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结直肠癌发病率在世界范围内位列恶性肿瘤第3位[1],肝脏因其在消化系统中的特殊性,是结直肠癌最常见的转移部位,约有四分之一的病人在初诊时已发生肝转移[2]。临床研究[3]表明,不干预的结直肠癌肝转移病人无进展生存时间仅为6.9个月,5年生存率较低,而进行根治术后,可将病人的无进展生存时间延长至35个月,且有30%~50%的病人总生存时间可长达5年。肿瘤细胞的侵袭、转移过程很复杂,有研究[4]表明上皮间质转化(epithelial-mesenchymal transition,EMT)在导致肿瘤细胞发生侵袭和转移过程中起着重要作用。上皮型钙黏蛋白(E-cadherin)、神经型钙黏蛋白(N-cadherin)是EMT中两个标志性蛋白[5]。由间隙连接蛋白(connexin, CX)构成的细胞间隙连接(gap junction)对细胞的增殖和分化起着重要的调控作用,CX蛋白表达下调引起细胞连接通讯(gap junctionintercellular communication,GJIC)功能缺失,对细胞的新陈代谢、增殖分化、凋亡的调控作用丧失,导致细胞处于增殖失控和分化紊乱状态,最终恶化。目前在哺乳动物身上发现的CX至少有20种,相对分子质量为26 000~50 000,依相对分子质量的不同而分别命名为CX26、CX50等[6]。相关研究[7]表明CX26、CX32、CX43与移行细胞癌恶性程度具有一定关系,但是结直肠癌发生肝脏转移和EMT及CX26、CX32、CX43的相关性鲜见报道。本研究通过免疫组织化学方法研究E-cadherin和N-cadherin、CX26、CX32、CX43在结直肠癌原发灶、肝转移组织中的表达水平及临床病理特征的关系,了解结直肠癌局部浸润及远处转移与上皮间质转化的相关关系及可能机制。
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40例结直肠癌标本中,CX26、CX32、CX43阳性着色主要分布于肿瘤细胞的细胞膜和/或细胞质;E-cadherin阳性着色主要分布于细胞膜,N-cadherin阳性着色主要分布于细胞膜和/或细胞质(见图 1)。3组除CX43蛋白阳性表达率差异有统计学意义(P < 0.05),CX26、CX32、E-cadherin和N-cadherin蛋白阳性表达率差异均无统计学意义(P>0.05)(见表 1)。
分组 n E-cadherin N-cadherin CX26 CX32 CX43 A组 40 32(80.0) 32(80.0) 33(82.5) 31(77.5) 31(77.5) B组 40 36(90.0) 28(70.0) 37(92.5) 36(90.0) 38(95.0) C组 40 28(70.0) 36(90.0) 29(72.5) 28(70.0) 29(72.5) χ2 — 5.00 5.00 5.54 4.95 7.46 P — >0.05 >0.05 >0.05 >0.05 < 0.05 表 1 3组E-cadherin、N-cadherin及CX26、CX32、CX43表达
[n ;百分率(%)] 分组 n E-cadherin N-cadherin CX26 CX32 CX43 性别 男 24 19(79.2) 18(75.0) 19(79.2) 20(83.3) 19(79.2) 女 16 13(81.2) 12(75.0) 12(75.0) 13(81.2) 12(75.0) χ2 — 0.03 0.00 0.10 0.03 0.10 P — >0.05 >0.05 >0.05 >0.05 >0.05 年龄/岁 <60 30 27(87.1) 28(90.3) 27(87.1) 28(90.3) 28(90.3) ≥60 10 8(80.0) 9(90.0) 9(80.0) 9(90.0) 9(90.0) χ2 — 1.21 0.01 0.06 0.01 0.01 P — >0.05 >0.05 >0.05 >0.05 >0.05 瘤浸润深度 T1和T2 12 10(83.3) 9(75.0) 9(75.0) 8(66.7) 10(83.3) T3 18 14(77.8) 13(72.2) 15(83.3) 14(77.8) 16(88.9) T4 10 7(70.0) 8(80.0) 8(80.0) 7(70.0) 9(90.0) χ2 — 0.56 0.21 0.31 0.49 0.27 P — >0.05 >0.05 >0.05 >0.05 >0.05 组织分化程度 高和中 20 16(80.0) 17(85.0) 17(85.0) 16(80.0) 18(90.0) 低 20 12(60.0) 11(55.0) 13(65.0) 12(60.0) 14(70.0) χ2 — 1.90 4.28 2.13 1.90 2.50 P — >0.05 < 0.05 >0.05 >0.05 >0.05 淋巴结转移情况 N0 4 3(75.0) 3(75.0) 3(75.0) 3(75.0) 3(75.0) N1 15 14(93.3) 13(86.7) 13(86.7) 12(80.0) 14(93.3) N2 21 13(61.9) 12(57.1) 13(61.9) 12(57.1) 13(61.9) χ2 — 4.61 3.68 2.70 2.20 4.61 P — >0.05 >0.05 >0.05 >0.05 >0.05 表 2 E-cadherin、N-cadherin及CX26、CX32、CX43阳性与与结直肠癌临床病理特征的关系
