口腔鳞状细胞癌中CADM1基因表达及启动子区甲基化研究
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摘要
口腔鳞状细胞癌(Oral Squamous Cell Carcinoma, OSCC)是口腔颌面部中最常见的恶性肿瘤之一,它的发生发展是一个多阶段的过程,在这个过程中多种基因水平发生变化,包括癌基因的激活和抑癌基因的失活。细胞粘附分子1 (cell adhesion molecule 1,CADM1),以前称为肺癌肿瘤阻抑基因1 (tumor suppressor in lung cancer-1, TSLC1)是2001年Kuramochi等在研究肺癌时,通过功能性互补的方法鉴别出的新的肿瘤抑制因子,属于细胞黏附分子中免疫球蛋白超家族,通过趋同性反式相互作用调节细胞与细胞间的黏附。在85%的原发性肿瘤中,CADM1的表达减弱,在多种肿瘤中检测到CADM1的表达缺失。
本研究应用免疫组织化学方法和实时荧光定量PCR的方法检测CADM1蛋白及mRNA表达,结果显示正常口腔黏膜组织CADM1蛋白及mRNA表达无减少或缺失。而口腔鳞状细胞癌组织中CADM1蛋白表达及mRNA表达均显著低于正常口腔黏膜组织。应用甲基化特异性PCR检测基因启动子区甲基化情况,结果显示正常口腔黏膜组织中CADM1基因启动子区无甲基化。口腔鳞状细胞癌组织中CADM1基因启动子区甲基化率均显著高于正常口腔黏膜,基因启动子区甲基化与其在肿瘤组织中CADM1的蛋白表达及mRNA表达下调呈正相关。CADM1基因的蛋白表达、mRNA表达及基因启动子区甲基化均与肿瘤组织的病理分级、临床分期相关,而与病人的年龄、性别、肿瘤部位、直径无明显相关性。应用去甲基化药物5-Aza-CdR处理舌鳞癌Tca8113、SCC-9细胞,结果显示经5-Aza-CdR处理,舌鳞癌Tca8113、SCC-9细胞的存活率明显降低,舌鳞癌Tca8113细胞系中CADM1基因发生去甲基化及mRNA表达上调,且呈药物剂量依赖性,而舌鳞癌SCC-9细胞系CADM1基因未发生去甲基化,且mRNA表达无明显变化。
通过本研究,得出以下结论：
1.在口腔鳞状细胞癌组织中,CADM1蛋白及mRNA表达明显降低,与口腔鳞状细胞癌的发生发展密切相关。
2.口腔鳞状细胞癌组织中,CADM1基因启动子区发生甲基化,是导致CADM1蛋白表达、mRNA表达下调的重要原因之一
3.舌鳞癌Tca8113细胞系CADM1基因去甲基化后,CADM1基因表达上调,而舌鳞癌SCC-9细胞系CADM1基因未发生去甲基化,CADM1基因表达无变化,进一步说明CADM1基因甲基化与其蛋白表达、mRNA表达下调密切相关。
4. CADM1基因的表达及甲基化均与口腔鳞状细胞癌的病理分级、临床分期相关,可能是影响口腔鳞癌预后的重要因素。
Oral Squamous Cell Carcinoma (OSCC) was one of the most common malignant tumors in oral maxillofacial part, and its development is a multi-stage process during which multiple genes changes including oncogene activation and inactivation of tumor suppressor genes.
With the deepening of research on tumor gene, people increasingly find gene inactivation may not be caused by mutation, but be related to gene methylation. At present, the DNA methylation is one of the hot spots in epigenetic studies. DNA methylation means the chemical modification process during which active methyl is catalyzed by DNA methyltransferase (DNMT), and transfers from s-adenomethionine to C5 of cytosine, forming 5-methyl cytosine, and it is an epigenetic modification. Methylation has important biological significance, and its role is to control gene expression, regulate certain links of DNA recombination, maintain the integrity of chromosome and may play an important role in resisting alien invasive parasitic DNA. In recent years it has been found that cells will have carcinogenesis if normal DNA methylation patterns are damaged such as excessive or too low methylation in the promoter region. Hypermethylation of the CpG islands in the promoter region causes the gene inactivation, and inactivation of tumor suppressor genes in a large number of tumor cells are related to excessive methylation of the promoter region. Methylation frequently occurs in the early period of cell canceration, therefore methylation screening for some diseases in high risk population can achieve the purposes of early diagnosis and treatment.
