VEGF、PLGF、P53的表达与肝细胞性肝癌新生血管的相关性研究
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摘要
目的：研究血管内皮生长因(VEGF)、胎盘生长因子(PLGF)和p53蛋白表达与原发性肝细胞肝癌(HCC)的关系,初步探讨VEGF、PLGF、P53之间的联合表达与肝细胞性肝癌的发生的关系。
方法：用免疫组织化学SP法.检测39例HCC组织VEGF、PLGF及p53蛋白的表达情况,计数微血管密度(MVD),并与临床病理指标比较分析。
结果：39例HCC中VEGF、PLGF和p53蛋白阳性表达分别为84.62%和76.92%和79.48%; VEGF蛋白的表达主要见于肿瘤细胞的胞浆或胞膜,在肝癌中其表达也具有明显的异质性,为弥漫性或集中表达于癌巢,VEGF表达较强,但与肿瘤大小、AFP水平及病理分级无相关性。PLGF蛋白的表达主要见于肿瘤细胞的胞浆或胞膜,肝细胞癌有浸润转移组的PLGF阳性表达率高于无转移组,PLGF阳性表达与肝细胞癌的大小及AFP水平无显著性差异,随着病理分级的增加,PLGF阳性表达率增高。P53蛋白阳性表达在细胞核内呈棕色,着色细胞大多呈片或弥漫分布,p53蛋白的表达与病理分级明显相关(P值<0.05),且和HBsAg及转移倾向明显相关(P值<0.01),与AFP水平和肿瘤直径无关。HCC组织中微血管经CD34染色后呈棕色或棕褐色,阳性染色局限于血管内皮胞质及胞膜,呈弥漫性分布。39个病灶MVD平均值是50.20±13.89。经统计学分析MVD表达与病理分极、AFP高低、转移倾向及HBsAg不同而不同,差异有统计学意义,但与肿瘤大小无显著差异。VEGF与PLGF在HCC中的阳性表达具有一定的关系(χ2=7.59,P=0.018,表3)。肿瘤组织VEGF阳性、阴性表达时MVD分别为52.67±13.65和37.25±5.55,差异明显(t=-3.124, P= 0.003); PLGF阳性、阴性表达时MVD平均值分别为5 1±13.77和40.36±7.60,也同样存在差异(t=2.462,P=0.046)。本组肝癌组织标本中联合表达情况表明多种因子联合表达与分化程度、AFP水平、乙肝病毒感染及转移倾向明显相关。VEGF与p53,VEGF与PLGF表达呈非常显著的正相关,P<0.01。经多因素分析,VEGF, p53, PLGF之间亦有非常显著相关性,P<0.01。
结论：HCC组织中VEGF、PLGF、p53蛋白过表达.通过促进HCC肿瘤血管的生成而促进HCC的生长浸润及转移.p53和PLGF及VEGF可作为评价HCC生物学行为的重要指标。HCC中VEGF、PLGF表达与p53基因有显著的相关性,可能受其调控。VEGF, P53, PLGF三者协同表达与HCC的恶性程度,侵袭和转移能力有关。
Objectiv:To investigate the correlation of the expression of vascular endothelial growth factor (VEGF), placental growth factor (PLGF) and p53 protein with primary hepatocellular carcinoma (HCC) and to study the probably mechanism of the co-expression of VEGF, PLGF, P53 and the occurrence of the HCC.
Methods The expressions of VEGF, PLGF and the p53 protein in the 39 patients suffering from HCC were detected by Immunohistochemical SP and MVD were quantitated in HCC tissues,compared with clinicopathological parameters were assayed.
Results:The expression rates of VEGF, PLGF, and p53 protein in the 39 patients suffering from HCC was 84.62% and 76.92% and 79.48% respectively; The expressions of VEGF protein was mainly found in the cytoplasm or membrane of tumor cells, there was significant differences qualitative in its expression diffused or concentrated in the cancer nest which closed to the margin or envelope of the tumor.The degree of VEGF expression was significantly high, but it had no correlation with tumor size, AFP and histological grade. The expressions of PLGF protein was mainly found in the cytoplasm or membrane of tumor cells, The expression rates of PLGF was significantly higher in the group with metastasis and recurrence than without metastasis and recurrence, There was no significant correlation between the positive expression of PLGF in hepatocellular carcinoma and tumor size and AFP. The expression rates of PLGF increased with the degree of pathological grade. The expressions of P53 protein in the nucleus showed brown, the colored cells showed mostly diffuse distribution, There was significant correlation between p53 protein and tumor grade (P<0.05), HBsAg and metastatic potential (P< 0.01), There was no significant correlation between p53 protein and the AFP and tumor size. HCC tissues by CD34 staining capillaries brown or brown, the positive staining confined to the cytoplasm and membrane of vascular endothelial form with diffuse distribution. The mean of MVD in 39 cases was 50.20±13.89. There was a significant difference in MVD expression and pathological grade, AFP, metastatic potential and HBsAg, the difference was statistically significant, but no significant difference in tumor size. There was correlation between the expressions of VEGF and PLGF in HCC (χ2= 7.59, P= 0.018, Table 3). MVD was 52.67±13.65 and 37.25±5.55 respectively, when the positive or negative expression of VEGF,the differences are significant (t=-3.124, P= 0.003); MVD was 51±13.77 and 40.36±7.60 respectively, when the positive or negative expression of PLGF the differences are significant (t= 2.462, P= 0.046). The co-expression of in liver tissue specimens showed that There was significant correlation between the expression of a variety of joint co-expression and differentiation factors, AFP, hepatitis B virus infection and metastatic potential. There was significant correlation between VEGF and p53 or between VEGF and PLGF P<0.01. After multivariate analysis, There was also significant correlation in VEGF, p53, PLGF, P＜0.01.
