胃乙醇脱氢酶与胃癌特征的相关性分析及酒精对胃癌细胞株作用的研究
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摘要
背景与目的：
胃癌是我国最常见的恶性肿瘤之一,胃癌的发生是多因素长期作用的结果,胃癌的发病率存在明显的国家和地区差异。胃癌的确切病因尚未完全阐明,有研究显示,幽门螺杆菌感染、饮食、吸烟及宿主的遗传易感性是影响胃癌发生的重要因素。饮酒与胃癌发生的危险相关度目前仍有争议。摄入酒精可直接刺激胃粘膜,与其代谢中间产物乙醛等因素共同造成胃粘膜损伤,导致胃粘膜上皮易受致癌物质侵犯或/和直接影响并导致粘膜上皮的恶性变。酒精的代谢过程中乙醇脱氢酶(alcohol dehydrogenase, ADH)起着至关重要的作用,它主要分布在肝脏,在胃肠道及其他组织中也有少量分布,ADH是酒精代谢的限速酶,决定局部组织、血液中酒精及代谢产物的浓度,是饮酒过程影响人体的决定性因素之一。ADH的水平与胃癌的发生是否相关尚不明确。为进一步探讨酒精刺激对胃癌细胞的作用,本研究收集胃癌患者组织标本及其临床资料,检测胃癌及癌旁组织中ADH表达并分析其与临床及病理特征等因素的相关性。然后通过细胞学实验室研究,采用不同浓度梯度酒精刺激不同胃癌细胞株,初步评价不同浓度梯度酒精对胃癌细胞增殖、凋亡的影响,分析酒精干预后ADH在不同胃癌细胞株的表达水平,在细胞水平探索酒精对胃癌细胞的作用。
方法：
1、收集胃癌患者的临床资料及组织标本,采用组织芯片技术处理胃癌及癌旁组织,免疫组化技术检测乙醇脱氢酶在胃癌及癌旁组织中的表达情况,观察不同胃组织中乙醇脱氢酶的表达情况,探讨临床特征、ADH表达与胃癌预后及临床病理特征之间的关系。
2、采用不同浓度梯度的酒精(0.03125%、0.0625%、0.125%、0.25%、0.5%、1%、2%、4%、6%)处理MGC803、BGC823和SGC7901三种不同胃癌细胞株,以MTT法检测酒精对细胞增殖的影响,并用流式细胞仪检测细胞凋亡。
3、采用WESTERN BLOT技术检测不同浓度酒精(0.125%、0.25%、0.5%)处理MGC803、BGC823和SGC7901三种胃癌细胞株乙醇脱氢酶的表达变化。
结果：
1、胃癌患者临床及病理资料统计分析结果：
(1)101例胃癌患者中男性64例,女性37例,年龄28-75岁,平均年龄57.46±10.88岁。
(2)胃癌组织ADH表达水平与饮酒情况和胃癌TNM分期有关(p<0.05)；癌旁组织ADH表达水平则与年龄相关(p<0.05)。
(3)胃癌组织ADH不同表达生存曲线呈现有意义分离(P<0.05)；危险及有害饮酒组与正常饮酒及未饮酒组的生存曲线出现分离(P<0.05)。
(4)COX风险比例模型单因素分析显示：年龄因素、饮酒情况、ADH癌旁表达、阳性淋巴结数及肿瘤TNM分期等因素与胃癌预后相关(P<0.05)；COX风险比例多因素分析显示,年龄与肿瘤TNM分期是胃癌预后相关的危险因素(P=0.000),ADH癌组织中表达可能影响胃癌预后(P=0.064)(注：多因素COX回归分析,方法用后退法,进入标准为0.05,删除标准为0.10。)。
2、0.03125%-6%浓度梯度的酒精作用于MGC803、BGC823和SGC7901三种胃癌细胞株48h后,可显著抑制胃癌细胞的增殖,并诱导胃癌细胞的凋亡。
3、0.125%、0.25%、0.5%浓度的酒精作用于MGC803、BGC823和SGC7901三种胃癌细胞48h后,其ADH的表达显著增加,且与酒精浓度呈正相关。
结论：
1、胃癌及癌旁组织临床资料及ADH表达分析结论：
(1)胃癌组织ADH表达水平与饮酒情况和胃癌TNM分期有关,癌旁组织ADH表达水平与年龄相关。
(2)胃癌组织ADH高表达组生存优于低表达组,正常及无饮酒组生存优于危险及有害饮酒组。
(3)年龄、肿瘤TNM分期是胃癌预后相关的危险因素,ADH癌组织中表达可能影响胃癌预后。
2、酒精可显著降低胃癌细胞活性,较低浓度酒精同样能抑制胃癌细胞增殖,并诱导其凋亡。
3、酒精可促进胃癌细胞ADH表达,表达水平随酒精浓度的增加而提高。
Background and aim:
Gastric cancer is one of the most common malignant tumor in the world and has high mortality and morbidity. It is caused by the result of long-term and multiple factors, and the incidence of gastric cancer are significant different in varied nation and region.The exact cause of gastric cancer has not yet been fully elucidated. Studies have shown that Helicobacter pylori infection, diet, smoking and genetic susceptibility of the host are important factors of gastric cancer. Risk related to drinking and gastric cancer is still controversial. Intaking alcohol can stimulate the gastric mucosa directly, and acetaldehyde, the metabolic intermediate item of alcohol, can cause gastric mucosal injury. Gastric epithelial susceptible affected by carcinogenic substance directly,and it can cause malignant transformation. Alcohol dehydrogenase (ADH) plays a vital role in alcohol metabolism process, which is mainly distributed in the liver, the