乙酰肝素酶mRNA在直肠癌组织中的表达及其临床意义
摘要
目的:研究HPAmRNA在直肠癌组织中的表达,探讨其与直肠癌分化、转移及预后的关系。
方法:采用RT-PCR方法检测40例直肠癌组织、癌旁正常组织、转移淋巴结、非转移淋巴结组织与对应远端正常肠黏膜组织中HPAmRNA表达情况,并分析其与直肠癌临床病理参数关系。
结果:
GAPDH在各标本中都有表达。在直肠癌组中,40例直肠癌组织标本中有27例HPAmRNA表达阳性,阳性率为67.5%;在转移淋巴结组中,有35例HPAmRNA表达阳性,阳性率为87.5%;癌旁正常组织组中无一例HPAmRNA表达阳性,阳性率为0.0%;非转移淋巴结组织中仅有一例表达阳性,阳性率为2.5%;对照组仅有一例HPAmRNA表达阳性,阳性率为2.5%。其中直肠癌组及转移淋巴结组HPAmRNA表达阳性率明显高于癌旁正常组织组、非转移淋巴结组及对照组(P<0.05),癌旁正常组织组、非转移淋巴结组及对照组HPAmRNA表达阳性率差异无显著性(P>0.05),转移淋巴结组HPAmRNA表达阳性率明显高非转移淋巴结组(P<0.05),而直肠癌组与转移淋巴结组比较HPAmRNA表达阳性率低于转移淋巴结组(P<0.05)。
在40例直肠癌组织中,肿瘤侵出外膜和肿瘤局限在外膜内的HPAmRNA阳性表达率分别为80.0%、30.0%,两组差异有显著性(P<0.05)。直肠癌Ⅲ、Ⅳ期HPAmRNA的阳性表达率为89.5%,明显高于Ⅰ、Ⅱ期(47.6%)(P<0.05),HPAmRNA表达在中晚期发生转移的直肠癌组织中表达明显增加;而HPAmRNA表达与患者性别、年龄及肿瘤分化程度无关(P>0.05)。
40例直肠癌组织标本中19例有淋巴结转移,其中16例HPAmRNA表达阳性,HPAmRNA阳性表达率为84.2%;21例直肠癌无淋巴结转移,其中11例HPAmRNA表达阳性,HPAmRNA阳性表达率为52.4%,直肠癌发生淋巴结转移HPAmRNA表达明显高于未发生淋巴结转移(P<0.05)。40例直肠癌中有6例伴有远处转移,HPAmRNA全部表达阳性,阳性表达率100%,呈高表达;40枚转移淋巴结35枚HPAmRNA表达阳性,阳性表达率87.5%;40枚无转移淋巴结1枚HPA表达阳性,阳性表达率2.5%,淋巴结转移组的HPAmRNA阳性表达率明显高于无转移淋巴结组(P<0.05)。
结论:
(1)HPA表达是直肠组织癌变后期现象,可能为直肠癌组织生长及浸润转移演变过程中的重要因素。
(2)HPA表达与患者年龄、性别及肿瘤细胞分化无明确相关。
(3)HPA与直肠癌肿瘤浸润深度相关,HPA参与直肠癌直接浸润扩散、血液系统转移及淋巴结转移过程,影响直肠癌临床分期。
Objective: To study the expression of heparanase mRNA in rectal cancer and it’s relationship with differentiation ,metastasis and clinical prognosis.
Methods: RT-PCR was used to detecting the expression of heparanase mRNA in 40 rectal cancer tissue, adjacent normal tissue, metastatic lymph nodes, non-metastatic lymph node tissues, and distant normal mucosa,then analyzed its relationship with clinicopathological parameters.
Results: GAPDH are expressed in all specimens. In the cancer group, 27 cases HPAmRNA expression was positive in 40 cases of rectal cancer specimens, the positive rate was 67.5%; in the metastatic lymph node group, 35 cases HPAmRNA expression was positive, the positive rate was 87.5%; adjacent normal tissue group none of the HPAmRNA expression, the positive rate was 0.0%; in non-metastatic lymph node tissue , only one case expression was positive, the positive rate was 2.5%; the control group only one case HPAmRNA expression, the positive rate was 2.5%. Cancer group and metastatic lymph node group HPAmRNA positive rate was significantly higher than in adjacent normal tissue group, non-metastatic lymph nodes and the control group (P <0.05), adjacent normal tissue group, non-metastatic lymph nodes and control groups HPAmRNA expression rate was no significant difference (P> 0.05), lymph node group HPAmRNA positive rate was significantly higher non-metastatic lymph node group (P <0.05), while the cancer group compared with lymph node positive rate lower than HPAmRNA lymph node metastasis group (P <0.05).
