乙酰肝素酶（HPSE）的蛋白表达与肺癌侵袭和转移的分子生物学研究
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摘要
目的:肿瘤的侵袭和转移是恶性肿瘤死亡的主要原因之一,但肿瘤侵袭和转移的途径和机制尚有许多不明之处有待探讨。乙酰肝素酶(heparanase,HPSE)是1999年Vlodavsky等克隆出来的一种内糖苷酶,可降解细胞外基质和基底膜中的硫酸乙酰肝素(heparansulfate,HS)。最近研究发现,HPSE在多种人类恶性肿瘤中高度表达,具有促进肿瘤细胞侵袭和转移的重要作用,并且与肿瘤新生血管的形成具有密切关系。肺癌是最常见的恶性肿瘤之一,HPSE的表达是否与肺癌的侵袭性生长和转移有关,尚未见报道。本研究通过免疫组织化学SABC法(streptavi Biotin-peroxidase complex),对一组肺癌标本HPSE蛋白表达进行检测,并结合肺癌临床病理学特征及预后进行分析,目的是:(1)探讨HPSE蛋白表达与肺癌发生、发展的关系,从而为肺癌复杂发病机理的阐明提供有意义的资料;(2)通过分析HPSE蛋白表达与肺癌临床病理学特征及预后的关系,试图寻找新的对临床有价值的肿瘤标记物,为肺癌的诊断和预后判断提供依据;(3)通过蛋白水平的研究,积累一定的经验,为进一步开展基因诊断和治疗以及抗癌药物的筛选等方面的研究探索,打下一定的基础。
方法:应用免疫组化SABC法检测HPSE在65例肺癌组织中的表达,并与癌旁组织和正常肺组织对比,同时结合肺癌的临床病理学特征及预后进行分析。
结果:免疫组化SABC法研究结果表明,肺癌组织中HPSE蛋白阳性表达率(50.8%)明显高于正常肺组织(4.6%)和癌旁组织(9.2%)(P＜0.05);不同病理类型肺癌组织中HPSE蛋白阳性表达率(48.4%、52.0%、66.7%、50.0%)均无显著性差异(P＞0.05);不同分化程度肺癌组织中HPSE蛋白阳性表达率(47.1%、47.8%、56.3%、55.6%)亦均无显著性差异(P＞0.05);Ⅲ期和Ⅳ期肺癌组织中HPSE蛋白阳性表达率(95.5%)明显高于Ⅰ期和Ⅱ期(27.9%和37.2%)(P＜0.05);生存3年以下的肺癌组织中HPSE蛋白阳性表达率(88.0%)明显高于生存3年以上者(27.8%)(P＜0.05)。
结论:HPSE蛋白的表达在肺癌发生、发展中发挥着一定作用;肺癌的发生、发展可能与HPSE促血管生成作用密切相关;HPSE可作为判断肺癌生物学行为和患者预后的一个参考指标。
OBJECTIVE: Recent researcheres have demonstrated that multiple gene changes result in tumor genesis and progression. In the complicated courses, many genes are involved, including activation of proto-oncogenes and inactivation of antioncogenes. In clinical tumor therapy , the major factor which influences patients'prognosis is the conditions of tumor invasiveness and metastasis, and tumor biological behavior is also a major element in determination of tumor therapy plan. Many tumor experts have always been working hard at the early diagnosis of tumor invasiveness and metastasis, In order to improve tumor prognosis and prolong patients'life as much as possible. Therefore, tumor markers which can provide information on the conditions of tumor invasiveness and metastasis have always been emphasized by many tumor experts and become a hot researching subject, among which is HPSE. Heparanase (HPSE) is a type of Heparin lyase which was cloned by Vlodavsky in 1991 and able to degrade the heparanase of the extracellular matrix and basement membrane. The recent research shows that HPSE is expressed highly in the malignant tumor which plays an important role in facilitating the invasion and metastasis of tumor and has a close relationship with the tumorigenesis as well. Lung cancer is the most usually malignant tumor. Whether the expression of HPSE gene relate to the invasive growth and lymph node metastasis of the lung cancer are not reported. The research tested expression of HPSE genes of 65 cases in lung cancer tissues, adjacent tissues of cancer and normal lung tissues by immunohistochemical staining so as to investigate their relationships.
