HMGB1、RAGE和VEGF在食管鳞状细胞癌的表达和意义
摘要
背景和目的
食管癌是最常见的恶性肿瘤之一,在我国尤其是河南一些地区,发病率和死亡率处于当地恶性肿瘤首位,严重影响国人的健康。食管癌临床治疗中困难在于浸润和转移,并且是导致多数患者死亡的重要因素。食管癌早期诊断及监测浸润和转移成为多数学者研究的热点。HMGB1是一种非组蛋白染色质结合蛋白,参与细胞内外的多种功能,参与转录DNA修复,并作为炎症细胞因子参与炎症反应。近来研究发现其与其受体RAGE在多种肿瘤中发挥重要作用。但是,HMGB1及其受体RAGE在食管癌的作用研究较少。本研究采用免疫组织化学SP法,检测食管鳞状细胞癌组织、正常食管组织中HMGB1、RAGE和VEGF表达,并分析其与临床病理参数的关系,探讨其在食管癌发生、发展和转移发挥的作用及相互关系,为食管癌的综合治疗及预后判断提供新理论基础。
材料与方法
收集郑州大学第一附属医院与河南省人民医院行食管癌根治术手术治疗食管癌患者临床标本51例及正常食管组织12例。应用SP免疫组织化学染色法,分别检测HMGB1、RAGE和VEGF在人食管癌组织中的表达,同时与其临床病理参数的关系进行统计学分析；采用SPSS 13.0软件包进行数据分析。HMGB1、RAGE和VEGF阳性率的比较采用x2检验,及非参数检验Fisher's精确概率检测法,针对蛋白表达相关性采用Spearman相关分析,检验水准a=0.05。
结果
1 HMGB1在食管鳞状细胞癌中表达
在51例食管鳞状细胞癌标本中,35例阳性表达,阳性率68.6%；正常对照组中阳性率16.7%,两者差异有统计学意义(x 2=10.821,P<0.01)。在51例食管鳞状细胞癌组织中,有淋巴结转移组和无淋巴结转移组阳组表达率分别为82.1%和56.5%,两组相比较差异具有统计学意义(x 2=5.268,P<0.05)；HMGB1的表达与患者的性别、年龄、肿瘤大小、肿瘤的T分期,以及分化程度差异无统计学意义(P>0.05)。
2 RAGE在食管鳞状细胞癌的表达
在51例食管鳞状细胞癌标本中,26例阳性表达,阳性率51%(26/51)；正常对照组中阳性率16.7%(2/12),两者差异有统计学意义(χ2=10.821,P<0.01)。在51例食管鳞状细胞癌组织中,有淋巴结转移组和无淋巴结转移组阳性表达率分别为67.9%和30.4%,两组相比较差异具有统计学意义(χ2=5.268,P<0.05);HMGB1的表达与患者的性别、年龄、肿瘤大小、肿瘤的T分期,以及分化程度差异无统计学意义(P>0.05)。
3 VEGF在食管鳞状细胞癌表达
在51例食管鳞状细胞癌标本中,29例阳性表达,阳性率56.9%；正常对照组中阳性率8.3%,两者差异有统计学意义(χ2=10.821,P<0.01)。在51例食管鳞状细胞癌组织中,有淋巴结转移组和无淋巴结转移组阳性表达率分别为75.0%和34.8%,两组相比较差异具有统计学意义(χ2=5.268,P<0.05);HMGB1的表达与患者的性别、年龄、肿瘤大小、肿瘤的T分期,以及分化程度差异无统计学意义(P>0.05)。
4 HMGB1、RAGE、VEGF在食管鳞状细胞癌中表达的相关性分析
在51例食管癌组织中,HMGB1与RAGE的阳性表达呈正相关(r=0.520,P<0.01)；HMGB1与VEGF在食管癌组织的的阳性表达呈正相关(r=0.350,P<0.05)；VEGF与RAGE在食管癌组织的的阳性表达呈正相关(r=0.413,P<0.01)。
结论
1 HMGB1、RAGE、VEGF在食管癌组织中呈过表达,提示三者之间在食管癌的发生,发展中发挥重要的作用；同时认为炎症与肿瘤具有相关性。
2 HMGB1、RAGE、VEGF在食管癌中都与淋巴结转移组过表达,提示三者参与淋巴结转移机制。
3在食管癌组织中HMGB1与RAGE、HMGB1与VEGF、RAGE与VEGF之间都成正相关。提示三者协同作用参与食管癌的淋巴结转移。
4 HMGB1、RAGE、VEGF可能在食管癌的发生发展中相互协调关系。联合检测食管癌组织中HMGB1、RAGE、VEGF的表达,有助于检测患者淋巴转移的状态,为食管癌的基因治疗提供新思路。
Background and Objective
Esophageal cancer is one of the most common malignant tumors, especially in some areas of China. The morbidity and mortality of esophageal cancer is the highest in local malignant tumor in some areas, this seriously affect the health of people. Infiltration and aversion are two tough problems in clinic therapy. They are also lethal factors for most patients. Therefore, there are more and more studies foucus on how to elevate early stage and monitor its aversion. HMGB1 is a non-histone, nuclear DNA-binding protein. HMGB1 is a versatile protein with intranuclear and extracellular functions,such as transcription, DNA repair, and response to infection and inflammation. HMGB1 has been recently demonstrated to paly an important role in many types of cancers. The role of HMGB1 and RAGE in esophagus carcinoma is unknown. To investigate the expression of HMGB1, RAGE and VEGF in esophagus squamous cell carcinoma. The immunohistochemical S-P method was used to