In the 40 cases of rectal cancer, tumor invasion of the pulp and tumor confined to the serous membrane of patients within the HPAmRNA positive rate was 80.0%, 30.0%, the difference was significant (P <0.05). CancerⅢ,Ⅳpatients with positive expression HPAmRNA 89.5%, significantly higher thanⅠ,Ⅱof patients (47.6%) (P <0.05), HPAmRNA expression occurred in the transfer of advanced rectal cancer was significantly increased; The HPAmRNA expression and patient gender, age and tumor histological grade (P> 0.05).
40 cases of rectal cancer tissues with lymph node metastasis in 19 cases, 16 patients HPAmRNA expression, HPAmRNA positive rate was 84.2%; 21 cases of rectal cancer without lymph node metastasis, 11 patients HPAmRNA expression, HPAmRNA positive rate 52.4% incidence of lymph node metastasis was significantly higher than in patients with HPAmRNA lymph node metastasis (P <0.05). 40 cases of rectal cancer, including 6 patients with distant metastasis, HPAmRNA all show positive. Positive expression rate of 100%, showing high expression; 40 metastatic lymph node 35 HPAmRNA expression, positive expression rate of 90%; 15 lymph nodes a positive expression of HPA, 6.67% positive rate of lymph node metastasis of HPA mRNA expression was significantly higher than those without lymph node metastasis (P <0.05); visible HPA mRNA expression increased in the lymph node metastasis in rectal cancer.
Conclusion:
(1) The expression of HPA is the presence or increased expression of the phenomenon of late rectal cancer, may be the evolution of growth and metastasis of important factors.
(2) The expression of HPA have nothing with the patients’age, sex, and tumor cell differentiation.
(3) HPA affect cancer depth of invasion, HPA directly involved in cancer invasion and proliferation of lymph node metastasis and blood system, HPA affect the clinical staging of rectal cancer.
方法:采用RT-PCR方法检测40例直肠癌组织、癌旁正常组织、转移淋巴结、非转移淋巴结组织与对应远端正常肠黏膜组织中HPAmRNA表达情况,并分析其与直肠癌临床病理参数关系。
结果:
GAPDH在各标本中都有表达。在直肠癌组中,40例直肠癌组织标本中有27例HPAmRNA表达阳性,阳性率为67.5%;在转移淋巴结组中,有35例HPAmRNA表达阳性,阳性率为87.5%;癌旁正常组织组中无一例HPAmRNA表达阳性,阳性率为0.0%;非转移淋巴结组织中仅有一例表达阳性,阳性率为2.5%;对照组仅有一例HPAmRNA表达阳性,阳性率为2.5%。其中直肠癌组及转移淋巴结组HPAmRNA表达阳性率明显高于癌旁正常组织组、非转移淋巴结组及对照组(P<0.05),癌旁正常组织组、非转移淋巴结组及对照组HPAmRNA表达阳性率差异无显著性(P>0.05),转移淋巴结组HPAmRNA表达阳性率明显高非转移淋巴结组(P<0.05),而直肠癌组与转移淋巴结组比较HPAmRNA表达阳性率低于转移淋巴结组(P<0.05)。
在40例直肠癌组织中,肿瘤侵出外膜和肿瘤局限在外膜内的HPAmRNA阳性表达率分别为80.0%、30.0%,两组差异有显著性(P<0.05)。直肠癌Ⅲ、Ⅳ期HPAmRNA的阳性表达率为89.5%,明显高于Ⅰ、Ⅱ期(47.6%)(P<0.05),HPAmRNA表达在中晚期发生转移的直肠癌组织中表达明显增加;而HPAmRNA表达与患者性别、年龄及肿瘤分化程度无关(P>0.05)。
40例直肠癌组织标本中19例有淋巴结转移,其中16例HPAmRNA表达阳性,HPAmRNA阳性表达率为84.2%;21例直肠癌无淋巴结转移,其中11例HPAmRNA表达阳性,HPAmRNA阳性表达率为52.4%,直肠癌发生淋巴结转移HPAmRNA表达明显高于未发生淋巴结转移(P<0.05)。40例直肠癌中有6例伴有远处转移,HPAmRNA全部表达阳性,阳性表达率100%,呈高表达;40枚转移淋巴结35枚HPAmRNA表达阳性,阳性表达率87.5%;40枚无转移淋巴结1枚HPA表达阳性,阳性表达率2.5%,淋巴结转移组的HPAmRNA阳性表达率明显高于无转移淋巴结组(P<0.05)。
结论:
(1)HPA表达是直肠组织癌变后期现象,可能为直肠癌组织生长及浸润转移演变过程中的重要因素。
(2)HPA表达与患者年龄、性别及肿瘤细胞分化无明确相关。
(3)HPA与直肠癌肿瘤浸润深度相关,HPA参与直肠癌直接浸润扩散、血液系统转移及淋巴结转移过程,影响直肠癌临床分期。
Objective: To study the expression of heparanase mRNA in rectal cancer and it’s relationship with differentiation ,metastasis and clinical prognosis.
