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近几十年来,随着人们生活方式的改变以及激素的过度使用,乳腺癌的发病率和发病人数在逐年提升,已成为全球发病人数第二高的恶性肿瘤[1],在我国也是最常见的恶性肿瘤之一[2]。浸润性乳腺癌(infiltrating breast carcinoma,IBC,非特殊型)是乳腺癌中最常见的组织学类型。尽管近年来各种新的治疗方法和技术层出不穷,但IBC病人总的生存时间并没有显著提高,这可能与IBC病人术后复发与转移有关。口腔癌过表达蛋白1(oral cancer overexpressed protein 1,ORAOV1)最初是从口腔鳞状细胞癌中发现的一个候选癌基因,其定位于人染色体11q13。ORAOV1参与细胞周期、凋亡及血管生成等生物学活动[3-4]。ORAOV1蛋白表达异常增高常常与肿瘤细胞增殖快、分化差、预后不良等密切相关[5]。肿瘤组织通过诱导大量新生血管形成促进其快速生长,并进一步促进其发生浸润转移,从而增加病人术后复发和转移的概率。血管生成抑制因子1(vasohibin 1,VASH1)是近年来才发现的一种关于血管生成的负反馈调节因子[6],该因子主要是由血管内皮细胞生长因子(VEGF)、成纤维细胞生长因子2(FGF2)及血小板源性生长因子(PDGF)等共同刺激血管内皮细胞合成的,并负反馈性地抑制血管生成[7-8]。但是,越来越多的研究[9]表明VASH1高表达却常常意味着病人预后不良。本研究旨在通过免疫组织化学EliVisionTM plus法寻找能够预测IBC病人术后浸润、转移和预后的生物预测因子,为临床治疗提供一点线索。
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VASH1蛋白在对照组中的阳性率为12.0%(12/100), 低于在IBC组的56.9%(136/239)(χ2=57.79,P < 0.01)(见图 1A、1B)。对IBC组VASH1蛋白阳性率与临床病理因素之间的关系分析显示,与组织的分化程度、TNM分期、淋巴结转移和肿瘤组织的大小均有关系(P < 0.05~P < 0.01),与IBC病人的年龄及肿瘤位置等之间均无相关性(P>0.05)(见表 1)。
变量 n ORAOV1 VASH1 阳性 χ2 P 阳性 χ2 P 年龄/岁 < 50
≥50110
12969(62.73)
70(54.26)1.75 >0.05 40(36.36)
63(48.84)3.77 >0.05 肿瘤长径/cm ≤2.0 82 46(56.10) 43(47.56) >2.0~5.0 133 80(60.15) 21.06 < 0.01 75(56.39) 14.76 < 0.01 >5.0 24 23(95.83) 23(91.67) 部位 左侧
右侧118
12166(55.93)
73(60.33)0.48 >0.05 60(50.85)
76(62.81)3.49 >0.05 分化程度 高 59 24(40.68) 25(42.37) 中 113 70(61.95) 10.31 < 0.01 67(59.29) 7.44 < 0.05 低 67 45((67.16) 44(32.84) 淋巴结转移 无
有111
12849(44.14)
90(70.31)16.73 < 0.01 44(39.64)
92(71.88)25.19 < 0.01 TNM分期 Ⅰ+Ⅱ
Ⅲ+Ⅳ128
11155(42.97)
84(75.68)26.13 < 0.01 57(44.53)
79(71.17)17.20 < 0.01 ER表达 阴性
阳性91
14858(63.74)
81(54.73)1.88 >0.05 63(69.23)
73(49.32)9.11 < 0.01 PR表达 阴性
阳性105
13455(52.38)
84(62.69)2.57 >0.05 61(58.10)
75(55.97)0.11 >0.05 HER2表达 阴性
阳性142
9775(52.82)
64(65.80)4.10 < 0.05 77(54.23)
59(60.82)1.02 >0.05 VASH1表达 阴性
阳性103
13630(29.13)
109(80.15)62.70 < 0.01 表 1 IBC中ORAOV1和VASH1的表达及其与临床各病理因素之间的关系[n;百分率(%)]
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对照组中ORAOV1蛋白的阳性率13.0%(13/100)低于IBC组中58.2%(139/239)(χ2=58.13,P < 0.01(见图 1C、1D)。对IBC组ORAOV1蛋白阳性率与临床病理因素之间的关系分析显示,与年龄组、肿瘤位置均无关系(P>0.05),随着IBC组织的分化越差、肿瘤组织越大,ORAOV1蛋白的阳性率也越高(P < 0.01),淋巴结转移组中的ORAOV1蛋白的阳性率明显高于淋巴结无转移组(P < 0.01),高TNM分期组中的ORAOV1蛋白的阳性率明显高于低TNM分期组(P < 0.01)(见表 1)。
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Spearman相关分析显示,在IBC组织中ORAOV1蛋白的阳性率与VASH1蛋白的阳性率呈正相关关系(r=0.512,P < 0.01),ORAOV1蛋白的阳性率与ER及PR蛋白之间无相关性(r=-0.089、0.104,P>0.05),与HER2蛋白呈正相关关系(r=0.131,P < 0.05);VASH1蛋白与ER蛋白呈负相关关系(r=-0.195,P < 0.01),与PR及HER2蛋白无相关性(r=-0.021、0.065,P>0.05)。