METHODS: The expression of HPSE protein in 65 cases of lung cancer, adjacent tissues of cancer and normal tissues was tested by immunohistochemical SABC method and analysed by clinico-pathological characteristics and prognosis of lung cancer.
RESULTS: The results of immunohistochemical SABC method are that the rate of expression of HPSE in tumor tissues (50.8%) was significantly higher than that in adjacent tissues of cancer (9.2%) and normal tissues (4.6%) (P<0.05); It was shown that HPSE expression did significantly not correlate with the type(48.4%、52.0%、66.7%、50.0%)(P>0.05) and grade of the tumor (47.1%、47.8%、56.3%、55.6%) (P<0.05); but it correlated with the clinical stage (95.5%) (P<0.05) and survival time of the patients (88.0%) (P<0.05).
CONCLUSIONS: The results suggested that there be overexpression of HPSE in lung cancer tissues, and which perhaps participate in regulation of tumorigenesis , progression in lung cancer . The expression of HPSE protein be used as an useful marker of the biological behavior of lung cancer and as an independent prognosis factor for the patients with lung cancer.
方法:应用免疫组化SABC法检测HPSE在65例肺癌组织中的表达,并与癌旁组织和正常肺组织对比,同时结合肺癌的临床病理学特征及预后进行分析。
结果:免疫组化SABC法研究结果表明,肺癌组织中HPSE蛋白阳性表达率(50.8%)明显高于正常肺组织(4.6%)和癌旁组织(9.2%)(P＜0.05);不同病理类型肺癌组织中HPSE蛋白阳性表达率(48.4%、52.0%、66.7%、50.0%)均无显著性差异(P＞0.05);不同分化程度肺癌组织中HPSE蛋白阳性表达率(47.1%、47.8%、56.3%、55.6%)亦均无显著性差异(P＞0.05);Ⅲ期和Ⅳ期肺癌组织中HPSE蛋白阳性表达率(95.5%)明显高于Ⅰ期和Ⅱ期(27.9%和37.2%)(P＜0.05);生存3年以下的肺癌组织中HPSE蛋白阳性表达率(88.0%)明显高于生存3年以上者(27.8%)(P＜0.05)。
结论:HPSE蛋白的表达在肺癌发生、发展中发挥着一定作用;肺癌的发生、发展可能与HPSE促血管生成作用密切相关;HPSE可作为判断肺癌生物学行为和患者预后的一个参考指标。
OBJECTIVE: Recent researcheres have demonstrated that multiple gene changes result in tumor genesis and progression. In the complicated courses, many genes are involved, including activation of proto-oncogenes and inactivation of antioncogenes. In clinical tumor therapy , the major factor which influences patients'prognosis is the conditions of tumor invasiveness and metastasis, and tumor biological behavior is also a major element in determination of tumor therapy plan. Many tumor experts have always been working hard at the early diagnosis of tumor invasiveness and metastasis, In order to improve tumor prognosis and prolong patients'life as much as possible. Therefore, tumor markers which can provide information on the conditions of tumor invasiveness and metastasis have always been emphasized by many tumor experts and become a hot researching subject, among which is HPSE. Heparanase (HPSE) is a type of Heparin lyase which was cloned by Vlodavsky in 1991 and able to degrade the heparanase of the extracellular matrix and basement membrane. The recent research shows that HPSE is expressed highly in the malignant tumor which plays an important role in facilitating the invasion and metastasis of tumor and has a close relationship with the tumorigenesis as well. Lung cancer is the most usually malignant tumor. Whether the expression of HPSE gene relate to the invasive growth and lymph node metastasis of the lung cancer are not reported. The research tested expression of HPSE genes of 65 cases in lung cancer tissues, adjacent tissues of cancer and normal lung tissues by immunohistochemical staining so as to investigate their relationships.
METHODS: The expression of HPSE protein in 65 cases of lung cancer, adjacent tissues of cancer and normal tissues was tested by immunohistochemical SABC method and analysed by clinico-pathological characteristics and prognosis of lung cancer.
