High frequency of hypermethylation of p14, p15 and p16 in oral pre‐cancerous lesions associated with betel‐quid chewing in Sri Lanka

Takeshima, Maiko; Saitoh, Masato; Kusano, Kanichi; Nagayasu, Hiroki; Kurashige, Yoshihito; Muthumala, Malsantha; Arakawa, Toshiya; Teratani, Takuma; Chiba, Itsuo; Kaku, Tohru; Shibata, Toshiyuki; Abiko, Yoshihiro

doi:10.1111/j.1600-0714.2008.00644.x

Cited by 67 publications

(68 citation statements)

References 40 publications

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“…There are already reports of p16 gene methylation marker linked to leukoplakia [21] populations who are at high risk for susceptibility to oral squamous cell carcinoma. MGMT gene also showed 30% methylation frequency in leukoplakia.…”

Section: Discussionmentioning

confidence: 99%

Promoter Hypermethylation Profile of Tumour Suppressor Genes in Oral Leukoplakia and Oral Squamous Cell Carcinoma

Asokan¹,

Jeelani²,

Gnanasundaram³

2014

JCDR

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Purpose of the Study: The present study was conducted to evaluate epigenetic alteration of five tumour suppressor genes in the oral precancer and cancer patients. Materials and Methods:The study was carried out in three groups namely control group of five people (normal healthy individuals), 10 oral leukoplakia patients and 10 oral squamous cell carcinoma patients. Incisional biopsy was done and part of the tissue sent for histological examination and part of tissue sent for hypermethylation study of p16, p15, hMLH, MGMT, E-cadherin tumour suppressor genes. Methylation specific polymerase chain reaction was carried out for detecting methylation in promoter regions of tumour suppressor genes. The resultant PCR products were run in a 2.5% agarose gel and the promoter hypermethylation status of the five tumour suppressor genes were analysed. Results:In oral Leukoplakia patients, 60% of methylation in the case of p16 gene, 30% of methylation in the case of MGMT gene and 60% of methylation in the case of E-cadherin gene. In oral Squamous cell carcinoma patients, 60% of methylation in the case of p16 gene, 40% of methylation in the case of MGMT, 60% of methylation in the case of E-cadherin gene, 20% in case of p15,10% in case of hMLH gene. Conclusion:Our results suggest that epigenetic mechanisms of inactivation of tumour suppressor genes, such as aberrant methylation of p16 and E-cadherin genes occur early in head and neck tumourigenesis and might play a role in the progression of these lesions.

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Section: Discussionmentioning

confidence: 99%

Promoter Hypermethylation Profile of Tumour Suppressor Genes in Oral Leukoplakia and Oral Squamous Cell Carcinoma

Asokan¹,

Jeelani²,

Gnanasundaram³

2014

JCDR

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“…Areca nut extract and arecoline induce the upregulation of various growth factors, enzymes and other molecules associated with oral submucous fibrosis, a precancerous condition (6), and stimulate oral cancer cells and immortalized cell lines to express molecules associated with cancer progression (7,8). Our previous studies analyzed p14, p15, p16 and p53 genes in precancerous oral lesions associated with betel quid chewing in Sri Lanka (1,9,10). A high frequency of hypermethyaltion of p14, p15 and p16 was detected in the pre-cancerous lesions.…”

Section: Introductionmentioning

confidence: 99%

Upregulated expression of MMP-9 in gingival epithelial cells induced by prolonged stimulation with arecoline

