: 3.61). 06/2008; 44(11):1052-8. DOI: 10.1016/j.oraloncology.2008.02.004
Source: PubMed


The RECK gene is a novel tumor suppressor gene that regulates matrix metalloproteinases (MMPs) to inhibit tumor angiogenesis, invasion and metastasis. We investigated the methylation status of the RECK gene in 40 primary oral squamous cell carcinomas (OSCC) and 20 paired adjacent normal mucosa by methylation-specific PCR. Furthermore, we determined the prognostic importance of RECK hypermethylation in OSCC patients. Our findings showed that the RECK gene was methylated in 52.5% (21 of 40) of the primary OSCC. Among the 20 cases with corresponding normal tissues, RECK hypermethylation was detected in both primary tumor (55%, 11 of 20) and adjacent normal mucosa (30%, 6 of 20). Methylation of the RECK gene was not detected in all normal oral mucosa samples of the 12 healthy controls. In univariate analysis, RECK hypermethylation was inversely correlated with recurrence-free survival (p=0.027) and overall survival (p=0.023) of the OSCC patients. Multivariate analysis showed that the methylation status of the RECK gene was the only independent prognostic factor affecting overall survival (p=0.037). The result indicates that hypermethylation of RECK promoter is a common event in human OSCC, occurs concurrently in tumor-adjacent normal mucosa and is correlated with poor prognosis in OSCC patients. Although additional work is needed, hypermethylation of the RECK gene is a promising biomarker in early detection and prognosis for oral cancer patients.

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    • "14-3-3-σ has also found to be recurrently methylated in histologically confirmed oral dysplasias and has been associated with coincident methylation at p16, making it an attractive candidate for further evaluation in an oral cancer progression context [95]. Another group observed that RECK, a gene that functions to inhibit angiogenesis, invasion, and metastasis, has a potential to be a biomarker as it is recurrently found to be hypermethylated in the normal mucosa adjacent to the tumor [96]. Ultimately, whole methylome analyses of a large panel of well-annotated OPLs with extensive followup are needed to uncover disease-relevant biomarkers that will impact disease management and oral cancer survival rates. "
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    ABSTRACT: Herein we provide a concise review of the state of methylation research as it pertains to clinical oral cancerous and precancerous tissues. We provide context for ongoing research efforts in this field and describe technologies that are presently being applied to analyze clinical specimens. We also discuss the various recurrent methylation changes that have been reported for oral malignancy (including those genes frequently silenced by promoter methylation and the small RNAs with activity modulated by methylation changes) and describe surrogate disease markers identified via epigenetic analysis of saliva and blood specimens from patients with oral cancer.
    Full-text · Article · May 2012 · Journal of Oncology
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    • "RECK downregulation is caused by promoter methylation in metastatic non-small cell lung cancer and promoter methylation was also detected in human lung cancer cell lines 11. Hypermethylation of RECK promoter is also a common event in human ESCC, which occurs concurrently in tumor-adjacent normal mucosa and is correlated with poor prognosis in ESCC patients 12. It implied that the promoter methylation of RECK could play a particularly important regulatory role for RECK expression in carcinogenesis. "
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    ABSTRACT: To evaluate the promoter methylation status of RECK gene and mRNA expression in patients with hepatocellular carcinoma (HCC). We analyzed RECK methylation by MSP, and RECK mRNA by real-time PCR in 74 HCC. The liver cell lines (7721, Chang and Hep-G2) were treated with 5-Aza-CdR and TSA. RECK mRNA were lower in HCC tissues (Mean (-∆Ct) = -3.29) than that in Non-Hcc tissues (Mean (-∆Ct) = -2.42). Expression of RECK was elevated in only 24 (32.43%) of the 74 HCC patients but decreased (-∆∆Ct<0) in 50 (67.57%) of the patients. RECK promoter was hypermethylated in 55.4% (41/74) of HCCs, and in only 17.6% (13/74) of Non-Hcc samples. RECK mRNA were lower in HCC patients with hypermethylation (∆MI>=0.5) (Mean (-∆∆Ct) = -1.75) than those with demethylation (∆MI<0.5) (Mean (-∆∆Ct) = 0.05), and there is a decreased tendency for RECK mRNA in HCC patients with promoter hypermethylation (p = 0.002). There was a significantly correlation found between RECK mRNA and poor survival after surgery. After treated by 5-Aza-CdR and TSA, we found that RECK mRNA induced different changes in 7721, Chang and Hep-G2 cells. And RECK demethylation also induced by epigenetic inhibitors. The results suggested that the hypermethylation may lead to promoter silencing of RECK mRNA and associated with poor survival in HCC.
    Preview · Article · Mar 2012 · International journal of biological sciences
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    • "Chen et al. illustrated that the invasion, motility, migration, and secretion of MMP-2 and u-PA in SCC-9 oral cancer cells, through attenuation of p-FAK and p-Src, could be significantly inhibited by epigallocatechin-3 gallate [63]. Long et al. reported that hypermethylation of the RECK gene is associated with a poor prognosis in oral squamous cell carcinoma [64]. A study by Kato et al. showed the treatment of oral cancer cells with EGCG partially reversed the hypermethylation status of the RECK gene and significantly increased the expression level of RECK mRNA [65]. "
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    ABSTRACT: Chemoprevention is a relatively novel and promising approach for controlling cancer that uses specific natural products or synthetic agents to suppress, reverse, or prevent premalignancy before transformation into invasive cancer. Oral cavity squamous cell carcinoma (OCSCC) represents a large, worldwide health burden with approximately 274,000 cases diagnosed annually worldwide. Smoking and alcohol consumption are major inducers of OCSCC. Recently, the human papilloma virus was also shown to potentially be an etiologic factor. Due to its easily identifiable risk factors and the presence of premalignant regions, oral cancer makes a good candidate for chemoprevention. Green tea is the most widely consumed beverage in the world, and it has received considerable attention because of its abundant, scientifically proven, beneficial effects on human health. In this review, we discuss the role of green tea in oral cancer chemoprevention with regard to the multiple molecular mechanisms proposed in various in vitro, in vivo, and clinical trials.
    Full-text · Article · May 2011
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