RESULTS: The results of immunohistochemical SABC method are that the rate of expression of HPSE in tumor tissues (50.8%) was significantly higher than that in adjacent tissues of cancer (9.2%) and normal tissues (4.6%) (P<0.05); It was shown that HPSE expression did significantly not correlate with the type(48.4%、52.0%、66.7%、50.0%)(P>0.05) and grade of the tumor (47.1%、47.8%、56.3%、55.6%) (P<0.05); but it correlated with the clinical stage (95.5%) (P<0.05) and survival time of the patients (88.0%) (P<0.05).
CONCLUSIONS: The results suggested that there be overexpression of HPSE in lung cancer tissues, and which perhaps participate in regulation of tumorigenesis , progression in lung cancer . The expression of HPSE protein be used as an useful marker of the biological behavior of lung cancer and as an independent prognosis factor for the patients with lung cancer.
引文
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7 Dong J , Kukula AK,Toyoshima M , et al . Genomic organization and chromosome localization of the newly identified human heparanase gene [J] . Gene,2000,253(2):171-178.
8 Pillarisetti S , Paka L , Sasaki A , et al. Endothelial cell heparanase modulation of lipoprotein lipase activity. Endence that heparan sulfate oligosaccharide is an extracellular chaperone[J]. J Biol Chem, 1997 ,272 (25): 15753-15759.
9 Tang WW. Glomerular extracellular matrix accumulation in experimental anti-GBM Ab glomerulonephritis[J]. Nephron, 2000 ,84 (1): 40-50.
10 Graham LD. Comparison of the heparanase enzymes from mouse melanoma cells ,mouse macrophages and human platelets [J] . Biochem Mol Biol , 1996 , 39(14): 563-571.
11 Vlodavsky I, Elkin M , Pappo O , et al. Mammalian heparanase as mediator of tumor metastasis and angiogenesis[J]. Isr Med Assoc J ,2000 , 2 (Suppl): 37-45.
12 Miao HQ , Ornitz DM ,Aingorn E , et al . Modulation of fibroblast growth factor22 receptor binding ,dimerization signaling ,and angiogenic activity by synthetic heparin2mimiclig polyanionic compound[J]. J Clin Invest, 1997 ; 99 (7): 1565-1575.
13 Ikuta M , Podyma KA , Maruyama K. Expression of heparanase in oral cancer cell lines and oral cancer tissues[J]. Oral Oncol, 2001,37 (2): 177-184.
14 Walch ET , Marchetti D. Role of neurotrophins and neurotrophins receptors in the in vitro invasion and heparanase production of human prostate cancer cells [J] . Clin Exp Metastasis, 1999 ,17 (4):.307-314.
15 Whitelock JM , Murdoch AD , Iozzo RV , et al . The degradation of human endothelial cell2derived perlecan and release of bound basic fibroblast growth factor by stromelysis , collagenase , plasmin , and heparanases[J]. J Biol Chem , 1996 ; 271 (17): 10079-10086.
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18 Miao HQ , Elkin M , Aingorn E , et al . Inhibition of heparanase activity and tumor meyastasis by laminarin sulfate and synthetic phosphorothioate[J] . Int J Cancer, 1999 , 83 (3) :424-431.
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21 Kim AW, Xu X , Hollinger EF , et al. Human heparanase-1 gene expression in pancreatic adenocarcinoma[J]. J Gastrointest Surg, 2002 , 6 (2): 167-172.
22 Kuniyasu H , Chihara Y, Kubozoe T , et al. Co-expression of CD44v3 and heparanase is correlated with metastasis of human colon cancer[J] . Int J Mol Med , 2002,10(3) :333-337.
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2 Vlodavsky I , Friemann Y, Elkin M , et al . Mammalian heparanase :gene cloning ..expression and function in tumor progression and metastasis [J]. Nat Med , 1999, 5 (7): 793-802.
3 Toyoshima M , Nakajima M. Human heparanase [J]. J Biol Chem ,1999 , 274 (34): 24153-24160.
4 Vaday GG, Lider O. Extracellular matrix moieties , cytokines , and enzymes :dynamic effects on immune cell behavior and inflammation[J]. J Leuk Biol, 2000,67(2): 149-158.
