VEGF、COX-2在HBV感染型和非HBV感染型肝细胞癌中的表达差异及意义
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摘要
【目的】
肝细胞肝癌(hepatocellular carcinoma,HCC)是世界范围内最常见的恶性肿瘤之一,居我国癌症死亡的第三位。大约80%的肝癌的发生与乙肝病毒HBV相关,流行病学研究表明HBsAg阳性患者肝癌的发生率比HBsAg阴性患者高100倍。肝细胞癌是一多血管肿瘤,新生血管在肝细胞肝癌的发生和侵袭中起关键的作用,有利于肝癌转移和复发。目前研究表明VEGF(vascular endothelial growth factor),COX-2(cyclooxygenase-2),在肝细胞癌中扮演关键角色,VEGF、COX-2的高表达与肝细胞癌的侵袭、预后相关,但VEGF、COX-2在HBV感染型肝癌和非HBV感染型肝癌中的表达是否存在差异尚不清楚。因此研究乙肝病毒HBV(hepatitis B virus)感染与肝癌组织中VEGF,COX-2的关系有助于我们进一步了解不同病因HCC的发生发展机制,为临床对HCC的早期诊断和防治提供实验依据。
【方法】
1.标本取自本院1996—2002年经手术切除并经病理学证实的石蜡包埋的原发性肝癌病理标本56例。根据血清学及免疫组化法HBsAg检查结果将其分为HBV感染组和非HBV感染组。
2.将病理切片应用采用快速免疫组化MaxVisionTM法检测标本中VEGF、COX-2的蛋白表达,采用χ2检验及spearman秩相关进行统计学分析,探讨VEGF、COX-2在HCC中的表达及其与HBV感染的关系。
3 .对HBV表达阴性的细胞株HepG2和稳定转染HBV基因并持续表达HBV的细胞株HepG2.215进行培养,用RT-PCR法检测VEGF、COX-2在各细胞株中的表达,进行比较。
【结果】
1、快速免疫组化法结果显示:(1) HBV感染组中VEGF、COX-2的阳性率分别为(78.9%)、(76.3%)高于非HBV感染组中的(50.0%)、(44.4%),差异有统计学意义(P < 0. 05)。(2)VEGF阳性的肿瘤组织COX-2也趋于阳性,相关性分析显示COX-2与VEGF的表达呈正相关(r=0.429,P<0.05)。
2. RT—PCR产物电泳结果显示,HepG2.215细胞中VEGF、COX-2 mRNA的表达显著高于HepG2细胞(P<0.05)。
【结论】
1、本研究中HBV感染型肝癌VEGF、COX-2的表达较非感染型肝癌组织明显增高,这表明HBV感染可能上调VEGF、COX-2在肝癌组织中的表达,促进肿瘤组织中的血管形成,有利于肿瘤组织的增殖和生长,促使肿瘤细胞的侵袭和转移
2、通过肝癌细胞株VEGF、COX-2表达的检测结果显示,在HepG2.215细胞中的mRNA表达明显高于HepG2细胞。这个结果与组织学研究的结果相一致,进一步证实了HBV感染与VEGF、COX-2表达存在相关性。有助于揭示HBV感染致HCC发生与发展的机制。
3、VEGF、COX-2在HBV感染型和非HBV感染型肝细胞癌组织和肝癌细胞株中的表达差异,对探讨HBV感染型与非HBV感染型肝细胞癌的临床表现和转归及探索针对不同病因肝癌的防治策略和方法提供了启示和方向。
【objective】
Hepatocellular carcinoma is one of the most common malignancies worldwide and the third leading cause of death in China. About 80% of the HCC is associated with HBV infection, and it has been shown that incidence of HCC in patients with HBsAg positive is 100 times higher than in those with HBsAg negative. HCC is a highly vascularized tumor and angiogenesis plays a critical role in the development and invasion, which is important for HCC metastasis and reoccurrence. VEGF (vascular endothelial growth factor) and COX-2 (cyclooxygenase-2) play critical role in the development and progression of HCC. It has been shown that overexpression of VEGF and COX-2 is correlated with HCC invasion and prognosis, but it’s not clear whether the expression of VEGF and COX-2 in HCC with HBV infection is different from those without HBV infection. Therefore, understanding the relationship between HBV infection and the expression level of VEGF and COX2 in HCC can further our understanding of the molecular mechanisms for HCC arising from different etiology and provide experimental evidences for the early diagnosis and treatment of HCC.
【Methods】
1. HCC tissue samples were obtained from the 56 surgical resected HCC confirmed by pathology in our hospital from year 1996-2002. The tissues samples were separated into two groups, with HBV infection or without HBV infection which was determine by the serology and immunohistochemistry analysis of HBsAg.
2. VEGF and COX-2 expression was determined by immunohistological staining on the sections from the HCC tissue samples using the quick MaxVisionTM immunohistochemical method. The statistical analysis with theχ~2 test and Spearman Rank Order Correlation was used to determine the relationship of between VEGF and COX-2 overexpression and HBV infection.