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将本研究中涉及到所有临床病理参数, 包括年龄、肿瘤长径、肿瘤位置、分化程度、淋巴结转移、TNM分期、ER、PR、HER2、ORAOV1及VASH1等因素全部带入COX多因素模型进行分析,结果表明阳性表达的ORAOV1和VASH1蛋白、肿瘤长径和TNM分期高低是影响IBC病人术后总生存时间的独立预后因素(P < 0.05~P < 0.01)(见表 2)。
自变量 B SE P Exp(B) 95%CI ORAOV1 0.576 0.195 < 0.01 1.779 1.213~2.609 VASH1 0.549 0.195 < 0.01 1.732 1.182~2.538 TNM分期 0.379 0.169 < 0.01 1.460 1.048~2.034 肿瘤长径 0.267 0.130 < 0.05 1.307 1.012~1.687 表 2 COX多因素分析
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本研究中总的5年生存率约为35.6%(85/239)。Kaplan-Meier法生存分析表明ORAOV1蛋白阳性组中位生存时间为(44.8±15.2)个月,低于阴性组的(61.7±13.6)个月(χ2=53.39,P < 0.01)(见图 2A);VASH1蛋白阳性组为(45.0±14.1)个月,低于阴性组的(61.0±15.6)个月(χ2=49.60,P < 0.01)(见图 2B);ER蛋白阳性组为(53.9±17.7)个月,低于阴性组的(48.6±14.6)个月(χ2=8.98,P < 0.01), (见图 2C);PR蛋白阳性组为(52.0±17.5)个月,与阴性组为(51.7±15.9)个月差异无统计学意义(χ2=0.17,P>0.05)(见图 2D);HER2蛋白阳性组为(48.0±16.9)个月,低于阴性组的(54.6±16.2)个月(χ2=5.11,P < 0.05)(见图 2E)。
ORAOV1和Vasohibin1在乳腺癌中的表达及其临床意义
Expression of ORAOV1 and Vasohibin1 in infiltrating breast carcinoma, and their clinicopathological significance
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摘要:
目的检测乳腺浸润性乳腺癌(infiltrating breast carcinoma,IBC)中口腔癌过表达蛋白1(oral cancer overexpressed protein 1,ORAOV1)和血管生成抑制因子1(vasohibin1,VASH1)的表达情况及其相互之间的关系,并分析它们在IBC中的临床意义。 方法通过免疫组织化学方法检测239例IBC和100例相应的正常乳腺组织中ORAOV1和VASH1蛋白的阳性表达情况。 结果在IBC组织中,ORAOV1和VASH1蛋白的阳性率分别为58.2%和56.9%;对照组中,ORAOV1和VASH1蛋白的阳性率分别为13.0%和12.0%,其表达差异在2组间均有统计学意义(P < 0.01)。ORAOV1和VASH1蛋白阳性率的差异在IBC病人肿瘤组织的不同分化程度之间、淋巴结转移与否之间、肿瘤大小之间及不同TNM分期之间差异均有统计学意义(P < 0.05~P < 0.01);且ORAOV1蛋白的阳性率与VASH1蛋白的阳性率之间呈正相关关系(P < 0.01)。在IBC病人中ORAOV1和VASH1蛋白阳性组术后的生存时间明显低于阴性组(P < 0.05~P < 0.01)。多因素回归分析显示阳性表达的ORAOV1和VASH1蛋白、肿瘤组织的大小及TNM分期高低均是影响IBC病人术后生存时间的独立预后因子(P < 0.05~P < 0.01)。 结论表达异常增高的ORAOV1和VASH1可能参与IBC的发生、发展,并促进其浸润和转移;在IBC病人肿瘤组织中联合检测ORAOV1和VASH1蛋白的表达情况对预测其发展和预后均有重要意义。 Abstract:ObjectiveTo investigate the expression levels of oral cancer overexpressed protein 1(ORAOV1)and vasohibin 1(VASH1)in infiltrating breast carcinoma(IBC), their relationship with each other, and their clinical significance in IBC. MethodsThe positive expression of ORAOV1 and VASH1 protein in 239 cases of IBC tissue and 100 cases of normal mammary tissue were detected using immunohistochemistry. ResultsThe positive rates of ORAOV1 and VASH1 protein in IBC tissue and control tissues were 58.2% & 56.9% and 