Methods: RT-PCR was used to detecting the expression of heparanase mRNA in 40 rectal cancer tissue, adjacent normal tissue, metastatic lymph nodes, non-metastatic lymph node tissues, and distant normal mucosa,then analyzed its relationship with clinicopathological parameters.
Results: GAPDH are expressed in all specimens. In the cancer group, 27 cases HPAmRNA expression was positive in 40 cases of rectal cancer specimens, the positive rate was 67.5%; in the metastatic lymph node group, 35 cases HPAmRNA expression was positive, the positive rate was 87.5%; adjacent normal tissue group none of the HPAmRNA expression, the positive rate was 0.0%; in non-metastatic lymph node tissue , only one case expression was positive, the positive rate was 2.5%; the control group only one case HPAmRNA expression, the positive rate was 2.5%. Cancer group and metastatic lymph node group HPAmRNA positive rate was significantly higher than in adjacent normal tissue group, non-metastatic lymph nodes and the control group (P <0.05), adjacent normal tissue group, non-metastatic lymph nodes and control groups HPAmRNA expression rate was no significant difference (P> 0.05), lymph node group HPAmRNA positive rate was significantly higher non-metastatic lymph node group (P <0.05), while the cancer group compared with lymph node positive rate lower than HPAmRNA lymph node metastasis group (P <0.05).
In the 40 cases of rectal cancer, tumor invasion of the pulp and tumor confined to the serous membrane of patients within the HPAmRNA positive rate was 80.0%, 30.0%, the difference was significant (P <0.05). CancerⅢ,Ⅳpatients with positive expression HPAmRNA 89.5%, significantly higher thanⅠ,Ⅱof patients (47.6%) (P <0.05), HPAmRNA expression occurred in the transfer of advanced rectal cancer was significantly increased; The HPAmRNA expression and patient gender, age and tumor histological grade (P> 0.05).
40 cases of rectal cancer tissues with lymph node metastasis in 19 cases, 16 patients HPAmRNA expression, HPAmRNA positive rate was 84.2%; 21 cases of rectal cancer without lymph node metastasis, 11 patients HPAmRNA expression, HPAmRNA positive rate 52.4% incidence of lymph node metastasis was significantly higher than in patients with HPAmRNA lymph node metastasis (P <0.05). 40 cases of rectal cancer, including 6 patients with distant metastasis, HPAmRNA all show positive. Positive expression rate of 100%, showing high expression; 40 metastatic lymph node 35 HPAmRNA expression, positive expression rate of 90%; 15 lymph nodes a positive expression of HPA, 6.67% positive rate of lymph node metastasis of HPA mRNA expression was significantly higher than those without lymph node metastasis (P <0.05); visible HPA mRNA expression increased in the lymph node metastasis in rectal cancer.
Conclusion:
(1) The expression of HPA is the presence or increased expression of the phenomenon of late rectal cancer, may be the evolution of growth and metastasis of important factors.
(2) The expression of HPA have nothing with the patients’age, sex, and tumor cell differentiation.
(3) HPA affect cancer depth of invasion, HPA directly involved in cancer invasion and proliferation of lymph node metastasis and blood system, HPA affect the clinical staging of rectal cancer.
引文
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[1] Watanabe M , Aoki Y, Kase H , et al. Heparanase expression and angiogenesis in endometrial cancer[J]. Gynecol Obstet Invest , 2003 ,56(2):77-82.
[2] Marchetti D , Reiland J , Erwin B , et al. Inhibition of heparanase activity and heparanase2 induced angiogenesis by suramin analogues. Int J Cancer [J] . 2003 , 104 (2) : 167-174.
[3] Voldavsky I ,Friedmann Y ,Elkin M , et al . Cloning of heparanase:gene cloning , expression and function in tumor progression and metastasis[J]. Nat Med , 1999 , 5(7) : 793.
[4] Dong J , Kukula AK , Toyoshima M , et al . Genomic organization and chromosome localization of the newly indentified human heparanase gene[J]. Gene , 2000 , 253(2) : 171.
