CCR6通过上皮间质转化促进结直肠癌肝转移的机制研究

摘要/Abstract

摘要：

目的检测人趋化因子受体6(CCR6)、人趋化因子配体20(CCL20)、E-钙黏着蛋白和波形蛋白在结直肠癌及肝转移组织中的表达,探讨CCR6参与结直肠癌肝转移的可能机制。方法选取山西医科大学第一医院及山西省肿瘤医院2009至2017年资料齐全的62例原发性结直肠癌患者(结肠癌54例、直肠癌8例)手术切除存档蜡块,其中包含同期切除结直肠癌伴肝转移病灶的标本20例。采用免疫组织化学法检测结直肠癌及肝转移组织中CCR6、CCL20、E-钙黏着蛋白和波形蛋白的表达情况,分析CCR6、E-钙黏着蛋白和波形蛋白的表达与患者临床病理特征之间的关系,采用logistic多因素回归分析肝转移与患者临床病理特征及CCR6、E-钙黏着蛋白和波形蛋白表达的关系,采用Spearman相关分析CCR6与E-钙黏着蛋白和波形蛋白的相关性。结果CCR6在结直肠癌组织中的阳性表达率为66.1%(41/62);在伴有肝转移的结直肠癌组织中的阳性表达率为85.0 %(17/20),在肝转移组织中的阳性表达率为70.0%(14/20)。CCL20在结直肠癌中的阳性表达率为83.9%(52/62);在伴有肝转移的结直肠癌组织中的阳性表达率为90.0%(18/20),在肝转移组织中的阳性表达率为90.0%(18/20)。E-钙黏着蛋白在结直肠癌中的阳性表达率为67.7%(42/62);在伴有肝转移的结直肠癌组织中的阳性表达率为50.0%(10/20),肝转移组织中的阳性表达率为65.0%(13/20)。波形蛋白在结直肠癌组织中阳性表达率为79.0%(49/62);在伴有肝转移的结直肠癌组织中的阳性表达率为85.0%(17/20),在肝转移组织中的阳性表达率为90.0%(18/20)。CCR6的表达与淋巴结转移(χ²=11.142,P=0.001)、肝转移(χ²=4.694,P=0.030)、TNM分期(χ²=21.785,P<0.001)密切相关;E-钙黏着蛋白的表达与患者淋巴结转移(χ²=4.694,P=0.030)、肝转移(χ²=4.253,P=0.039)、TNM分期(χ²=7.867,P=0.005)密切相关;波形蛋白的表达与患者淋巴结转移(χ²=7.293,P=0.007)、TNM分期(χ²=5.712,P=0.017)密切相关。CCR6、E-钙黏着蛋白、波形蛋白均与结直肠癌患者的性别、年龄、肿瘤部位、肿瘤大小及分化程度无关(均P>0.05)。logistic多因素回归分析发现,CCR6(OR=6.812,95%CI为1.206~38.474,P=0.030)、E-钙黏着蛋白(OR=0.256,95%CI为0.069~0.945,P=0.041)是结直肠癌患者肝转移的独立影响因素。Spearman相关分析显示,在20例晚期结直肠癌患者肝转移组织中,CCR6与E-钙黏着蛋白表达(r=0.454,P=0.044)、波形蛋白表达(r=0.509,P=0.022)相关。结论CCR6可能通过上皮间质转化机制促进结直肠癌的进展和肝转移。

关键词:结直肠肿瘤,受体,CCR6,钙黏着糖蛋白类,波形蛋白,肝转移

Abstract:

ObjectiveTo detect the expressions of chemokine receptor 6 (CCR6), CC chemokine ligand 20 (CCL20) E-cadherin and vimentin in tissues of colorectal cancer and their paired liver metastases, and to investigate the possible mechanism of CCR6 in liver metastasis of colorectal cancer.MethodsA total of 62 cases (54 cases of colon cancer and 8 cases of rectal cancer) of primary colorectal adenocarcinoma resection with wax lumps were selected from the First Hospital of Shanxi Medical University and Shanxi Oncology Hospital from 2009 to 2017 with complete data, including 20 samples of colorectal cancer resection with liver metastasis during the same period. The expressions of CCR6, CCL20, E-cadherin and vimentin in colorectal cancer and liver metastases tissues were detected by immunohistochemistry, and the relationships between the expressions of CCR6, E-cadherin and vimentin and the clinicopathological features of patients were analyzed. Logistic multivariate regression was used to analyze the relationship between liver metastasis and clinicopathological features, CCR6, E-cadherin and vimentin. Spearman correlation was used to analyze the correlations between CCR6 and E-cadherin and vimentin.ResultsThe positive expression rate of CCR6 in colorectal cancer tissues was 66.1% (41/62), 85.0% (17/20) in colorectal cancer with liver metastasis and 70.0% (14/20) in liver metastasis tissues. The positive expression rate of CCL20 in colorectal cancer tissues was 83.9% (52/62), 90.0% (18/20) in colorectal cancer with liver metastasis and 90.0% (18/20) in liver metastasis tissues. The positive expression rate of E-cadherin in colorectal cancer tissues was 67.7% (42/62), 50.0% (10/20) in colorectal cancer with liver metastasis and 65.0% (13/20) in liver metastasis tissues. The positive expression rate of vimentin in colorectal cancer tissues was 79.0% (49/62), 85.0% (17/20) in colorectal cancer with liver metastasis and 90.0% (18/20) in liver metastasis tissues. The expression of CCR6 was closely related to lymph node metastasis (χ²=11.142,P=0.001), liver metastasis (χ²=4.694,P=0.030) and TNM stage (χ²=21.785,P<0.001). E-cadherin was closely related to lymph node metastasis (χ²=4.694,P=0.030), liver metastasis (χ²=4.253,P=0.039) and TNM stage (χ²=7.867,P=0.005). Vimentin was closely related to lymph node metastasis (χ²=7.293,P=0.007) and TNM stage (χ²=5.712,P=0.017). CCR6, E-cadherin and vimentin were independent of gender, age, tumor site, tumor size and differentiation degree of colorectal cancer patients (allP>0.05). Logistic regression analysis showed that the expressions of CCR6 (OR=6.812, 95%CI: 1.206-38.474,P=0.030) and E-cadherin (OR=0.256, 95%CI: 0.069-0.945,P=0.041) were independent factors affecting the liver metastasis of colorectal cancer. Spearman correlation analysis showed that CCR6 was associated with E-cadherin expression (r=0.454,P=0.044) and vimentin expression (r=0.509,P=0.022) in 20 iver metastasis tissues of colorectal cancer.ConclusionCCR6 may promote colorectal cancer progress and liver metastasis by part of epithelial-mesenchymal transition.