distribution of a small amount in the gastrointestinal tract and other organs. ADH, the rate-limited enzyme of alcohol metabolism, can influence on local tissue blood alcohol concentration. It is one of the decisive factors affecting the body's Drinking process. Relationship between ADH levels and gastric cancer are still not clear. We studied on collected tissue specimens and clinical data of patients with gastric cancer. The aim of the study was to analyze the relationship between the clinical pathological characteristics, alcohol consumption and ADH expression. And the study also investigated the influence of diverse concentrations of alcohol on gastric adenocarcinoma cell viability, apoptosis, and the expression changes of ADH with alcohol management.
Methods:
1. The expression of ADH in a tissue microarray containing101gastric cancer and67paracancer in those spots of gastric cancer tissues was detected by immunohistochemical technique. The correlation among the expression of the ADH and clinicopathalogic variables and overall survival of the gastric cancer was analyzed.
2. Gastric adenocarcinoma cell lines (MGC803, BGC823and SGC7901) were treated with different concentrations of alcohol (0.03125%,0.0625%,0.125%,0.25%,0.5%,1%,2%,4%and6%). An MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and flow cytometry were used to analyze the effect of alcohol treatment on cell viability and apoptosis.
3、Western blotting was used to analyze the expression of ADH in gastric carcinoma cells treated with different concentrations of alcohol (0.125%,0.25%,0.5%).
Results:
1,39.6%of101gastric cancer were positive for ADH expression, and47.76%of67gastric paracancer were positive for ADH expression. The expression of ADH in paracancer tissue was correlated with the prognosis in gastric cancer. One-way Anova analyses showed that gastric ADH expression differed in patients with different volumn of alcohol consumption. Alcohol consumption, TNM stage was closely correlated to overall survival(P<0.05).
2, Alcohol treatment inhibited cell proliferation in gastric adenocarcinoma cell lines in a significant dose-dependent manner. Alcohol was also able to induce the apoptosis of gastric adenocarcinoma cells in a dose-dependent manner.
3, ADH activity of gastric adenocarcinoma cells increased with the increase of the concentration of alcohol.
Conclusions:
1. The age,tumor TNM stage would be the predictive factors of gastric cancer prognosis, and gastric ADH expression level may be relevant to gastric cancer prognosis.
2、Alcohol inhibited cell viability and growth of gastric adenocarcinoma cell lines. Low concentrations of alcohol also induced apoptosis of the gastric adenocarcinoma cell lines.