[5] Fux L , Feibish N , Cohen-KaplanV , et al . Structure-function approach identifies a COOH-termInal domain that mediates heparanase signaling[J].Cancer Res , 2009 , 69(5) : 1758-1767.
[6] Ma P , Beck S , Raab R , et al . Heparanase deglycanation of syndecan-1 is required for binding of the epithelial-restricted prosecretory mitogen lacritin[J].J Cell Biol , 2006 , 174(7) : 1097-1106.
[7] Ilan N , Elkin M , Voldavsky I , et al . Regulation , function and clinical significance of heparanase in cancer metastasis and angiogenesis[J]. Int J Biochem Cell Biol , 2006 , 38(12) : 2018-2039.
[8] Hong X , Jiang F, Kalkanis SN , et al . Increased chemotactic migration and growth in heparanase overexpressing human U251n glioma cells[J]. J Exp Clin Cancer Res , 2008 , 27:23.
[9] Zhou Y , Song B , Qin WJ , et al. Heparanase promotes bone destruction and invasiveness in prostate cancer[J]. Cancer Lett , 2008 , 268(2) : 252-259.
[10] Chen G , Dang YW , Luo DZ , et al . Expression of heparanase in hepatocellular carcinoma has prognostic significance:a tissue microarray study[J]. Oncol Res , 2008 , 17(4) : 183-189.
[11] Cohen-Kaplan V , Doweck I , Naroditsky I , et al. Heparanase augments epidermal growthfactor receptor phosphorlation :correlation with head and neck tumor progression[J] .Cancer Res , 2008, 68(24) : 10077-10085.
[12] Friedmann Y , Vlodavsky I , Aingom H , et al. Expression of heparanase in normol,dysplastic and neoplastic human colon mucosa and stroma[J]. Am J Pathol , 2000 , 157(4) : 1167-1175.
[13] Finekl E . Potential target foud for antimetastasis drugs [J]. Sience , 1999 , 258(24) : 33-34.
[14] 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.
[15] Bentolila A , Vlodavsky I , Ishai MR , et al . Poly(Nacryi amion acids): A New class of biologically active ployanions[J]. J Med Chem , 2000 , 43(13) : 2591-2606.
[16] Hoffmann-AC , Mori R , Vallbohmer D ,et al.High expression of heparanase is significantly associated with dedifferentiation and lymph node metastasis in patients with pancreatic ductal adenocarcinomas and correlated to PDGFA and via HIF1a to HB-EGF and bFGF[J]. Journal of Gastrointestinal Surgery , 2008, 12(10) : 1674-1682.
[17] Cohen E , Doweck I , Naroditsky I , et al . Heparanase is overexpressed in lung cancer and correlates inversely with patient survival[J]. Cancer , 2008 , 113(5): 1004-1011.
[18] Endo K , Maejara U , Baba H , et al . Heparanase gene expression and metastatic potential in huma n gastric cancer[J]. Anticancer Res , 2001 , 21(5) : 3365-3369.
[19] Inamine M , Naqai Y , Hirakawa M , et al . Heparanase expression in endometrial cancer:analysis of immunohistochemistry[J]. J Obstet Gynaecol , 2008 , 28(6) : 634-637.
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[1] Watanabe M , Aoki Y, Kase H , et al. Heparanase expression and angiogenesis in endometrial cancer[J]. Gynecol Obstet Invest , 2003 ,56(2):77-82.
[2] Marchetti D , Reiland J , Erwin B , et al. Inhibition of heparanase activity and heparanase2 induced angiogenesis by suramin analogues. Int J Cancer [J] . 2003 , 104 (2) : 167-174.
[3] Voldavsky I ,Friedmann Y ,Elkin M , et al . Cloning of heparanase:gene cloning , expression and function in tumor progression and metastasis[J]. Nat Med , 1999 , 5(7) : 793.
[4] Dong J , Kukula AK , Toyoshima M , et al . Genomic organization and chromosome localization of the newly indentified human heparanase gene[J]. Gene , 2000 , 253(2) : 171.
[5] Fux L , Feibish N , Cohen-KaplanV , et al . Structure-function approach identifies a COOH-termInal domain that mediates heparanase signaling[J].Cancer Res , 2009 , 69(5) : 1758-1767.
[6] Ma P , Beck S , Raab R , et al . Heparanase deglycanation of syndecan-1 is required for binding of the epithelial-restricted prosecretory mitogen lacritin[J].J Cell Biol , 2006 , 174(7) : 1097-1106.
