CCR6 promotes liver metastasis of colorectal cancer through epithelial-mesenchymal transition

Abstract

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

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.

Figures/Tables3

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

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

References10

[1]	Ferlay J, Soerjomataram I, Dikshit R , et al. Cancer incidence and mortality wordwide: sourse, methods and major patterns in GLOBOCAN 2012[J]. Int J Cancer, 2015,136(5):E359-E386. DOI: 10.1002/ijc.29210.
[2]	Frick VO, Rubie C, Keilholz U , et al. Chemokine/Chemokine receptor pair CCL20/CCR6 in human colorectal malignancy: an overview[J]. World J Gastroenterol, 2016,22(2):833-841. DOI: 10.3748/wjg.v22.i2.833.
[3]	Kucharzik T, Hudson JT 3rd, Waikel RL , et al. CCR6 expression distinguishes mouse myeloid and lymphoid dendritic cell subsets: demonstration using a CCR6 EGFP knock-in mouse[J]. Eur J Immunol, 2002,32(1):104-112. DOI: 10.1002/1521-4141(200201)32:1<104::AID-IMMU104>3.0.CO;2-C.
[4]	Liu J, Zheng X, Deng H , et al. Expression of CCR6 in esophageal squamous cell carcinoma and its effects on epithelial-to-mesenchymal transition[J]. Oncotarget, 2017,8(70):115244-115253. DOI: 10.18632/oncotarget.23318.
[5]	Balacescu O, Sur D, Cainap C , et al. The impact of miRNA in colorectal cancer progression and its liver metastases[J]. Int J Mol Sci, 2018, 19(12). pii: E3711. DOI: 10.3390/ijms19123711.
[6]	Lu E, Su J, Zhou Y , et al. CCL20/CCR6 promotes cell proliferation and metastasis in laryngeal cancer by activating p38 pathway[J]. Biomed Pharmacother, 2017,85:486-492. DOI: 10.1016/j.biopha.2016.11.055.
[7]	He H, Wu J, Zang M , et al. CCR6⁺B lymphocytes responding to tumor cell-derived CCL20 support hepatocellular carcinoma progression via enhancing angiogenesis [J]. Am J Cancer Res, 2017,7(5):1151-1163.
[8]	Shimizu Y, Murata H, Kashii Y , et al. CC-chemokine receptor 6 and its ligand macrophage inflammatory protein 3alpha might be involved in the amplification of local necroinflammatory response in the liver[J]. Hepatology, 2001,34(2):311-319. DOI: 10.1053/jhep.2001.26631.
[9]	Rubie C, Frick VO, Ghadjar P , et al. Effect of preoperative FOLFOX chemotherapy on CCL20/CCR6 expression in colorectal liver metastases[J]. World J Gastroenterol, 2011,17(26):3109-3116. DOI: 10.3748/wjg.v17.i26.3109.
[10]	Kapur N, Mir H, Clark lii CE , et al. CCR6 expression in colon cancer isassociated with advanced disease and supports epithelial-to-mesenchymal transition[J]. Br J Cancer, 2016,114(12):1343-1351. DOI: 10.1038/bjc.2016.113.

[1]	Zhang Rui, Chu Yanliu.Research progress of colorectal cancer risk assessment models based on FIT and gut microbiota[J]. Journal of International Oncology, 2024, 51(6): 370-375.
[2]	Gao Fan, Wang Ping, Du Chao, Chu Yanliu.Research progress on intestinal flora and non-surgical treatment of the colorectal cancer[J]. Journal of International Oncology, 2024, 51(6): 376-381.
[3]	Wang Junyi, Hong Kaibin, Ji Rongjia, Chen Dachao.Effect of cancer nodules on liver metastases after radical resection of colorectal cancer[J]. Journal of International Oncology, 2024, 51(5): 280-285.
[4]	Sun Guobao, Yang Qian, Zhuang Qingchun, Gao Binbin, Sun Xiaogang, Song Wei, Sha Dan.Research progress on the histopathological growth patterns of colorectal liver metastasis[J]. Journal of International Oncology, 2024, 51(2): 114-118.
[5]	Liu Debao, Sun Ziwen, Lu Shoutang, Xu Haidong.Expression and clinical significance of ASB6 in colorectal cancer tissues[J]. Journal of International Oncology, 2023, 50(8): 470-474.
[6]	Wang Wende, Zeng De.Research progress on the mechanism of endocrine therapy resistance for breast cancer[J]. Journal of International Oncology, 2023, 50(6): 352-356.
[7]	Chen Zhuo, Tao Jun, Chen Lin, Ke Jing.Value of detection of peripheral blood miR-194 combined with fecal miR-143 in the clinical screening of colorectal cancer[J]. Journal of International Oncology, 2023, 50(5): 268-273.
[8]	Ding Hao, Ying Jintao, Fu Maoyong.Research progress of CAR-T in the treatment of esophageal squamous cell carcinoma[J]. Journal of International Oncology, 2023, 50(4): 231-235.
[9]	Li Jiaxuan, Feng Yinglu.Mechanism of action of glucocorticoid receptors in the growth of hepatoma cells[J]. Journal of International Oncology, 2023, 50(4): 241-243.
[10]	Huang Zhen, Zhang Caiyutian, Ke Shaobo, Shi Wei, Zhao Wensi, Chen Yongshun.Construction of postoperative prognosis model for patients with colorectal cancer[J]. Journal of International Oncology, 2023, 50(3): 157-163.
[11]	Xu Liangfu, Li Yuanfei.Research progress on tumor microenvironment and immune combination therapy of MSS colorectal cancer[J]. Journal of International Oncology, 2023, 50(3): 186-190.
[12]	Zhang Bixia, Ding Jianghua.Immunotherapy for EGFR-mutant non-small cell lung cancer after EGFR-TKI acquired resistance[J]. Journal of International Oncology, 2023, 50(2): 97-101.
[13]	Liu Yujie, Zhao Zhiqiang, Wang Zicheng.Levels and diagnostic value of TOP2A and ERBB2 in peripheral blood mononuclear cells of patients with early colorectal cancer[J]. Journal of International Oncology, 2023, 50(12): 717-722.
[14]	Tao Hong, Yin Hong, Luo Hong, Tao Jiayu.Potential strategies for targeting tumor-associated macrophages to enhance the efficacy of immune checkpoint inhibitors for colorectal cancer[J]. Journal of International Oncology, 2023, 50(11): 683-687.
[15]	Wang Xi, Wu Chuanqing.Research progress in reversing multidrug resistance in colorectal cancer[J]. Journal of International Oncology, 2023, 50(1): 42-46.