BMP-2在肝细胞癌中表达及与肿瘤血管生成的关系
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摘要
目的研究骨形成蛋白2(bone morphogenetic protein 2,BMP-2)在肝细胞癌(hepatocellular carcinoma,HCC)组织的表达情况及与肿瘤血管生成的关系.方法应用免疫组织化学方法检测BMP-2在40例HCC组织及40例癌旁组织的表达,分析其与临床病理特征之间的关系,CD34染色标记肿瘤微血管密度(microvascular density,MVD).结果免疫组织化学显示,HCC组织中的BMP-2和血管内皮生长因子(vascular endothelial growth factor,VEGF)表达与癌旁组织中比较,阳性率显著增加(75%vs 40%;80.0%vs42.5%,P<0.05),并且BMP-2与VEGF蛋白表达与HCC包膜完整、结节、门静脉癌栓、TNM分期、细胞分化有关,而与患者的年龄、性别、血清AFP、肝硬化无关.根据Spearman相关性分析,BMP-2与VEGF蛋白表达呈正相关(r=7.316,P=0.0068),提示BMP-2参与到肿瘤血管生成过程.HCC组织血管生成活跃(55%vs 15%,P<0.05),血管生成与BMP-2表达有关.结论 HCC中BMP-2高表达在肿瘤血管生成中有重要的作用.
AIM To detect the expression of bone morphogenetic protein 2(BMP-2) in hepatocellular carcinoma(HCC) and analyze its correlation with tumor angiogenesis.METHODS Immunohistochemical(IHC) method was used to detect the expression of BMP-2 in 40 cases of HCC and matched tumor-adjacent specimens.The relationship between BMP-2 expression and clinicopathologic features was analyzed.Microvascular density was determined by labeling vascular endothelial cells with CD34,and the correlation of BMP-2 expression with tumor angiogenesis was analyzed.RESULTS IHC data showed that the positive rates of BMP-2 and vascular endothelial growth factor(VEGF) expression in HCC were significantly higher than those in tumor-adjacent tissues(75% vs 40%; 80.0% vs 42.5%, P < 0.05 for both). Expression of BMP-2 and VEGF was positively associated with intact tumor capsule, nodules, portal venous tumor emboli,TNM stage, and tumor cell differentiation,but not with patient's age, sex, serum AFP, or live cirrhosis. Tumor angiogenesis was related with BMP-2 expression in HCC. Spearman correlation analysis showed that there was a positive correlation between BMP-2 and VEGF expression(r = 7.316, P = 0.0068). Active angiogenesis was detected more frequently in HCC compared to tumor-adjacent tissues(55%vs 15%, P < 0.05).CONCLUSION High expression of BMP-2 in HCC plays an important role in tumor angiogenesis.
AIM To detect the expression of bone morphogenetic protein 2(BMP-2) in hepatocellular carcinoma(HCC) and analyze its correlation with tumor angiogenesis.METHODS Immunohistochemical(IHC) method was used to detect the expression of BMP-2 in 40 cases of HCC and matched tumor-adjacent specimens.The relationship between BMP-2 expression and clinicopathologic features was analyzed.Microvascular density was determined by labeling vascular endothelial cells with CD34,and the correlation of BMP-2 expression with tumor angiogenesis was analyzed.RESULTS IHC data showed that the positive rates of BMP-2 and vascular endothelial growth factor(VEGF) expression in HCC were significantly higher than those in tumor-adjacent tissues(75% vs 40%; 80.0% vs 42.5%, P < 0.05 for both). Expression of BMP-2 and VEGF was positively associated with intact tumor capsule, nodules, portal venous tumor emboli,TNM stage, and tumor cell differentiation,but not with patient's age, sex, serum AFP, or live cirrhosis. Tumor angiogenesis was related with BMP-2 expression in HCC. Spearman correlation analysis showed that there was a positive correlation between BMP-2 and VEGF expression(r = 7.316, P = 0.0068). Active angiogenesis was detected more frequently in HCC compared to tumor-adjacent tissues(55%vs 15%, P < 0.05).CONCLUSION High expression of BMP-2 in HCC plays an important role in tumor angiogenesis.