13.0% & 12.0%, respectively, and the expression differences of whose were statistically significant between two groups(P < 0.05).The differences of the positive expression rates of ORAOV1 and VASH1 protein among IBC patients with different degrees of differentiation, lymph node metastasis, tumor size and TNM stage were statistically significant(P < 0.05 to P < 0.01).The positive rate of ORAOV1 protein was positively correlated with the positive rate of VASH1 protein(P < 0.01).The overall survival time of IBC's patients with positive expression ORAOV1 and VASH1 was lower than that of IBC's patients with negative expression of ORAOV1 and VASH1(P < 0.01).The results of multivariate COX regression analysis showed that the positive expression of ORAOV1 and VASH1 protein, tumor size and TNM stages were the independent prognostic factor affecting postoperative survival time of IBC patients. ConclusionsThe ORAOV1 and VASH1 with abnormally high expression may participate in the occurrence and development of IBC, and promote its infiltration and metastasis.The combined detection of ORAOV1 and VASH1 protein expression in tumor tissues of IBC patients is of great significance for the prediction of development and prognosis. -
表 1 IBC中ORAOV1和VASH1的表达及其与临床各病理因素之间的关系[n;百分率(%)]
变量 n ORAOV1 VASH1 阳性 χ2 P 阳性 χ2 P 年龄/岁 < 50
≥50110
12969(62.73)
70(54.26)1.75 >0.05 40(36.36)
63(48.84)3.77 >0.05 肿瘤长径/cm ≤2.0 82 46(56.10) 43(47.56) >2.0~5.0 133 80(60.15) 21.06 < 0.01 75(56.39) 14.76 < 0.01 >5.0 24 23(95.83) 23(91.67) 部位 左侧
右侧118
12166(55.93)
73(60.33)0.48 >0.05 60(50.85)
76(62.81)3.49 >0.05 分化程度 高 59 24(40.68) 25(42.37) 中 113 70(61.95) 10.31 < 0.01 67(59.29) 7.44 < 0.05 低 67 45((67.16) 44(32.84) 淋巴结转移 无
有111
12849(44.14)
90(70.31)16.73 < 0.01 44(39.64)
92(71.88)25.19 < 0.01 TNM分期 Ⅰ+Ⅱ
Ⅲ+Ⅳ128
11155(42.97)
84(75.68)26.13 < 0.01 57(44.53)
79(71.17)17.20 < 0.01 ER表达 阴性
阳性91
14858(63.74)
81(54.73)1.88 >0.05 63(69.23)
73(49.32)9.11 < 0.01 PR表达 阴性
阳性105
13455(52.38)
84(62.69)2.57 >0.05 61(58.10)
75(55.97)0.11 >0.05 HER2表达 阴性
阳性142
9775(52.82)
64(65.80)4.10 < 0.05 77(54.23)
59(60.82)1.02 >0.05 VASH1表达 阴性
阳性103
13630(29.13)
109(80.15)62.70 < 0.01 表 2 COX多因素分析
自变量 B SE P Exp(B) 95%CI ORAOV1 0.576 0.195 < 0.01 1.779 1.213~2.609 VASH1 0.549 0.195 < 0.01 1.732 1.182~2.538 TNM分期 0.379 0.169 < 0.01 1.460 1.048~2.034 肿瘤长径 0.267 0.130 < 0.05 1.307 1.012~1.687 -
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