5 Hulett MD , Freeman C , Hamdorf BJ , et al . Cloning of mammalian heparanase , an important enzyme in tumor invasion and metastasis [J]. Nat Med , 1999, 5 (7): 803-809.
6 Marchetti D ,Li J ,Shen R , et al. Astrocytes contribute to the brain-metastatic specificity of melanoma cells by producing heparanase [J].Cancer Res ,2000 ,60 (17): 4767-4770.
7 Dong J , Kukula AK,Toyoshima M , et al . Genomic organization and chromosome localization of the newly identified human heparanase gene [J] . Gene,2000,253(2):171-178.
8 Pillarisetti S , Paka L , Sasaki A , et al. Endothelial cell heparanase modulation of lipoprotein lipase activity. Endence that heparan sulfate oligosaccharide is an extracellular chaperone[J]. J Biol Chem, 1997 ,272 (25): 15753-15759.
9 Tang WW. Glomerular extracellular matrix accumulation in experimental anti-GBM Ab glomerulonephritis[J]. Nephron, 2000 ,84 (1): 40-50.
10 Graham LD. Comparison of the heparanase enzymes from mouse melanoma cells ,mouse macrophages and human platelets [J] . Biochem Mol Biol , 1996 , 39(14): 563-571.
11 Vlodavsky I, Elkin M , Pappo O , et al. Mammalian heparanase as mediator of tumor metastasis and angiogenesis[J]. Isr Med Assoc J ,2000 , 2 (Suppl): 37-45.
12 Miao HQ , Ornitz DM ,Aingorn E , et al . Modulation of fibroblast growth factor22 receptor binding ,dimerization signaling ,and angiogenic activity by synthetic heparin2mimiclig polyanionic compound[J]. J Clin Invest, 1997 ; 99 (7): 1565-1575.
13 Ikuta M , Podyma KA , Maruyama K. Expression of heparanase in oral cancer cell lines and oral cancer tissues[J]. Oral Oncol, 2001,37 (2): 177-184.
14 Walch ET , Marchetti D. Role of neurotrophins and neurotrophins receptors in the in vitro invasion and heparanase production of human prostate cancer cells [J] . Clin Exp Metastasis, 1999 ,17 (4):.307-314.
15 Whitelock JM , Murdoch AD , Iozzo RV , et al . The degradation of human endothelial cell2derived perlecan and release of bound basic fibroblast growth factor by stromelysis , collagenase , plasmin , and heparanases[J]. J Biol Chem , 1996 ; 271 (17): 10079-10086.
16 Parish CR , Freeman C , Brown KJ , et al . Identification of sulfated oligosaccharide2based inhibitors of tumor growth and metastasis using novel in vitro for angiogensis and heparanase activity[J]. Cancer Res , 1999 , 59 (14): 3433-3441.
17 Bentolila A ,Vlodavsky I , Ishai MR , et al . Poly (N2acryi amion acids) :A New class of biologically active polyanions[J]. J Med Chem ,2000 ,43 :2591-2600.
18 Miao HQ , Elkin M , Aingorn E , et al . Inhibition of heparanase activity and tumor meyastasis by laminarin sulfate and synthetic phosphorothioate[J] . Int J Cancer, 1999 , 83 (3) :424-431.
19 Marchetti D , Reiland J , Erwin B , et al. Inhibition of heparanase activity and heparanase-induced angiogenesis by suramin analogues[J] . Int J Cancer , 2003 , 104 (2): 167-174.
20 Koliopanos A , Friess H , Kleeff J , et al. Heparanase expression in primary and metastatic pancreatic cancer[J]. Cancer Res, 2001 , 61(12) :4655-4659.
21 Kim AW, Xu X , Hollinger EF , et al. Human heparanase-1 gene expression in pancreatic adenocarcinoma[J]. J Gastrointest Surg, 2002 , 6 (2): 167-172.
22 Kuniyasu H , Chihara Y, Kubozoe T , et al. Co-expression of CD44v3 and heparanase is correlated with metastasis of human colon cancer[J] . Int J Mol Med , 2002,10(3) :333-337.
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