引文
1 Pascual S,Herrera I,Irurzun J.New advances in hepatocellular carcinoma.World J Hepatol 2016;8:421-438[PMID:27028578 DOI:10.4254/wjh.v8.i9.421]
2 Urist MR.Bone:formation by autoinduction.Science 1965;150:893-899[PMID:5319761 DOI:10.1126/science.150.3698.893]
3 Raida M,Clement JH,Leek RD,Ameri K,Bicknell R,Niederwieser D,Harris AL.Bone morphogenetic protein 2(BMP-2)and induction of tumor angiogenesis.J Cancer Res Clin Oncol2005;131:741-750[PMID:16136355 DOI:10.1007/s00432-005-0024-1]
4 Hogan BL.Bone morphogenetic proteins:multifunctional regulators of vertebrate development.Genes Dev 1996;10:1580-1594[PMID:8682290 DOI:10.1101/gad.10.13.1580]
5 Wozney JM,Rosen V.Bone morphogenetic protein and bone morphogenetic protein gene family in bone formation and repair.Clin Orthop Relat Res 1998;(346):26-37[PMID:9577407 DOI:10.1097/00003086-199801000-00006]
6 Langenfeld EM,Langenfeld J.Bone morphogenetic protein-2 stimulates angiogenesis in developing tumors.Mol Cancer Res 2004;2:141-149[PMID:15037653]
7 Deckers MM,van Bezooijen RL,van der Horst G,Hoogendam J,van der Bent C,Papapoulos SE,Lo Wik CW.Bone Morphogenetic Proteins Stimulate Angiogenesis through Osteoblast-Derived Vascular Endothelial Growth Factor A.Endocrinology 2002;143:1545-1553[PMID:28201565 DOI:10.1210/endo.143.4.8719]
8李桂梅,侯宁,杨志慧,殷正进,曹晓卉.glypican-3、HepPar1和CD34在肝细胞癌中的表达及临床意义.诊断病理学杂志2015;22:95-98
9 Weidner N.Current pathologic methods for measuring intratumoral microvessel density within breast carcinoma and other solid tumors.Breast Cancer Res Treat 1995;36:169-180[PMID:8534865 DOI:10.1007/BF00666038]
10李德宇,陈孝平.ANGPTL3在肝细胞癌中的表达及其与肿瘤血管生成的关系.世界华人消化杂志2010;18:3471-3475
11陈丹,王凯冰,李加桩,隋红.原发性肝癌的抗血管生成靶向治疗现状与挑战.中国肿瘤2017;26:203-209
12 Yance DR,Sagar SM.Targeting angiogenesis with integrative cancer therapies.Integr Cancer Ther2006;5:9-29[PMID:16484711 DOI:10.1177/1534735405285562]
13 Onishi M,Ichikawa T,Kurozumi K,Date I.Angiogenesis and invasion in glioma.Brain Tumor Pathol 2011;28:13-24[PMID:21221826DOI:10.1007/s10014-010-0007-z]
14 Folkman J.Angiogenesis:an organizing principle for drug discovery?Nat Rev Drug Discov 2007;6:273-286[PMID:17396134 DOI:10.1038/nrd2115]
15 Zhu AX,Duda DG,Sahani DV,Jain RK.HCCand angiogenesis:possible targets and future directions.Nat Rev Clin Oncol 2011;8:292-301[PMID:21386818 DOI:10.1038/nrclinonc.2011.30]
16 Wu SD,Ma YS,Fang Y,Liu LL,Fu D,Shen XZ.Role of the microenvironment in hepatocellular carcinoma development and progression.Cancer Treat Rev 2012;38:218-225[PMID:21763074 DOI:10.1016/j.ctrv.2011.06.010]