DNA methylation is not the same as structural variation of the gene such as mutation or missing, it's an epigenetic modification, and the primary structure of DNA is not changed, so it is a reversible change. Demethylating drug effects on tumor cell lines, enables gene re-expression, and thus plays the role of suppressing cancer. When 5-Aza or its deoxidation isomer 5'-Aza-2'-deoxycytidine acts on tumor cells with highly methylated gene promoter, corresponding mRNA and protein expression are found to be recovered, and expression level changes with the change of cell types and drug doses, confirming that promoter methylation is the main cause of gene expression close.
Cell adhesion molecule 1 (CADM1), formerly known as tumor suppressor in lung cancer-1(TSLC1), is a new tumor suppressor identified with methods of functional complementarity by Kuramochi in 2001 when he was researching lung cancer. It belongs to the immunoglobulin superfamily of cell adhesion molecules, regulating the adhesion between cells through convergent TRANS interactions. CADM1 expression reduction in 85% of primary tumors, and CADM1 expression missing were detected in a variety of tumors. CADM1 expression missing is mainly through two channels:one is the loss of heterozygosity (LOH), and the other is the promoter methylation, of which CADM1 promoter methylation is the main missing mechanism. CADM1 expression missing can damage cell adhesion, in addition, it may transfer a signal enabling tumor metastasis and/or infiltrating to the surrounding or peripheral tissues, on the contrary, normal CADM1 expression inhibits tumor development.
It was reported that promoter methylation was detected in 44% of non-small cell lung cancer,48% of breast cancer,32% of prostate cancer,29% of liver cancer, and 27% of pancreatic cancer, and associated with CADM1 expression missing or reduction. In addition, the CADM1 gene expression missing can be found in a variety of tumors, such as esophageal cancer, laryngeal cancer, nasopharyngeal cancer, gastric cancer and Lymphoma, especially obvious in the more invasive tumors, and is associated with the promoter methylation. Therefore, the study indicated that CADM1 not only has a close relationship with the occurrence of multiple tumors, but also has an important role in biological invasive control of tumor, may be a important biological marker predicting the prognosis of patients.
There is no research on CADM1 and promoter methylation in oral squamous cell carcinoma in China up to now. This experiment used immunohistochemistry, real-time fluorescence quantitative PCR, methylation-specific PCR, gene de-methylation and other methods to detect CADM1 gene expression in oral squamous cell carcinoma tissues and cells, promoter methylation, and the impact of demethylation on biological behavior of tumor cells. Specific study contents and results are as follows:
Ⅰ.CADM1 expression and its significance in oral squamous cell carcinoma
The subjects were patients with oral squamous cell carcinoma in the research, immunohistochemical method and real-time fluorescent quantitative PCR method were used for observation of CADM1 protein and mRNA expression in the tissues of 52 cases of oral squamous cell carcinoma and 30 cases of normal mucosa.
The results indicated:
1. There was no reduction or missing in CADM1 protein and mRNA expression in normal oral mucosa tissue.
2. Compared with normal oral mucosa, CADM1 protein and mRNA expression reduced significantly in the tissue of oral squamous cell carcinoma, with significant difference (P＜0.01)
3. Reduction of CADM1 protein and mRNA expression was related with the differentiation level and clinical phase(P<0.05), and low CADM1 protein and mRNA expression predicted bad prognosis of the patient.
Ⅱ. Methylation of CADM1 gene in oral squamous cell carcinoma
This study used methylation-specific PCR methods to detect the methylation of CADM1 promoter CpG islet in tumor suppressor genes in 52 cases of oral squamous cell carcinoma and 30 cases of normal mucosa.
The results indicated:
1. There was no methylation in CADM1 gene in 30 cases of normal oral mucosa tissue.
2. Methylation of CADM1 gene promoter occurred in 24 of 52 cases of oral squamous cell carcinoma tissue, accounting for 46.15%; methylation rate in normal oral mucosa tissue and in oral squamous cell carcinoma had more significance (P<0.05).
3. Methylation condition of CADM1 promoter was related with the differentiation level and clinical phase of tumor tissue(P<0.05),maybe an important factor affecting the prognosis of oral squamous cell carcinoma.
4. Methylation condition of CADM1 promoter was not markedly related with the age, sex, tumor site and diameter of the patient (P>0.05).
5. Methylation of CADM1 gene promoter was highly consistent with the reduction of CADM1 protein and mRNA expression, Methylation of CADM1 promoter was the important reason leading to the reduction of CADM1 protein and mRNA expression.