Key words:Colorectal neoplasms,Receptors,CCR6,Cadherins,Vimentin,Liver metastasis

张海利, 李娟芳, 李晓晴, 史淋洁, 李袁飞. CCR6通过上皮间质转化促进结直肠癌肝转移的机制研究[J]. 国际肿瘤学杂志, 2020, 47(1): 29-34.

Zhang Haili, Li Juanfang, Li Xiaoqing, Shi Linjie, Li Yuanfei. CCR6 promotes liver metastasis of colorectal cancer through epithelial-mesenchymal transition[J]. Journal of International Oncology, 2020, 47(1): 29-34.

图/表3

图1

表1

62例结直肠癌患者CCR6、E-钙黏着蛋白、波形蛋白的表达与临床病理特征的关系(例)"

临床病理特征	CCR6		χ²值	P值	E-钙黏着蛋白				χ²值		P值		波形蛋白		χ²值	P值
临床病理特征	+	-	χ²值	P值	+		-		χ²值		P值		+	-	χ²值	P值
性别
男	18	12	0.975	0.323	20		10		0.031		0.861		23	7	0.196	0.658
女	23	9			22		10						26	6
年龄(岁)
≤55	14	6	0.198	0.657	12		8		0.810		0.368		17	3	0.214	0.643
>55	27	15			30		12						32	10
肿瘤部位
结肠	36	18	0.000	1.000	35		19		0.767		0.381		42	12	0.027	0.869
直肠	5	3			7		1						7	1
肿瘤最大径(cm)
≤5	21	15	2.329	0.127	25		11		0.114		0.736		26	10	2.403	0.121
>5	20	6			17		9						23	3
有无淋巴结转移
无	8	13	11.142	0.001	18		3		4.694		0.030		12	9	7.293	0.007
有	33	8			24		17						37	4
有无肝转移
无	24	18	4.694	0.030	32		10		4.253		0.039		32	10	0.214	0.643
有	17	3			10		10						17	3
临床病理特征	CCR6		χ²值	P值		E-钙黏着蛋白				χ²值		P值	波形蛋白		χ²值	P值
临床病理特征	+	-	χ²值	P值		+		-		χ²值		P值	+	-	χ²值	P值
TNM分期
Ⅰ~Ⅱ期	8	17	21.785	<0.001		22		3		7.867		0.005	16	9	5.712	0.017
Ⅲ~Ⅳ期	33	4				20		17					33	4
分化程度
低分化	9	1	1.896	0.169		6		4		0.041		0.839	10	0	1.835	0.176
高中分化	32	20				36		16					39	13

表1

表2

62例结直肠癌患者肝转移与临床病理特征及与CCR6、E-钙黏着蛋白和波形蛋白表达的多因素分析"

参数	β值	SE值	Wald值	P值	OR值	95%CI
性别	0.465	0.661	0.495	0.482	1.592	0.436~5.811
年龄	-0.158	0.676	0.055	0.815	0.854	0.227~3.212
肿瘤部位	-1.011	1.176	0.739	0.390	0.364	0.036~3.645
肿瘤最大径	-0.300	0.682	0.193	0.660	0.741	0.195~2.820
分化程度	1.430	0.958	2.229	0.135	4.177	0.639~27.293
CCR6	1.919	0.883	4.717	0.030	6.812	1.206~38.474
E-钙黏着蛋白	-1.363	0.666	4.183	0.041	0.256	0.069~0.945
波形蛋白	-0.210	0.975	0.046	0.830	0.811	0.120~5.480

表2

参考文献10

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