[7] Ilan N , Elkin M , Voldavsky I , et al . Regulation , function and clinical significance of heparanase in cancer metastasis and angiogenesis[J]. Int J Biochem Cell Biol , 2006 , 38(12) : 2018-2039.
[8] Hong X , Jiang F, Kalkanis SN , et al . Increased chemotactic migration and growth in heparanase overexpressing human U251n glioma cells[J]. J Exp Clin Cancer Res , 2008 , 27:23.
[9] Zhou Y , Song B , Qin WJ , et al. Heparanase promotes bone destruction and invasiveness in prostate cancer[J]. Cancer Lett , 2008 , 268(2) : 252-259.
[10] Chen G , Dang YW , Luo DZ , et al . Expression of heparanase in hepatocellular carcinoma has prognostic significance:a tissue microarray study[J]. Oncol Res , 2008 , 17(4) : 183-189.
[11] Cohen-Kaplan V , Doweck I , Naroditsky I , et al. Heparanase augments epidermal growthfactor receptor phosphorlation :correlation with head and neck tumor progression[J] .Cancer Res , 2008, 68(24) : 10077-10085.
[12] Friedmann Y , Vlodavsky I , Aingom H , et al. Expression of heparanase in normol,dysplastic and neoplastic human colon mucosa and stroma[J]. Am J Pathol , 2000 , 157(4) : 1167-1175.
[13] Finekl E . Potential target foud for antimetastasis drugs [J]. Sience , 1999 , 258(24) : 33-34.
[14] 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.
[15] Bentolila A , Vlodavsky I , Ishai MR , et al . Poly(Nacryi amion acids): A New class of biologically active ployanions[J]. J Med Chem , 2000 , 43(13) : 2591-2606.
[16] Hoffmann-AC , Mori R , Vallbohmer D ,et al.High expression of heparanase is significantly associated with dedifferentiation and lymph node metastasis in patients with pancreatic ductal adenocarcinomas and correlated to PDGFA and via HIF1a to HB-EGF and bFGF[J]. Journal of Gastrointestinal Surgery , 2008, 12(10) : 1674-1682.
[17] Cohen E , Doweck I , Naroditsky I , et al . Heparanase is overexpressed in lung cancer and correlates inversely with patient survival[J]. Cancer , 2008 , 113(5): 1004-1011.
[18] Endo K , Maejara U , Baba H , et al . Heparanase gene expression and metastatic potential in huma n gastric cancer[J]. Anticancer Res , 2001 , 21(5) : 3365-3369.
[19] Inamine M , Naqai Y , Hirakawa M , et al . Heparanase expression in endometrial cancer:analysis of immunohistochemistry[J]. J Obstet Gynaecol , 2008 , 28(6) : 634-637.
[20] Casu B , Voldavsky I , Sandenson RD , et al . Non-anticoagulant heparins and inhibition of cance r [J]. Pathophysiol Haemost Thromb , 2008 , 36(3-4) : 195-203.
[21] Naggi A , Casu B , Perez M , et al . Modulation of the heparanase-inhibiting activity of heparin through slective desulfation,graded N-acetylation,and glycol splitting[J]. J biolChem , 2005 , 280(13) : 12103-12113.
[22] Chen P , Chang S , Lai C , et al . Use of PI-88 , a novel heparanase inhibitor , as adjuvant therapy in post-resection hepatocellular carcinoma:a large randomized phaseⅡclinical trial[C]. Shanghai- Hong Kong International Liver Congress , shanghai , 2006.
[23] Liu XY , Fang H , Yang ZG , et al. Inhibtion of invasiveness and expression of heparana se-mRNA in human maligrant melanoma cell line A375 by matrine[J]. Zhong Yao Cai , 2006 , 29(3) : 253-256.
[24] Chen T , Tang XD , Wan Y , et al . HLA-A2-restricted cytotoxic T lymphocyte epitopes from human heparanase as novel targets for broad-spectrum tumor immunotherapy[J]. Neoplasia , 2008 , 10(9) : 977-986.
[25] Yang JM , Wang HJ , Han XM , et al . Screening and identification of novel B cell epitopes in human heparanase and their anti-invasion property for hepatocellular carcinoma[J]. Cancer Immunol Immunother , 2009 , 58(9):1387-1396.
[26] Edovitsky E , Elkin M , Zcharia E , et al . Heparanase Gene Silencing , Tumor Invasiveness ,angiogenesis , and Metastasis[J] . J Natl Cancer Inst , 2004 , 96(16) : 1219 -1230.
[27]张勇,王振宇,张学,等.小干扰RNA抑制胃癌细胞表达及侵袭的实验研究[J].中华医学杂志, 2007 , 87(24) : 1717-1720.