3. Two cell lines, HeG2 and HeG2.215 with stable HBV expression were cultured and total RNA was isolated from these cells. The expression of VEGF and COX-2 in these two cell lines was determined by RT-PCR.
【Results】
1. Rapid Immunohistochemical staining shows that (1) the positive rates in VEGF and COX-2 in the HBV infected group were 78.9% and 76.3% respectively, which were higher than the group without HBV infection (50.0% and 44.4% respectively). The difference between the two groups is statistically significant (P < 0. 05). (2)VEGF positive tumors were also positive with COX-2 and the correlation analysis shows that the expression of COX-2 and VEGF is positively correlated (r=0.429,P<0.05)
2. Eletrophoresis of the RT-PCR products showed that VEGF and COX-2 expression in HepG2.215 cells was significantly higher than the HepG2 cells (P<0.05)
【Conclusion】
1. This study showed that the expression of VEGF and COX-2 in the HCC with HBV infection was significantly higher than those without HBV infection, suggesting that HBV infection upregulates the expression of VEGF and COX-2 in HCC. The overexpression of VEGF and COX-2 will promote angiogenesis in the tumors, thus enhance the proliferation and growth of the tumors, which will lead to tumor invasion and metastasis.
2. The expression of VEGF and COX-2 in HepG2.215 cells is significantly higher than the HepG2 cell, which is consistent with the immunohistochemical analysis and highly suggests that HBV infection correlates with VEGF and COX-2 overexpression. This is important for understanding the mechanisms for the HCC development and progression after HBV infection.
3. The differential expression of VEGF and COX-2 in HCC with or without HBV infection suggests a significant difference in clinical manifestation and outcome between the HCC with HBV infection and that without HBV infection and provides directions for the prevention and treatment of HCC of different etiology.
肝细胞肝癌(hepatocellular carcinoma,HCC)是世界范围内最常见的恶性肿瘤之一,居我国癌症死亡的第三位。大约80%的肝癌的发生与乙肝病毒HBV相关,流行病学研究表明HBsAg阳性患者肝癌的发生率比HBsAg阴性患者高100倍。肝细胞癌是一多血管肿瘤,新生血管在肝细胞肝癌的发生和侵袭中起关键的作用,有利于肝癌转移和复发。目前研究表明VEGF(vascular endothelial growth factor),COX-2(cyclooxygenase-2),在肝细胞癌中扮演关键角色,VEGF、COX-2的高表达与肝细胞癌的侵袭、预后相关,但VEGF、COX-2在HBV感染型肝癌和非HBV感染型肝癌中的表达是否存在差异尚不清楚。因此研究乙肝病毒HBV(hepatitis B virus)感染与肝癌组织中VEGF,COX-2的关系有助于我们进一步了解不同病因HCC的发生发展机制,为临床对HCC的早期诊断和防治提供实验依据。
【方法】
1.标本取自本院1996—2002年经手术切除并经病理学证实的石蜡包埋的原发性肝癌病理标本56例。根据血清学及免疫组化法HBsAg检查结果将其分为HBV感染组和非HBV感染组。
2.将病理切片应用采用快速免疫组化MaxVisionTM法检测标本中VEGF、COX-2的蛋白表达,采用χ2检验及spearman秩相关进行统计学分析,探讨VEGF、COX-2在HCC中的表达及其与HBV感染的关系。
3 .对HBV表达阴性的细胞株HepG2和稳定转染HBV基因并持续表达HBV的细胞株HepG2.215进行培养,用RT-PCR法检测VEGF、COX-2在各细胞株中的表达,进行比较。
【结果】
1、快速免疫组化法结果显示:(1) HBV感染组中VEGF、COX-2的阳性率分别为(78.9%)、(76.3%)高于非HBV感染组中的(50.0%)、(44.4%),差异有统计学意义(P < 0. 05)。(2)VEGF阳性的肿瘤组织COX-2也趋于阳性,相关性分析显示COX-2与VEGF的表达呈正相关(r=0.429,P<0.05)。
2. RT—PCR产物电泳结果显示,HepG2.215细胞中VEGF、COX-2 mRNA的表达显著高于HepG2细胞(P<0.05)。
【结论】
1、本研究中HBV感染型肝癌VEGF、COX-2的表达较非感染型肝癌组织明显增高,这表明HBV感染可能上调VEGF、COX-2在肝癌组织中的表达,促进肿瘤组织中的血管形成,有利于肿瘤组织的增殖和生长,促使肿瘤细胞的侵袭和转移
2、通过肝癌细胞株VEGF、COX-2表达的检测结果显示,在HepG2.215细胞中的mRNA表达明显高于HepG2细胞。这个结果与组织学研究的结果相一致,进一步证实了HBV感染与VEGF、COX-2表达存在相关性。有助于揭示HBV感染致HCC发生与发展的机制。
3、VEGF、COX-2在HBV感染型和非HBV感染型肝细胞癌组织和肝癌细胞株中的表达差异,对探讨HBV感染型与非HBV感染型肝细胞癌的临床表现和转归及探索针对不同病因肝癌的防治策略和方法提供了启示和方向。
【objective】
Hepatocellular carcinoma is one of the most common malignancies worldwide and the third leading cause of death in China. About 80% of the HCC is associated with HBV infection, and it has been shown that incidence of HCC in patients with HBsAg positive is 100 times higher than in those with HBsAg negative. HCC is a highly vascularized tumor and angiogenesis plays a critical role in the development and invasion, which is important for HCC metastasis and reoccurrence. VEGF (vascular endothelial growth factor) and COX-2 (cyclooxygenase-2) play critical role in the development and progression of HCC. It has been shown that overexpression of VEGF and COX-2 is correlated with HCC invasion and prognosis, but it’s not clear whether the expression of VEGF and COX-2 in HCC with HBV infection is different from those without HBV infection. Therefore, understanding the relationship between HBV infection and the expression level of VEGF and COX2 in HCC can further our understanding of the molecular mechanisms for HCC arising from different etiology and provide experimental evidences for the early diagnosis and treatment of HCC.