Conclusion:There was overexpression of VEGF, PLGF, p53 protein in HCC tissue. The promotion of the growth and metastasis in HCC was made by promoting tumor angiogenesis. p53, PLGF and VEGF was responsible of an important indicator of biological behavior. HCC, The expression of VEGF, PLGF and p53 gene has significant correlation. The co-expression of VEGF, P53, PLGF in HCC has significant correlation with the degree of malignancy, metastasis and recurrence.
方法：用免疫组织化学SP法.检测39例HCC组织VEGF、PLGF及p53蛋白的表达情况,计数微血管密度(MVD),并与临床病理指标比较分析。
结果：39例HCC中VEGF、PLGF和p53蛋白阳性表达分别为84.62%和76.92%和79.48%; VEGF蛋白的表达主要见于肿瘤细胞的胞浆或胞膜,在肝癌中其表达也具有明显的异质性,为弥漫性或集中表达于癌巢,VEGF表达较强,但与肿瘤大小、AFP水平及病理分级无相关性。PLGF蛋白的表达主要见于肿瘤细胞的胞浆或胞膜,肝细胞癌有浸润转移组的PLGF阳性表达率高于无转移组,PLGF阳性表达与肝细胞癌的大小及AFP水平无显著性差异,随着病理分级的增加,PLGF阳性表达率增高。P53蛋白阳性表达在细胞核内呈棕色,着色细胞大多呈片或弥漫分布,p53蛋白的表达与病理分级明显相关(P值<0.05),且和HBsAg及转移倾向明显相关(P值<0.01),与AFP水平和肿瘤直径无关。HCC组织中微血管经CD34染色后呈棕色或棕褐色,阳性染色局限于血管内皮胞质及胞膜,呈弥漫性分布。39个病灶MVD平均值是50.20±13.89。经统计学分析MVD表达与病理分极、AFP高低、转移倾向及HBsAg不同而不同,差异有统计学意义,但与肿瘤大小无显著差异。VEGF与PLGF在HCC中的阳性表达具有一定的关系(χ2=7.59,P=0.018,表3)。肿瘤组织VEGF阳性、阴性表达时MVD分别为52.67±13.65和37.25±5.55,差异明显(t=-3.124, P= 0.003); PLGF阳性、阴性表达时MVD平均值分别为5 1±13.77和40.36±7.60,也同样存在差异(t=2.462,P=0.046)。本组肝癌组织标本中联合表达情况表明多种因子联合表达与分化程度、AFP水平、乙肝病毒感染及转移倾向明显相关。VEGF与p53,VEGF与PLGF表达呈非常显著的正相关,P<0.01。经多因素分析,VEGF, p53, PLGF之间亦有非常显著相关性,P<0.01。
结论：HCC组织中VEGF、PLGF、p53蛋白过表达.通过促进HCC肿瘤血管的生成而促进HCC的生长浸润及转移.p53和PLGF及VEGF可作为评价HCC生物学行为的重要指标。HCC中VEGF、PLGF表达与p53基因有显著的相关性,可能受其调控。VEGF, P53, PLGF三者协同表达与HCC的恶性程度,侵袭和转移能力有关。
Objectiv:To investigate the correlation of the expression of vascular endothelial growth factor (VEGF), placental growth factor (PLGF) and p53 protein with primary hepatocellular carcinoma (HCC) and to study the probably mechanism of the co-expression of VEGF, PLGF, P53 and the occurrence of the HCC.
Methods The expressions of VEGF, PLGF and the p53 protein in the 39 patients suffering from HCC were detected by Immunohistochemical SP and MVD were quantitated in HCC tissues,compared with clinicopathological parameters were assayed.