17 Chen JC,Uang BJ,Lyu PC,Chang JY,Liu KJ,Kuo CC,Hsieh HP,Wang HC,Cheng CS,Chang YH,Chang MD,Chang WS,Lin CC.Design and synthesis of alpha-ketoamides as cathepsin S inhibitors with potential applications against tumor invasion and angiogenesis.J Med Chem 2010;53:4545-4549[PMID:20481438 DOI:10.1021/jm100089e]
18 Manikandan P,Murugan RS,Priyadarsini RV,Vinothini G,Nagini S.Eugenol induces apoptosis and inhibits invasion and angiogenesis in a rat model of gastric carcinogenesis induced by MNNG.Life Sci 2010;86:936-941[PMID:20434464DOI:10.1016/j.lfs.2010.04.010]
19 Blagosklonny MV.Antiangiogenic therapy and tumor progression.Cancer Cell 2004;5:13-17[PMID:14749122 DOI:10.1016/S1535-6108(03)00336-2]
20柴斌,杨述华,王渝.BMP-2、OPN、VEGF的表达在骨肉瘤肺转移中的意义.肿瘤防治研究2007;34:270-273
21 Xu GJ,Cai S,Wu JB.Effect of insulin-like growth factor-1 on bone morphogenetic protein-2expression in hepatic carcinoma SMMC7721cells through the p38 MAPK signaling pathway.Asian Pac J Cancer Prev 2012;13:1183-1186[PMID:22799302 DOI:10.7314/APJCP.2012.13.4.1183]
22 Willette RN,Gu JL,Lysko PG,Anderson KM,Minehart H,Yue T.BMP-2 gene expression and effects on human vascular smooth muscle cells.JVasc Res 1999;36:120-125[PMID:10213907 DOI:10.1159/000025634]
23 Glienke J,Schmitt AO,Pilarsky C,Hinzmann B,Weiss B,Rosenthal A,Thierauch KH.Differential gene expression by endothelial cells in distinct angiogenic states.Eur J Biochem 2000;267:2820-2830[PMID:10785405 DOI:10.1046/j.1432-1327.2000.01325.x]
24吴建兵,傅华群,黄龙璋.骨形态发生蛋白2、6在肝癌中的表达及意义.世界华人消化杂志2009;17:834-837
25 Wu JB,Fu HQ,Huang LZ,Liu AW,Zhang JX.Effects of siRNA-targeting BMP-2 on the abilities of migration and invasion of human liver cancer SMMC7721 cells and its mechanism.Cancer Gene Ther 2011;18:20-25[PMID:20885449 DOI:10.1038/cgt.2010.55]
26吴建兵,傅华群,刘安文,黄龙璋,张吉翔.BMP-2对人肝癌SMMC7721细胞MMP-2、MMP-9表达的影响.实用医学杂志2010;26:559-561
27李志伟,鲁广恩,胡安国,杨五计,戴勇.VEGF表达及MVD与肝细胞癌侵袭、转移和预后的关系.中国现代医学杂志2003;13:15-17
28 Borovikova LV,Ivanova S,Zhang M,Yang H,Botchkina GI,Watkins LR,Wang H,Abumrad N,Eaton JW,Tracey KJ.Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin.Nature 2000;405:458-462[PMID:10839541 DOI:10.1038/35013070]
29 Carbajo-Pescador S,Ordo馿z R,Benet M,Jover R,García-Palomo A,Mauriz JL,González-Gallego J.Inhibition of VEGF expression through blockade of Hif1αand STAT3 signalling mediates the antiangiogenic effect of melatonin in HepG2 liver cancer cells.Br J Cancer 2013;109:83-91[PMID:23756865 DOI:10.1038/bjc.2013.285]
30马捷,周晓军,张泰和,张泰和,孙桂勤,孟奎.人肝癌组织中CD34和血管内皮生长因子的表达及微血管密度的病理意义.中华病理学杂志2000;29:6-9
31张骏.Maspin在原发性肝癌中的表达及其与Caspase-3、MVD的关系.江苏医药2013;39:46-48
32 Zuo WH,Zeng P,Chen X,Lu YJ,Li A,Wu JB.Promotive effects of bone morphogenetic protein 2 on angiogenesis in hepatocarcinoma via multiple signal pathways.Sci Rep 2016;6:37499[PMID:27886213 DOI:10.1038/srep37499]