III. CADM1 demethylation of the cell line in tongue squamous cell carcinoma
The experiment used demethylation drug 5-Aza-CdR to treat Tca8113 cell line and SCC-9 cell line of tongue squamous cell carcinoma, used MTT method to observe the survival rate of cells; used methylation-specific PCR to detect methylation condition of CADM1 gene; real-time quantitative PCR to detect the expression change of CADM1 gene.
The results indicated:
1.The survival rate of Tca8113 and SCC-9 cells of tongue squamous cell carcinoma markedly reduced after the treatment with 5-Aza-CdR, with significant difference compared with the survival rate of cells in the control group, and showed dosage dependence.
2. Demethylation occurred in the CADM1 gene of Tca8113 cell line in tongue squamous cell carcinoma after the treatment with 5-Aza-CdR, and the demethylation effect was the most obvious in the 5μmol/L 5-Aza group.
3. Demethylation didn't occur in the CADM1 gene of SCC-9 cell line in tongue squamous cell carcinoma after the treatment with 5-Aza-CdR, and CADM1 gene remained the non-methylation condition in the SCC-9 cell line.
4. The expression of the CADM1 gene of Tca8113 cell line in tongue squamous cell carcinoma upregulated after the treatment with 5-Aza-CdR, with dosage dependence (P＜0.05).
5. The expression of the CADM1 gene of SCC-9 cell in tongue squamous cell carcinoma showed no significant difference after the treatment with 5-Aza-CdR (P>0.05)
6. There was a close relationship between methylation of the CADM1 promoter gene and the downregulation of the gene expression in the cell line of tongue carcinoma, demethylation of the CADM1 gene lead to the upregulation of gene expression and played its role in suppressing cancer, maybe a potential target for the treatment of oral squamous cell carcinoma.
The following conclusions were drawn according to the results of this experiment:
1. Development of oral squamous cell carcinoma was closely related with the significant reduction of CADM1 protein and mRNA expression.
2. In oral Squamous Cell Carcinoma, methylation of CADM1 gene promoter was one of the important reasons leading to downregulation of CADM1 protein and mRNA expression.
3. CADM1 gene expression upregulated after demethylation of CADM1 gene of Tca8113 cell line in tongue squamous cell carcinoma, while demethylation didn't occur in the CADM1 gene of SCC-9 cell line in tongue squamous cell carcinoma, and there was no changes in the CADM1 gene expression, further indicating methylation of the CADM1 gene was closely related with the downregulation of protein and mRNA expression.
4. expression and methylation of CADM1 gene were both related with the pathological grading and clinical phase(P<0.05), maybe the important factor affecting the prognosis of Oral squamous cell carcinoma.
本研究应用免疫组织化学方法和实时荧光定量PCR的方法检测CADM1蛋白及mRNA表达,结果显示正常口腔黏膜组织CADM1蛋白及mRNA表达无减少或缺失。而口腔鳞状细胞癌组织中CADM1蛋白表达及mRNA表达均显著低于正常口腔黏膜组织。应用甲基化特异性PCR检测基因启动子区甲基化情况,结果显示正常口腔黏膜组织中CADM1基因启动子区无甲基化。口腔鳞状细胞癌组织中CADM1基因启动子区甲基化率均显著高于正常口腔黏膜,基因启动子区甲基化与其在肿瘤组织中CADM1的蛋白表达及mRNA表达下调呈正相关。CADM1基因的蛋白表达、mRNA表达及基因启动子区甲基化均与肿瘤组织的病理分级、临床分期相关,而与病人的年龄、性别、肿瘤部位、直径无明显相关性。应用去甲基化药物5-Aza-CdR处理舌鳞癌Tca8113、SCC-9细胞,结果显示经5-Aza-CdR处理,舌鳞癌Tca8113、SCC-9细胞的存活率明显降低,舌鳞癌Tca8113细胞系中CADM1基因发生去甲基化及mRNA表达上调,且呈药物剂量依赖性,而舌鳞癌SCC-9细胞系CADM1基因未发生去甲基化,且mRNA表达无明显变化。
通过本研究,得出以下结论：
1.在口腔鳞状细胞癌组织中,CADM1蛋白及mRNA表达明显降低,与口腔鳞状细胞癌的发生发展密切相关。
2.口腔鳞状细胞癌组织中,CADM1基因启动子区发生甲基化,是导致CADM1蛋白表达、mRNA表达下调的重要原因之一
3.舌鳞癌Tca8113细胞系CADM1基因去甲基化后,CADM1基因表达上调,而舌鳞癌SCC-9细胞系CADM1基因未发生去甲基化,CADM1基因表达无变化,进一步说明CADM1基因甲基化与其蛋白表达、mRNA表达下调密切相关。
4. CADM1基因的表达及甲基化均与口腔鳞状细胞癌的病理分级、临床分期相关,可能是影响口腔鳞癌预后的重要因素。
Oral Squamous Cell Carcinoma (OSCC) was one of the most common malignant tumors in oral maxillofacial part, and its development is a multi-stage process during which multiple genes changes including oncogene activation and inactivation of tumor suppressor genes.