【Methods】
1. HCC tissue samples were obtained from the 56 surgical resected HCC confirmed by pathology in our hospital from year 1996-2002. The tissues samples were separated into two groups, with HBV infection or without HBV infection which was determine by the serology and immunohistochemistry analysis of HBsAg.
2. VEGF and COX-2 expression was determined by immunohistological staining on the sections from the HCC tissue samples using the quick MaxVisionTM immunohistochemical method. The statistical analysis with theχ~2 test and Spearman Rank Order Correlation was used to determine the relationship of between VEGF and COX-2 overexpression and HBV infection.
3. Two cell lines, HeG2 and HeG2.215 with stable HBV expression were cultured and total RNA was isolated from these cells. The expression of VEGF and COX-2 in these two cell lines was determined by RT-PCR.
【Results】
1. Rapid Immunohistochemical staining shows that (1) the positive rates in VEGF and COX-2 in the HBV infected group were 78.9% and 76.3% respectively, which were higher than the group without HBV infection (50.0% and 44.4% respectively). The difference between the two groups is statistically significant (P < 0. 05). (2)VEGF positive tumors were also positive with COX-2 and the correlation analysis shows that the expression of COX-2 and VEGF is positively correlated (r=0.429,P<0.05)
2. Eletrophoresis of the RT-PCR products showed that VEGF and COX-2 expression in HepG2.215 cells was significantly higher than the HepG2 cells (P<0.05)
【Conclusion】
1. This study showed that the expression of VEGF and COX-2 in the HCC with HBV infection was significantly higher than those without HBV infection, suggesting that HBV infection upregulates the expression of VEGF and COX-2 in HCC. The overexpression of VEGF and COX-2 will promote angiogenesis in the tumors, thus enhance the proliferation and growth of the tumors, which will lead to tumor invasion and metastasis.
2. The expression of VEGF and COX-2 in HepG2.215 cells is significantly higher than the HepG2 cell, which is consistent with the immunohistochemical analysis and highly suggests that HBV infection correlates with VEGF and COX-2 overexpression. This is important for understanding the mechanisms for the HCC development and progression after HBV infection.
3. The differential expression of VEGF and COX-2 in HCC with or without HBV infection suggests a significant difference in clinical manifestation and outcome between the HCC with HBV infection and that without HBV infection and provides directions for the prevention and treatment of HCC of different etiology.
引文
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84. Liu XH ,Kirschenbaum A ,Yao S ,et al. Inhibition of cyclooxygenase-2 suppresses angiogenesis and tumor growth of prostrate cancer in vivo. J Urol , 2000:164 :820-825.
85. T sujii M , Kaw ano S, DuBo is RN. Cyclooxygenase-2 expression in humancolon cancer cells increases metastatic potential. P roc N at l A cad Sci, 1997:94(7) : 3336- 3340.
86. Terence C. Tang, Ronnie T. Tumor cyclooxygenase-2 levels correlate with tumor invasiveness in human hepatocellular carcinoma. World J Gastroenterol, 2005,11;(13):1896-1902.
87. Suzuki H, Seto K. Paracrine upregulation of VEGF receptor mRNA in endothelial cells by hypoxia-exposed HepG2 cell. Am J Phusiol, 1999,276: 92-97.
88. Gallo O masini. Prognostic significance of cyclooxygenase-2 pathway and angigogenesis in head and neck squamous cell carcinoma. Hum Pathol, 2002,33:708-714.
89. Fujiwaki Iida k. Cyclooxygenase-2 expression in endometrial cancer:correlation with microvessel count and expression of vascular endothelial growth factor and thymidine phosphorylase. Hum Pathol, 2002,33:213-219.
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