et al. 2017

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Abstract. Betel quid chewing is implicated in the high prevalence of oral cancer in Southeast Asian countries. One of the major components of betel quid is arecoline. In the present study, in order to characterize the association between chronic arecoline stimulation and carcinogenesis the expression level of matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 mRNA in human gingival epithelial progenitor cells (HGEPs) stimulated with arecoline was assessed. The HGEPs were alternated between 3 days of incubation with arecoline (50 µg/ml), and 3 days without arecoline, for up to 30 days. The expression levels of the MMPs and TIMPs in the cells stimulated with arecoline were evaluated by reverse transcription-quantitative polymerase chain reaction at 18 and 30 days. The expression of MMP-9 mRNA in the experimental group was significantly increased compared with in the control group (P<0.01). No significant differences in the expression of MMP-2, TIMP-1 or TIMP-2 mRNA were observed between the experimental and control groups. Using an MMP-9 activity assay, the levels of MMP-9 activity in the experimental group were demonstrated to be significantly higher than in the control group (P<0.05). To investigate associated cellular signaling pathways, PDTC [a nuclear factor (NF)-κB/inhibitor of NF-κB (IκB) inhibitor], PD98059 [a mitogen-activated protein kinase kinase (MAPKK)1 and MAPKK2 inhibitor], SB203580 (a p38 MAPK inhibitor) and 5,15-DPP [a signal transduction and activator of transcription (STAT) 3 inhibitor] were used. All inhibitors decreased the extent of MMP-9 upregulation induced by stimulation with arecoline. Based on the data, it is hypothesized that MMP-9 activity may be involved in the pathological alterations of oral epithelium induced by betel quid chewing, and that the NF-κB/IκB, MAPK, p38 MAPK and STAT3 signaling pathways may be involved in the production of MMP-9 induced by betel quid chewing.

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“…These data indicate that promoter methylation of several TRG in pre-cancerous tissue is an early event and may occur as a result of exposure to different agents (e.g. alcohol, betel quid and tobacco) that were related to HNSCC (5)(6)(7)41). To confirm this hypothesis it would be interesting to analyze methylation of TRG in normal mucosa of healthy persons, who were exposed to these substances or not.…”

Section: Discussionmentioning

confidence: 99%

Frequent promoter hypermethylation of tumor-related genes in head and neck squamous cell carcinoma

Steinmann

Sandner²,

Schagdarsurengin³

et al. 2009

Oncol Rep

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Abstract. Squamous cell carcinomas of head and neck (HNSCC) are a result of multiple genetic and epigenetic alterations. Epigenetic inactivation of tumor suppressor genes is an important event in head and neck carcinogenesis. Here we analyzed the promoter methylation of 15 genes (RASSF1A, p16, MGMT, DAPK, RARß, MLH1, CDH1, GSTP1, RASSF2, RASSF4, RASSF5, MST1, MST2, LATS1, LATS2) in 54 HNSCC and in matching 23 normal tissues. Methylation of these tumor-related genes (TRG) was significantly more frequent in HNSCC (42%) compared to normal samples (23%; p<0.05). Particularly, methylation of p16 (60%), MGMT (53%), DAPK (67%), RARß (75%), MLH1 (69%), CDH1 (43%), RASSF5 and MST1 (96%) was often found in HNSCC. Methylation of RASSF1A (18%), GSTP1 (4%), RASSF4 (13%), MST2 (4%), LATS1 (24%) and LATS2 (8%) was less frequently detected. A trend of increased TRG methylation in more advanced tumor stages and less differentiated HNSCC was observed. Methylation of p16 was significantly higher in poorly differentiated HNSCC (p=0.037) and RASSF5 methylation occurred preferentially in advanced tumor stages (p<0.05). Methylation of RASSF4 was higher in patients with recurrent HNSCC (23%) than patients without relapse (0%; p=0.033). Methylation of TRG in head and neck cancer cell lines was observed at similar frequency as in primary HNSCC. In summary, frequent hypermethylation of tumor-related genes in HNSCC was detected and this epigenetic silencing event may have an essential role in head and neck carcinogenesis.

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High frequency of hypermethylation of p14, p15 and p16 in oral pre‐cancerous lesions associated with betel‐quid chewing in Sri Lanka

Abstract: The present study indicates that hypermethylation may be involved in the pathogenesis of oral pre-cancerous lesions associated with betel-quid chewing in Sri Lanka.

Cited by 67 publications

References 40 publications

Promoter Hypermethylation Profile of Tumour Suppressor Genes in Oral Leukoplakia and Oral Squamous Cell Carcinoma

Promoter Hypermethylation Profile of Tumour Suppressor Genes in Oral Leukoplakia and Oral Squamous Cell Carcinoma

Upregulated expression of MMP-9 in gingival epithelial cells induced by prolonged stimulation with arecoline

Frequent promoter hypermethylation of tumor-related genes in head and neck squamous cell carcinoma

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