With the deepening of research on tumor gene, people increasingly find gene inactivation may not be caused by mutation, but be related to gene methylation. At present, the DNA methylation is one of the hot spots in epigenetic studies. DNA methylation means the chemical modification process during which active methyl is catalyzed by DNA methyltransferase (DNMT), and transfers from s-adenomethionine to C5 of cytosine, forming 5-methyl cytosine, and it is an epigenetic modification. Methylation has important biological significance, and its role is to control gene expression, regulate certain links of DNA recombination, maintain the integrity of chromosome and may play an important role in resisting alien invasive parasitic DNA. In recent years it has been found that cells will have carcinogenesis if normal DNA methylation patterns are damaged such as excessive or too low methylation in the promoter region. Hypermethylation of the CpG islands in the promoter region causes the gene inactivation, and inactivation of tumor suppressor genes in a large number of tumor cells are related to excessive methylation of the promoter region. Methylation frequently occurs in the early period of cell canceration, therefore methylation screening for some diseases in high risk population can achieve the purposes of early diagnosis and treatment.
DNA methylation is not the same as structural variation of the gene such as mutation or missing, it's an epigenetic modification, and the primary structure of DNA is not changed, so it is a reversible change. Demethylating drug effects on tumor cell lines, enables gene re-expression, and thus plays the role of suppressing cancer. When 5-Aza or its deoxidation isomer 5'-Aza-2'-deoxycytidine acts on tumor cells with highly methylated gene promoter, corresponding mRNA and protein expression are found to be recovered, and expression level changes with the change of cell types and drug doses, confirming that promoter methylation is the main cause of gene expression close.
Cell adhesion molecule 1 (CADM1), formerly known as tumor suppressor in lung cancer-1(TSLC1), is a new tumor suppressor identified with methods of functional complementarity by Kuramochi in 2001 when he was researching lung cancer. It belongs to the immunoglobulin superfamily of cell adhesion molecules, regulating the adhesion between cells through convergent TRANS interactions. CADM1 expression reduction in 85% of primary tumors, and CADM1 expression missing were detected in a variety of tumors. CADM1 expression missing is mainly through two channels:one is the loss of heterozygosity (LOH), and the other is the promoter methylation, of which CADM1 promoter methylation is the main missing mechanism. CADM1 expression missing can damage cell adhesion, in addition, it may transfer a signal enabling tumor metastasis and/or infiltrating to the surrounding or peripheral tissues, on the contrary, normal CADM1 expression inhibits tumor development.
It was reported that promoter methylation was detected in 44% of non-small cell lung cancer,48% of breast cancer,32% of prostate cancer,29% of liver cancer, and 27% of pancreatic cancer, and associated with CADM1 expression missing or reduction. In addition, the CADM1 gene expression missing can be found in a variety of tumors, such as esophageal cancer, laryngeal cancer, nasopharyngeal cancer, gastric cancer and Lymphoma, especially obvious in the more invasive tumors, and is associated with the promoter methylation. Therefore, the study indicated that CADM1 not only has a close relationship with the occurrence of multiple tumors, but also has an important role in biological invasive control of tumor, may be a important biological marker predicting the prognosis of patients.
There is no research on CADM1 and promoter methylation in oral squamous cell carcinoma in China up to now. This experiment used immunohistochemistry, real-time fluorescence quantitative PCR, methylation-specific PCR, gene de-methylation and other methods to detect CADM1 gene expression in oral squamous cell carcinoma tissues and cells, promoter methylation, and the impact of demethylation on biological behavior of tumor cells. Specific study contents and results are as follows:
Ⅰ.CADM1 expression and its significance in oral squamous cell carcinoma
The subjects were patients with oral squamous cell carcinoma in the research, immunohistochemical method and real-time fluorescent quantitative PCR method were used for observation of CADM1 protein and mRNA expression in the tissues of 52 cases of oral squamous cell carcinoma and 30 cases of normal mucosa.