[n ;百分率(%)] -
E-cadherin、N-cadherin及CX26、CX32、CX43与病人的性别、年龄、肿瘤浸润深度及淋巴结转移情况差异均无统计学意义(P>0.05),而N-cadherin与组织分化程度呈明显相关关系(P < 0.05)。
CX26、CX32、CX43与上皮间质转化相关蛋白在结直肠原发癌和肝脏转移之间的相关性
Study on the correlation between the levels of CX26, CX32, CX43 and epithelial mesenchymal transformation-associated protein, and colorectal primary carcinoma and liver metastasis
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摘要:
目的 探讨间隙连接蛋白(CX)26、CX32、CX43与上皮间质转化相关蛋白[上皮型钙黏蛋白(E-cadherin)、神经型钙黏蛋白(N-cadherin)]在结直肠原发癌和肝脏转移之间的相关性。 方法 选取初诊时已发生结直肠癌肝脏转移并手术治疗者40例,经手术治疗病理确诊为结直肠癌肝转移石蜡标本40例,以上研究对象分为3组:A组为结、直肠癌组织40例,B组为癌旁正常组织40例,C组为肝转移灶40例,所有病人术前均未行化疗、放射、介入及免疫治疗。利用免疫组织化学SP法检测E-cadherin、N-cadherin及CX26、CX32、CX43的表达。分析E-cadherin、N-cadherin及CX26、CX32、CX43表达与结直肠癌肝脏转移的临床病理特征(性别、年龄、肿瘤浸润深度、组织分化程度、淋巴结转移情况)的关系;及结直肠癌发生肝脏转移和上皮间质转化及细胞间隙蛋白CX26、CX32、CX43的相关性。 结果 3组除CX43蛋白阳性表达率差异有统计学意义(P < 0.05)外,CX26、CX32、E-cadherin和N-cadherin蛋白阳性表达率差异均无统计学意义(P>0.05);E-cadherin、N-cadherin及CX26、CX32、CX43与病人的性别、年龄、肿瘤浸润深度及淋巴结转移情况差异均无统计学意义(P>0.05),而N-cadherin与组织分化程度呈明显相关关系(P < 0.05)。 结论 CX43、N-cadherin与结直肠原发癌和肝脏转移有关。 -
关键词:
- 结直肠肿瘤 /
- 肝脏转移 /
- 间隙连接蛋白 /
- 上皮间质转化相关蛋白
Abstract:Objective To investigate the correlation between connexin(CX) 26, CX32, CX43 and epithelial mesenchymal transformation associated protein(E-cadherin and N-cadherin), and colorectal primary carcinoma and liver metastasis. Methods Forty colorectal cancer patients with liver metastasis diagnosed by pathological examination were investigated, and treated without chemotherapy, radiation, intervention and immunity therapy before operation.Forty colorectal cancer tissue specimens, 40 normal tissues adjacent to cancer specimens and 40 liver metastasis tissue specimens were divided into the group A, group B and group C, respectively.The expression levels of E-cadherin, N-cadherin, CX26, CX32 and CX43 in three groups were detected by immunohistochemical SP method.The relationship between the expression levels of E-cadherin, N-cadherin, CX26, CX32 and CX43 and clinicopathological features(including gender, age, depth of tumor invasion, degree of tissue differentiation and lymph node metastasis) of colorectal cancer were analyzed.The correlations of liver metastasis with levels of epithelial mesenchymal