detect expression of HMGB1, RAGE and VEGF in 51 esophagus squamous cell carcinoma tissues and 12 normal tissues, and to study the significance of expression of HMGB1, RAGE and VEGF protein. Explore esophageal lymph node metastases, molecular mechanism of comprehensive treatment for esophageal provides new ideas. This study is to explore the mechanism and interrelation of them in the incidence, infiltrating and metastasis. It provids a new rationale to therapy and judgement of prognosis of esophageal carcinoma.
Materials and methods
S-P Immunohistochemical studies were performed in all 51 cases with esophageal squamous cell carcinoma, the expression of HMGB1,RAGE and VEGF was detected in Esophageal carcinoma and normal esophageal tissues. The results were analyzed with the clinical parameters. Statistical SPSS software 13.0 was used in the study.χ2 test, Fisher test and spearman rank correlation were used to analyze the difference of the results, the P value less than 0.05 was considered as significant.
Results
1. The expression of HMGB1 in esophageal squamous cell carcinoma
Immunohistochemical studies were performed in all 51 cases with esophageal squamous cell carcinoma. Immunostaining for HMGB1 in tumor cells were observed in nuclei and cytoplasm, the positive rate of HMGB1 was 68.6% in esophageal cancer,16.7% in normal tissues. There was a significant difference between two groups (P<0.01).the association between HMGB1 expression and clinicopathological characteristics of tumors was examined. There was no significant correlation between HMGB1 expression and gender, age, differentiation degree or T classification (p>0.05). However, HMGB1 expression was positively correlated with N classification (P<0.05). A trend that patients with high HMGB1 expression had a partial response to tumor size and T classification in the entire cohort was found, but there was no correlation between HMGB1 expression and tumor size and T classification.
2. RAGE in esophageal squamous cell carcinoma
RAGE protein was detected in 26 cases. The positive rate is 51%.RAGE staining was mostly observed in the cytoplasm and membran of carcinoma cells. RAGE staining was weaker in normal tissues than in NPC tissues. There was significantly different between groups with high and low expression of RAGE.According to results, there was was no significant correlation between RAGE expression and gender, age, differentiation degree or T classification (p>0.05). However, RAGE expression was positively correlated with N classification (P<0.05). There is a similar with the exprssion of HMGB1 in tumor size and T classification, a trend that patients with high HMGB1 expression had a partial response to tumor size and T classification in the entire cohort was found.