Results:The expression rates of VEGF, PLGF, and p53 protein in the 39 patients suffering from HCC was 84.62% and 76.92% and 79.48% respectively; The expressions of VEGF protein was mainly found in the cytoplasm or membrane of tumor cells, there was significant differences qualitative in its expression diffused or concentrated in the cancer nest which closed to the margin or envelope of the tumor.The degree of VEGF expression was significantly high, but it had no correlation with tumor size, AFP and histological grade. The expressions of PLGF protein was mainly found in the cytoplasm or membrane of tumor cells, The expression rates of PLGF was significantly higher in the group with metastasis and recurrence than without metastasis and recurrence, There was no significant correlation between the positive expression of PLGF in hepatocellular carcinoma and tumor size and AFP. The expression rates of PLGF increased with the degree of pathological grade. The expressions of P53 protein in the nucleus showed brown, the colored cells showed mostly diffuse distribution, There was significant correlation between p53 protein and tumor grade (P<0.05), HBsAg and metastatic potential (P< 0.01), There was no significant correlation between p53 protein and the AFP and tumor size. HCC tissues by CD34 staining capillaries brown or brown, the positive staining confined to the cytoplasm and membrane of vascular endothelial form with diffuse distribution. The mean of MVD in 39 cases was 50.20±13.89. There was a significant difference in MVD expression and pathological grade, AFP, metastatic potential and HBsAg, the difference was statistically significant, but no significant difference in tumor size. There was correlation between the expressions of VEGF and PLGF in HCC (χ2= 7.59, P= 0.018, Table 3). MVD was 52.67±13.65 and 37.25±5.55 respectively, when the positive or negative expression of VEGF,the differences are significant (t=-3.124, P= 0.003); MVD was 51±13.77 and 40.36±7.60 respectively, when the positive or negative expression of PLGF the differences are significant (t= 2.462, P= 0.046). The co-expression of in liver tissue specimens showed that There was significant correlation between the expression of a variety of joint co-expression and differentiation factors, AFP, hepatitis B virus infection and metastatic potential. There was significant correlation between VEGF and p53 or between VEGF and PLGF P<0.01. After multivariate analysis, There was also significant correlation in VEGF, p53, PLGF, P＜0.01.
Conclusion:There was overexpression of VEGF, PLGF, p53 protein in HCC tissue. The promotion of the growth and metastasis in HCC was made by promoting tumor angiogenesis. p53, PLGF and VEGF was responsible of an important indicator of biological behavior. HCC, The expression of VEGF, PLGF and p53 gene has significant correlation. The co-expression of VEGF, P53, PLGF in HCC has significant correlation with the degree of malignancy, metastasis and recurrence.
引文
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2. FolkmanJ,ShingY.Angiogenesis[J].JBiolChem,1992,267(16):10931-10934.
3. OkamotoH,OhigashiH,NakamoriS,etal.Reciprocal functionsofLiver tumor cells and end othelialcells:involvement of end othelialcell migration and tumor proliferationata primary siteindistantmetas2tasis[J].EurSurgRes,2000,32(6):374-379
4. HanahanD,FolkmanJ.Patternsandemergingmechanismsoftheangiogenicswitchduri ngtumorigenes[J].Cell,1996,86(3):353-364.
5. XU Y. Regulation of p53 responses by post-translational modFications[J]. Cell Death Differ,2003,10(4):400-403.
6. SAGAR SENGUPTA, CURTIS C. Harris. P53:Traffic cop at the crossroads of repair and rec0mbina￡i0n[J]. Nat Rev Mol Cell Biol,2005,6(1):44-55.
7. ATFARDI LD. 111e role of p53 - mediated apoptosis as a crucial anti-tumor response to genomic instability:lessons from mouse models. [J]Murat Res, 2005,569(1-2):145-157.
8. Chang SC, Lin JK, unTC, et al. Genetic alteration of p53, but not overexpression of intratumoral p53 protein, or serum p53 antibody is a prognostic factor in sporadic colorectal adenocarcinoma[J]. Int J Oneol,2005,26(1):65-75.
9. Bergqvist M, Brattstrom D, Lal'sson A, et al. The role of circulating anti——p53 antibodies in patients with advanced non——small cell lung cancer and their correlation to clinical parameters and survival f J 1. BMC Cancer,2004,14(4): 66.
10.卢勤,滕皋军.p53基因治疗肿瘤的研究进展[J].中华放射学杂志,2000,34(10)：659-661.
11.龚玲,景钊,邹长林.乙肝相关性肝癌组织中p27、p53及增殖细胞核抗原的表达[J].中国基层医药,2007,14(1)：96-97.
12.任勇,陈寿松,李擒龙,等.肝细胞肝癌VEGF与p53的表达及其意义[J].华南国防医学杂志,2006,20(6)：25-26.
13.喻宏,钟仁华,黄振林.P53、AR、ER在原发性肝癌、癌旁组织中的表达及意义[J].国际医药卫生导报,2006,12(24)：12-14.
14.张志培,程庆书，黄立军,等.HCVC蛋白、p53、Mdm2、p14和p21在原发 性肝癌中的表达及相关性[J].现代肿瘤医学,2006,14(10)：1252-1255.
15.官泳松,刘源,贺庆,等.P53抗体与原发性肝癌临床特征的关系[J].世界华人消化杂志,2007,15(3)：246-253.
16. Aleria V,Pajusola K,Kumar V,et al.Circulation,1996,93:1493.
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