transformation, intercellular protein, CX26, CX32 and CX43 in colorectal cancer were analyzed. Results The differences of the positive expression rate of CX43 among the three groups were statistically significant(P < 0.05), and the differences of the positive expression rate of CX26, CX32, E-cadherin and N-cadherin among three groups were not statistically significant(P>0.05).The differences of the expression levels of E-cadherin, E-cadherin, CX26, CX32 and CX43 in different sex, age, depth of tumor invasion, degree of tissue differentiation and lymph node metastasis were not statistically significant(P>0.05), and the expression level of N-cadherin was positively correlated with degree of tissue differentiation(P < 0.05). Conclusions The expression levels of CX43 and epithelial mesenchymal transformation-associated proteins are significantly associated with colorectal primary carcinoma and liver metastasis. -
表 1 3组E-cadherin、N-cadherin及CX26、CX32、CX43表达
[n ;百分率(%)] 分组 n E-cadherin N-cadherin CX26 CX32 CX43 A组 40 32(80.0) 32(80.0) 33(82.5) 31(77.5) 31(77.5) B组 40 36(90.0) 28(70.0) 37(92.5) 36(90.0) 38(95.0) C组 40 28(70.0) 36(90.0) 29(72.5) 28(70.0) 29(72.5) χ2 — 5.00 5.00 5.54 4.95 7.46 P — >0.05 >0.05 >0.05 >0.05 < 0.05 表 2 E-cadherin、N-cadherin及CX26、CX32、CX43阳性与与结直肠癌临床病理特征的关系
[n ;百分率(%)] 分组 n E-cadherin N-cadherin CX26 CX32 CX43 性别 男 24 19(79.2) 18(75.0) 19(79.2) 20(83.3) 19(79.2) 女 16 13(81.2) 12(75.0) 12(75.0) 13(81.2) 12(75.0) χ2 — 0.03 0.00 0.10 0.03 0.10 P — >0.05 >0.05 >0.05 >0.05 >0.05 年龄/岁 <60 30 27(87.1) 28(90.3) 27(87.1) 28(90.3) 28(90.3) ≥60 10 8(80.0) 9(90.0) 9(80.0) 9(90.0) 9(90.0) χ2 — 1.21 0.01 0.06 0.01 0.01 P — >0.05 >0.05 >0.05 >0.05 >0.05 瘤浸润深度 T1和T2 12 10(83.3) 9(75.0) 9(75.0) 8(66.7) 10(83.3) T3 18 14(77.8) 13(72.2) 15(83.3) 14(77.8) 16(88.9) T4 10 7(70.0) 8(80.0) 8(80.0) 7(70.0) 9(90.0) χ2 — 0.56 0.21 0.31 0.49 0.27 P — >0.05 >0.05 >0.05 >0.05 >0.05 组织分化程度 高和中 20 16(80.0) 17(85.0) 17(85.0) 16(80.0) 18(90.0) 低 20 12(60.0) 11(55.0) 13(65.0) 12(60.0) 14(70.0) χ2 — 1.90 4.28 2.13 1.90 2.50 P — >0.05 < 0.05 >0.05 >0.05 >0.05 淋巴结转移情况 N0 4 3(75.0) 3(75.0) 3(75.0) 3(75.0) 3(75.0) N1 15 14(93.3) 13(86.7) 13(86.7) 12(80.0) 14(93.3) N2 21 13(61.9) 12(57.1) 13(61.9) 12(57.1) 13(61.9) χ2 — 4.61 3.68 2.70 2.20 4.61 P — >0.05 >0.05 >0.05 >0.05 >0.05 -
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