3. VEGF in esophageal squamous cell carcinoma
The positive rate of VEGF is higher than in normal control group (56.9% vs 8.3%, P<0.01). There is a significantly different between esophageal carcinoma group and normal control group. Over expression of VEGF was significantly correlated with N classification (P<0.05). No significant correlation was found between RAGE expression and gender, age, differentiation degree or T classification (p>0.05).
4. The correlation of expression among HMGB1, RAGE and VEGF in esophageal squamous cell carcinoma
There was a positive correlation of the positive expression between HMGB1 and RAGE (r=0.520, P<0.01). The expression of HMGB1 is correlation with the VEGF (r=0.350, P<0.05). There was a positive correlation of the positive expression between VEGF and RAGE (r=0.413, P<0.01)
Conclusions
1 The expression of HMGBl, RAGE and VEGF is increased in esophageal carcinoma. It suggests that HMGB1, RAGE and VEGF overexpression has a role in the incident of esophageal carcinoma. Inflammation is associated with tumor.
2 Overexpression of HMGB1, RAGE and VEGF is a associated with lymphatic metastasis in human esophageal squamous cell carcinoma. It support that overexpression of HMGB1, RAGE and VEGF has a role in the lymphatic metastasis.
3 In human esophageal squamous cell carcinoma, there is correlation in HMGB1, RAGE and VEGF. HMGB1, RAGE and VEGF interact with each other play an important role in incident of esophageal carcinoma and lymphatic metastasis.
4 HMGB1, RAGE and VEGF may play a synergistic action in oncogenesis and lymphatic metastasis of esophageal carcinoma. The expression of HMGB1, RAGE and VEGF is detected may contribute to evaluate the statue of lymphatic metastasis and study the mechanism of lymphatic metastasis. Our study may provide a new target for gene therapy of esophageal carcinoma.
食管癌是最常见的恶性肿瘤之一,在我国尤其是河南一些地区,发病率和死亡率处于当地恶性肿瘤首位,严重影响国人的健康。食管癌临床治疗中困难在于浸润和转移,并且是导致多数患者死亡的重要因素。食管癌早期诊断及监测浸润和转移成为多数学者研究的热点。HMGB1是一种非组蛋白染色质结合蛋白,参与细胞内外的多种功能,参与转录DNA修复,并作为炎症细胞因子参与炎症反应。近来研究发现其与其受体RAGE在多种肿瘤中发挥重要作用。但是,HMGB1及其受体RAGE在食管癌的作用研究较少。本研究采用免疫组织化学SP法,检测食管鳞状细胞癌组织、正常食管组织中HMGB1、RAGE和VEGF表达,并分析其与临床病理参数的关系,探讨其在食管癌发生、发展和转移发挥的作用及相互关系,为食管癌的综合治疗及预后判断提供新理论基础。
材料与方法
收集郑州大学第一附属医院与河南省人民医院行食管癌根治术手术治疗食管癌患者临床标本51例及正常食管组织12例。应用SP免疫组织化学染色法,分别检测HMGB1、RAGE和VEGF在人食管癌组织中的表达,同时与其临床病理参数的关系进行统计学分析；采用SPSS 13.0软件包进行数据分析。HMGB1、RAGE和VEGF阳性率的比较采用x2检验,及非参数检验Fisher's精确概率检测法,针对蛋白表达相关性采用Spearman相关分析,检验水准a=0.05。
结果
1 HMGB1在食管鳞状细胞癌中表达