2 Urist MR.Bone:formation by autoinduction.Science 1965;150:893-899[PMID:5319761 DOI:10.1126/science.150.3698.893]
3 Raida M,Clement JH,Leek RD,Ameri K,Bicknell R,Niederwieser D,Harris AL.Bone morphogenetic protein 2(BMP-2)and induction of tumor angiogenesis.J Cancer Res Clin Oncol2005;131:741-750[PMID:16136355 DOI:10.1007/s00432-005-0024-1]
4 Hogan BL.Bone morphogenetic proteins:multifunctional regulators of vertebrate development.Genes Dev 1996;10:1580-1594[PMID:8682290 DOI:10.1101/gad.10.13.1580]
5 Wozney JM,Rosen V.Bone morphogenetic protein and bone morphogenetic protein gene family in bone formation and repair.Clin Orthop Relat Res 1998;(346):26-37[PMID:9577407 DOI:10.1097/00003086-199801000-00006]
6 Langenfeld EM,Langenfeld J.Bone morphogenetic protein-2 stimulates angiogenesis in developing tumors.Mol Cancer Res 2004;2:141-149[PMID:15037653]
7 Deckers MM,van Bezooijen RL,van der Horst G,Hoogendam J,van der Bent C,Papapoulos SE,Lo Wik CW.Bone Morphogenetic Proteins Stimulate Angiogenesis through Osteoblast-Derived Vascular Endothelial Growth Factor A.Endocrinology 2002;143:1545-1553[PMID:28201565 DOI:10.1210/endo.143.4.8719]
8李桂梅,侯宁,杨志慧,殷正进,曹晓卉.glypican-3、HepPar1和CD34在肝细胞癌中的表达及临床意义.诊断病理学杂志2015;22:95-98
9 Weidner N.Current pathologic methods for measuring intratumoral microvessel density within breast carcinoma and other solid tumors.Breast Cancer Res Treat 1995;36:169-180[PMID:8534865 DOI:10.1007/BF00666038]
10李德宇,陈孝平.ANGPTL3在肝细胞癌中的表达及其与肿瘤血管生成的关系.世界华人消化杂志2010;18:3471-3475
11陈丹,王凯冰,李加桩,隋红.原发性肝癌的抗血管生成靶向治疗现状与挑战.中国肿瘤2017;26:203-209
12 Yance DR,Sagar SM.Targeting angiogenesis with integrative cancer therapies.Integr Cancer Ther2006;5:9-29[PMID:16484711 DOI:10.1177/1534735405285562]
13 Onishi M,Ichikawa T,Kurozumi K,Date I.Angiogenesis and invasion in glioma.Brain Tumor Pathol 2011;28:13-24[PMID:21221826DOI:10.1007/s10014-010-0007-z]
14 Folkman J.Angiogenesis:an organizing principle for drug discovery?Nat Rev Drug Discov 2007;6:273-286[PMID:17396134 DOI:10.1038/nrd2115]
15 Zhu AX,Duda DG,Sahani DV,Jain RK.HCCand angiogenesis:possible targets and future directions.Nat Rev Clin Oncol 2011;8:292-301[PMID:21386818 DOI:10.1038/nrclinonc.2011.30]
16 Wu SD,Ma YS,Fang Y,Liu LL,Fu D,Shen XZ.Role of the microenvironment in hepatocellular carcinoma development and progression.Cancer Treat Rev 2012;38:218-225[PMID:21763074 DOI:10.1016/j.ctrv.2011.06.010]
17 Chen JC,Uang BJ,Lyu PC,Chang JY,Liu KJ,Kuo CC,Hsieh HP,Wang HC,Cheng CS,Chang YH,Chang MD,Chang WS,Lin CC.Design and synthesis of alpha-ketoamides as cathepsin S inhibitors with potential applications against tumor invasion and angiogenesis.J Med Chem 2010;53:4545-4549[PMID:20481438 DOI:10.1021/jm100089e]