3、Alcohol increased the expression of ADH of the gastric adenocarcinoma cell lines.
胃癌是我国最常见的恶性肿瘤之一,胃癌的发生是多因素长期作用的结果,胃癌的发病率存在明显的国家和地区差异。胃癌的确切病因尚未完全阐明,有研究显示,幽门螺杆菌感染、饮食、吸烟及宿主的遗传易感性是影响胃癌发生的重要因素。饮酒与胃癌发生的危险相关度目前仍有争议。摄入酒精可直接刺激胃粘膜,与其代谢中间产物乙醛等因素共同造成胃粘膜损伤,导致胃粘膜上皮易受致癌物质侵犯或/和直接影响并导致粘膜上皮的恶性变。酒精的代谢过程中乙醇脱氢酶(alcohol dehydrogenase, ADH)起着至关重要的作用,它主要分布在肝脏,在胃肠道及其他组织中也有少量分布,ADH是酒精代谢的限速酶,决定局部组织、血液中酒精及代谢产物的浓度,是饮酒过程影响人体的决定性因素之一。ADH的水平与胃癌的发生是否相关尚不明确。为进一步探讨酒精刺激对胃癌细胞的作用,本研究收集胃癌患者组织标本及其临床资料,检测胃癌及癌旁组织中ADH表达并分析其与临床及病理特征等因素的相关性。然后通过细胞学实验室研究,采用不同浓度梯度酒精刺激不同胃癌细胞株,初步评价不同浓度梯度酒精对胃癌细胞增殖、凋亡的影响,分析酒精干预后ADH在不同胃癌细胞株的表达水平,在细胞水平探索酒精对胃癌细胞的作用。
方法：
1、收集胃癌患者的临床资料及组织标本,采用组织芯片技术处理胃癌及癌旁组织,免疫组化技术检测乙醇脱氢酶在胃癌及癌旁组织中的表达情况,观察不同胃组织中乙醇脱氢酶的表达情况,探讨临床特征、ADH表达与胃癌预后及临床病理特征之间的关系。
2、采用不同浓度梯度的酒精(0.03125%、0.0625%、0.125%、0.25%、0.5%、1%、2%、4%、6%)处理MGC803、BGC823和SGC7901三种不同胃癌细胞株,以MTT法检测酒精对细胞增殖的影响,并用流式细胞仪检测细胞凋亡。
3、采用WESTERN BLOT技术检测不同浓度酒精(0.125%、0.25%、0.5%)处理MGC803、BGC823和SGC7901三种胃癌细胞株乙醇脱氢酶的表达变化。
结果：
1、胃癌患者临床及病理资料统计分析结果：
(1)101例胃癌患者中男性64例,女性37例,年龄28-75岁,平均年龄57.46±10.88岁。
(2)胃癌组织ADH表达水平与饮酒情况和胃癌TNM分期有关(p<0.05)；癌旁组织ADH表达水平则与年龄相关(p<0.05)。
(3)胃癌组织ADH不同表达生存曲线呈现有意义分离(P<0.05)；危险及有害饮酒组与正常饮酒及未饮酒组的生存曲线出现分离(P<0.05)。
(4)COX风险比例模型单因素分析显示：年龄因素、饮酒情况、ADH癌旁表达、阳性淋巴结数及肿瘤TNM分期等因素与胃癌预后相关(P<0.05)；COX风险比例多因素分析显示,年龄与肿瘤TNM分期是胃癌预后相关的危险因素(P=0.000),ADH癌组织中表达可能影响胃癌预后(P=0.064)(注：多因素COX回归分析,方法用后退法,进入标准为0.05,删除标准为0.10。)。
2、0.03125%-6%浓度梯度的酒精作用于MGC803、BGC823和SGC7901三种胃癌细胞株48h后,可显著抑制胃癌细胞的增殖,并诱导胃癌细胞的凋亡。
3、0.125%、0.25%、0.5%浓度的酒精作用于MGC803、BGC823和SGC7901三种胃癌细胞48h后,其ADH的表达显著增加,且与酒精浓度呈正相关。
结论：
1、胃癌及癌旁组织临床资料及ADH表达分析结论：
(1)胃癌组织ADH表达水平与饮酒情况和胃癌TNM分期有关,癌旁组织ADH表达水平与年龄相关。
(2)胃癌组织ADH高表达组生存优于低表达组,正常及无饮酒组生存优于危险及有害饮酒组。
(3)年龄、肿瘤TNM分期是胃癌预后相关的危险因素,ADH癌组织中表达可能影响胃癌预后。
2、酒精可显著降低胃癌细胞活性,较低浓度酒精同样能抑制胃癌细胞增殖,并诱导其凋亡。
3、酒精可促进胃癌细胞ADH表达,表达水平随酒精浓度的增加而提高。
Background and aim:
Gastric cancer is one of the most common malignant tumor in the world and has high mortality and morbidity. It is caused by the result of long-term and multiple factors, and the incidence of gastric cancer are significant different in varied nation and region.The exact cause of gastric cancer has not yet been fully elucidated. Studies have shown that Helicobacter pylori infection, diet, smoking and genetic susceptibility of the host are important factors of gastric cancer. Risk related to drinking and gastric cancer is still controversial. Intaking alcohol can stimulate the gastric mucosa directly, and acetaldehyde, the metabolic intermediate item of alcohol, can cause gastric mucosal injury. Gastric epithelial susceptible affected by carcinogenic substance directly,and it can cause malignant transformation. Alcohol dehydrogenase (ADH) plays a vital role in alcohol metabolism process, which is mainly distributed in the liver, the distribution of a small amount in the gastrointestinal tract and other