在51例食管鳞状细胞癌标本中,35例阳性表达,阳性率68.6%；正常对照组中阳性率16.7%,两者差异有统计学意义(x 2=10.821,P<0.01)。在51例食管鳞状细胞癌组织中,有淋巴结转移组和无淋巴结转移组阳组表达率分别为82.1%和56.5%,两组相比较差异具有统计学意义(x 2=5.268,P<0.05)；HMGB1的表达与患者的性别、年龄、肿瘤大小、肿瘤的T分期,以及分化程度差异无统计学意义(P>0.05)。
2 RAGE在食管鳞状细胞癌的表达
在51例食管鳞状细胞癌标本中,26例阳性表达,阳性率51%(26/51)；正常对照组中阳性率16.7%(2/12),两者差异有统计学意义(χ2=10.821,P<0.01)。在51例食管鳞状细胞癌组织中,有淋巴结转移组和无淋巴结转移组阳性表达率分别为67.9%和30.4%,两组相比较差异具有统计学意义(χ2=5.268,P<0.05);HMGB1的表达与患者的性别、年龄、肿瘤大小、肿瘤的T分期,以及分化程度差异无统计学意义(P>0.05)。
3 VEGF在食管鳞状细胞癌表达
在51例食管鳞状细胞癌标本中,29例阳性表达,阳性率56.9%；正常对照组中阳性率8.3%,两者差异有统计学意义(χ2=10.821,P<0.01)。在51例食管鳞状细胞癌组织中,有淋巴结转移组和无淋巴结转移组阳性表达率分别为75.0%和34.8%,两组相比较差异具有统计学意义(χ2=5.268,P<0.05);HMGB1的表达与患者的性别、年龄、肿瘤大小、肿瘤的T分期,以及分化程度差异无统计学意义(P>0.05)。
4 HMGB1、RAGE、VEGF在食管鳞状细胞癌中表达的相关性分析
在51例食管癌组织中,HMGB1与RAGE的阳性表达呈正相关(r=0.520,P<0.01)；HMGB1与VEGF在食管癌组织的的阳性表达呈正相关(r=0.350,P<0.05)；VEGF与RAGE在食管癌组织的的阳性表达呈正相关(r=0.413,P<0.01)。
结论
1 HMGB1、RAGE、VEGF在食管癌组织中呈过表达,提示三者之间在食管癌的发生,发展中发挥重要的作用；同时认为炎症与肿瘤具有相关性。
2 HMGB1、RAGE、VEGF在食管癌中都与淋巴结转移组过表达,提示三者参与淋巴结转移机制。
3在食管癌组织中HMGB1与RAGE、HMGB1与VEGF、RAGE与VEGF之间都成正相关。提示三者协同作用参与食管癌的淋巴结转移。
4 HMGB1、RAGE、VEGF可能在食管癌的发生发展中相互协调关系。联合检测食管癌组织中HMGB1、RAGE、VEGF的表达,有助于检测患者淋巴转移的状态,为食管癌的基因治疗提供新思路。
Background and Objective
Esophageal cancer is one of the most common malignant tumors, especially in some areas of China. The morbidity and mortality of esophageal cancer is the highest in local malignant tumor in some areas, this seriously affect the health of people. Infiltration and aversion are two tough problems in clinic therapy. They are also lethal factors for most patients. Therefore, there are more and more studies foucus on how to elevate early stage and monitor its aversion. HMGB1 is a non-histone, nuclear DNA-binding protein. HMGB1 is a versatile protein with intranuclear and extracellular functions,such as transcription, DNA repair, and response to infection and inflammation. HMGB1 has been recently demonstrated to paly an important role in many types of cancers. The role of HMGB1 and RAGE in esophagus carcinoma is unknown. To investigate the expression of HMGB1, RAGE and VEGF in esophagus squamous cell carcinoma. The immunohistochemical S-P method was used to detect expression of HMGB1, RAGE and VEGF in 51 esophagus squamous cell carcinoma tissues and 12 normal tissues, and to study the significance of expression of HMGB1, RAGE and VEGF protein. Explore esophageal lymph node metastases, molecular mechanism of comprehensive treatment for esophageal provides new ideas. This study is to explore the mechanism and interrelation of them in the incidence, infiltrating and metastasis. It provids a new rationale to therapy and judgement of prognosis of esophageal carcinoma.