The results indicated:
1. There was no reduction or missing in CADM1 protein and mRNA expression in normal oral mucosa tissue.
2. Compared with normal oral mucosa, CADM1 protein and mRNA expression reduced significantly in the tissue of oral squamous cell carcinoma, with significant difference (P＜0.01)
3. Reduction of CADM1 protein and mRNA expression was related with the differentiation level and clinical phase(P<0.05), and low CADM1 protein and mRNA expression predicted bad prognosis of the patient.
Ⅱ. Methylation of CADM1 gene in oral squamous cell carcinoma
This study used methylation-specific PCR methods to detect the methylation of CADM1 promoter CpG islet in tumor suppressor genes in 52 cases of oral squamous cell carcinoma and 30 cases of normal mucosa.
The results indicated:
1. There was no methylation in CADM1 gene in 30 cases of normal oral mucosa tissue.
2. Methylation of CADM1 gene promoter occurred in 24 of 52 cases of oral squamous cell carcinoma tissue, accounting for 46.15%; methylation rate in normal oral mucosa tissue and in oral squamous cell carcinoma had more significance (P<0.05).
3. Methylation condition of CADM1 promoter was related with the differentiation level and clinical phase of tumor tissue(P<0.05),maybe an important factor affecting the prognosis of oral squamous cell carcinoma.
4. Methylation condition of CADM1 promoter was not markedly related with the age, sex, tumor site and diameter of the patient (P>0.05).
5. Methylation of CADM1 gene promoter was highly consistent with the reduction of CADM1 protein and mRNA expression, Methylation of CADM1 promoter was the important reason leading to the reduction of CADM1 protein and mRNA expression.
III. CADM1 demethylation of the cell line in tongue squamous cell carcinoma
The experiment used demethylation drug 5-Aza-CdR to treat Tca8113 cell line and SCC-9 cell line of tongue squamous cell carcinoma, used MTT method to observe the survival rate of cells; used methylation-specific PCR to detect methylation condition of CADM1 gene; real-time quantitative PCR to detect the expression change of CADM1 gene.
The results indicated:
1.The survival rate of Tca8113 and SCC-9 cells of tongue squamous cell carcinoma markedly reduced after the treatment with 5-Aza-CdR, with significant difference compared with the survival rate of cells in the control group, and showed dosage dependence.
2. Demethylation occurred in the CADM1 gene of Tca8113 cell line in tongue squamous cell carcinoma after the treatment with 5-Aza-CdR, and the demethylation effect was the most obvious in the 5μmol/L 5-Aza group.
3. Demethylation didn't occur in the CADM1 gene of SCC-9 cell line in tongue squamous cell carcinoma after the treatment with 5-Aza-CdR, and CADM1 gene remained the non-methylation condition in the SCC-9 cell line.
4. The expression of the CADM1 gene of Tca8113 cell line in tongue squamous cell carcinoma upregulated after the treatment with 5-Aza-CdR, with dosage dependence (P＜0.05).
5. The expression of the CADM1 gene of SCC-9 cell in tongue squamous cell carcinoma showed no significant difference after the treatment with 5-Aza-CdR (P>0.05)
6. There was a close relationship between methylation of the CADM1 promoter gene and the downregulation of the gene expression in the cell line of tongue carcinoma, demethylation of the CADM1 gene lead to the upregulation of gene expression and played its role in suppressing cancer, maybe a potential target for the treatment of oral squamous cell carcinoma.
The following conclusions were drawn according to the results of this experiment:
1. Development of oral squamous cell carcinoma was closely related with the significant reduction of CADM1 protein and mRNA expression.
2. In oral Squamous Cell Carcinoma, methylation of CADM1 gene promoter was one of the important reasons leading to downregulation of CADM1 protein and mRNA expression.
3. CADM1 gene expression upregulated after demethylation of CADM1 gene of Tca8113 cell line in tongue squamous cell carcinoma, while demethylation didn't occur in the CADM1 gene of SCC-9 cell line in tongue squamous cell carcinoma, and there was no changes in the CADM1 gene expression, further indicating methylation of the CADM1 gene was closely related with the downregulation of protein and mRNA expression.
4. expression and methylation of CADM1 gene were both related with the pathological grading and clinical phase(P<0.05), maybe the important factor affecting the prognosis of Oral squamous cell carcinoma.
引文
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