organs. ADH, the rate-limited enzyme of alcohol metabolism, can influence on local tissue blood alcohol concentration. It is one of the decisive factors affecting the body's Drinking process. Relationship between ADH levels and gastric cancer are still not clear. We studied on collected tissue specimens and clinical data of patients with gastric cancer. The aim of the study was to analyze the relationship between the clinical pathological characteristics, alcohol consumption and ADH expression. And the study also investigated the influence of diverse concentrations of alcohol on gastric adenocarcinoma cell viability, apoptosis, and the expression changes of ADH with alcohol management.
Methods:
1. The expression of ADH in a tissue microarray containing101gastric cancer and67paracancer in those spots of gastric cancer tissues was detected by immunohistochemical technique. The correlation among the expression of the ADH and clinicopathalogic variables and overall survival of the gastric cancer was analyzed.
2. Gastric adenocarcinoma cell lines (MGC803, BGC823and SGC7901) were treated with different concentrations of alcohol (0.03125%,0.0625%,0.125%,0.25%,0.5%,1%,2%,4%and6%). An MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and flow cytometry were used to analyze the effect of alcohol treatment on cell viability and apoptosis.
3、Western blotting was used to analyze the expression of ADH in gastric carcinoma cells treated with different concentrations of alcohol (0.125%,0.25%,0.5%).
Results:
1,39.6%of101gastric cancer were positive for ADH expression, and47.76%of67gastric paracancer were positive for ADH expression. The expression of ADH in paracancer tissue was correlated with the prognosis in gastric cancer. One-way Anova analyses showed that gastric ADH expression differed in patients with different volumn of alcohol consumption. Alcohol consumption, TNM stage was closely correlated to overall survival(P<0.05).
2, Alcohol treatment inhibited cell proliferation in gastric adenocarcinoma cell lines in a significant dose-dependent manner. Alcohol was also able to induce the apoptosis of gastric adenocarcinoma cells in a dose-dependent manner.
3, ADH activity of gastric adenocarcinoma cells increased with the increase of the concentration of alcohol.
Conclusions:
1. The age,tumor TNM stage would be the predictive factors of gastric cancer prognosis, and gastric ADH expression level may be relevant to gastric cancer prognosis.
2、Alcohol inhibited cell viability and growth of gastric adenocarcinoma cell lines. Low concentrations of alcohol also induced apoptosis of the gastric adenocarcinoma cell lines.
3、Alcohol increased the expression of ADH of the gastric adenocarcinoma cell lines.
引文
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