Materials and methods
S-P Immunohistochemical studies were performed in all 51 cases with esophageal squamous cell carcinoma, the expression of HMGB1,RAGE and VEGF was detected in Esophageal carcinoma and normal esophageal tissues. The results were analyzed with the clinical parameters. Statistical SPSS software 13.0 was used in the study.χ2 test, Fisher test and spearman rank correlation were used to analyze the difference of the results, the P value less than 0.05 was considered as significant.
Results
1. The expression of HMGB1 in esophageal squamous cell carcinoma
Immunohistochemical studies were performed in all 51 cases with esophageal squamous cell carcinoma. Immunostaining for HMGB1 in tumor cells were observed in nuclei and cytoplasm, the positive rate of HMGB1 was 68.6% in esophageal cancer,16.7% in normal tissues. There was a significant difference between two groups (P<0.01).the association between HMGB1 expression and clinicopathological characteristics of tumors was examined. There was no significant correlation between HMGB1 expression and gender, age, differentiation degree or T classification (p>0.05). However, HMGB1 expression was positively correlated with N classification (P<0.05). A trend that patients with high HMGB1 expression had a partial response to tumor size and T classification in the entire cohort was found, but there was no correlation between HMGB1 expression and tumor size and T classification.
2. RAGE in esophageal squamous cell carcinoma
RAGE protein was detected in 26 cases. The positive rate is 51%.RAGE staining was mostly observed in the cytoplasm and membran of carcinoma cells. RAGE staining was weaker in normal tissues than in NPC tissues. There was significantly different between groups with high and low expression of RAGE.According to results, there was was no significant correlation between RAGE expression and gender, age, differentiation degree or T classification (p>0.05). However, RAGE expression was positively correlated with N classification (P<0.05). There is a similar with the exprssion of HMGB1 in tumor size and T classification, a trend that patients with high HMGB1 expression had a partial response to tumor size and T classification in the entire cohort was found.
3. VEGF in esophageal squamous cell carcinoma
The positive rate of VEGF is higher than in normal control group (56.9% vs 8.3%, P<0.01). There is a significantly different between esophageal carcinoma group and normal control group. Over expression of VEGF was significantly correlated with N classification (P<0.05). No significant correlation was found between RAGE expression and gender, age, differentiation degree or T classification (p>0.05).
4. The correlation of expression among HMGB1, RAGE and VEGF in esophageal squamous cell carcinoma
There was a positive correlation of the positive expression between HMGB1 and RAGE (r=0.520, P<0.01). The expression of HMGB1 is correlation with the VEGF (r=0.350, P<0.05). There was a positive correlation of the positive expression between VEGF and RAGE (r=0.413, P<0.01)
Conclusions
1 The expression of HMGBl, RAGE and VEGF is increased in esophageal carcinoma. It suggests that HMGB1, RAGE and VEGF overexpression has a role in the incident of esophageal carcinoma. Inflammation is associated with tumor.
2 Overexpression of HMGB1, RAGE and VEGF is a associated with lymphatic metastasis in human esophageal squamous cell carcinoma. It support that overexpression of HMGB1, RAGE and VEGF has a role in the lymphatic metastasis.
3 In human esophageal squamous cell carcinoma, there is correlation in HMGB1, RAGE and VEGF. HMGB1, RAGE and VEGF interact with each other play an important role in incident of esophageal carcinoma and lymphatic metastasis.
4 HMGB1, RAGE and VEGF may play a synergistic action in oncogenesis and lymphatic metastasis of esophageal carcinoma. The expression of HMGB1, RAGE and VEGF is detected may contribute to evaluate the statue of lymphatic metastasis and study the mechanism of lymphatic metastasis. Our study may provide a new target for gene therapy of esophageal carcinoma.
引文
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