18 Manikandan P,Murugan RS,Priyadarsini RV,Vinothini G,Nagini S.Eugenol induces apoptosis and inhibits invasion and angiogenesis in a rat model of gastric carcinogenesis induced by MNNG.Life Sci 2010;86:936-941[PMID:20434464DOI:10.1016/j.lfs.2010.04.010]
19 Blagosklonny MV.Antiangiogenic therapy and tumor progression.Cancer Cell 2004;5:13-17[PMID:14749122 DOI:10.1016/S1535-6108(03)00336-2]
20柴斌,杨述华,王渝.BMP-2、OPN、VEGF的表达在骨肉瘤肺转移中的意义.肿瘤防治研究2007;34:270-273
21 Xu GJ,Cai S,Wu JB.Effect of insulin-like growth factor-1 on bone morphogenetic protein-2expression in hepatic carcinoma SMMC7721cells through the p38 MAPK signaling pathway.Asian Pac J Cancer Prev 2012;13:1183-1186[PMID:22799302 DOI:10.7314/APJCP.2012.13.4.1183]
22 Willette RN,Gu JL,Lysko PG,Anderson KM,Minehart H,Yue T.BMP-2 gene expression and effects on human vascular smooth muscle cells.JVasc Res 1999;36:120-125[PMID:10213907 DOI:10.1159/000025634]
23 Glienke J,Schmitt AO,Pilarsky C,Hinzmann B,Weiss B,Rosenthal A,Thierauch KH.Differential gene expression by endothelial cells in distinct angiogenic states.Eur J Biochem 2000;267:2820-2830[PMID:10785405 DOI:10.1046/j.1432-1327.2000.01325.x]
24吴建兵,傅华群,黄龙璋.骨形态发生蛋白2、6在肝癌中的表达及意义.世界华人消化杂志2009;17:834-837
25 Wu JB,Fu HQ,Huang LZ,Liu AW,Zhang JX.Effects of siRNA-targeting BMP-2 on the abilities of migration and invasion of human liver cancer SMMC7721 cells and its mechanism.Cancer Gene Ther 2011;18:20-25[PMID:20885449 DOI:10.1038/cgt.2010.55]
26吴建兵,傅华群,刘安文,黄龙璋,张吉翔.BMP-2对人肝癌SMMC7721细胞MMP-2、MMP-9表达的影响.实用医学杂志2010;26:559-561
27李志伟,鲁广恩,胡安国,杨五计,戴勇.VEGF表达及MVD与肝细胞癌侵袭、转移和预后的关系.中国现代医学杂志2003;13:15-17
28 Borovikova LV,Ivanova S,Zhang M,Yang H,Botchkina GI,Watkins LR,Wang H,Abumrad N,Eaton JW,Tracey KJ.Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin.Nature 2000;405:458-462[PMID:10839541 DOI:10.1038/35013070]
29 Carbajo-Pescador S,Ordo馿z R,Benet M,Jover R,García-Palomo A,Mauriz JL,González-Gallego J.Inhibition of VEGF expression through blockade of Hif1αand STAT3 signalling mediates the antiangiogenic effect of melatonin in HepG2 liver cancer cells.Br J Cancer 2013;109:83-91[PMID:23756865 DOI:10.1038/bjc.2013.285]
30马捷,周晓军,张泰和,张泰和,孙桂勤,孟奎.人肝癌组织中CD34和血管内皮生长因子的表达及微血管密度的病理意义.中华病理学杂志2000;29:6-9
31张骏.Maspin在原发性肝癌中的表达及其与Caspase-3、MVD的关系.江苏医药2013;39:46-48
32 Zuo WH,Zeng P,Chen X,Lu YJ,Li A,Wu JB.Promotive effects of bone morphogenetic protein 2 on angiogenesis in hepatocarcinoma via multiple signal pathways.Sci Rep 2016;6:37499[PMID:27886213 DOI:10.1038/srep37499]