Abstract
BackgroundCCR7 and MUC1 are correlated with lymph node metastasis in ESCC, but the role of MUC1 in the CCR7-induced lymphatic metastasis and the underlying molecular mechanism is still unclear.MethodsThe expression of CCR7 and MUC1 was detected in the ESCC samples by IHC, and the clinical significance of CCR7 and MUC1 in ESCC was analyzed. The expression of CCR7 and MUC1 in ESCC cell lines was detected by qRT-PCR and western blot. The effect of CCL21 on the migration and invasion of ESCC cells was determined by transwell assay. The activity of MUC1 promoter was determined by luciferase reporter assay. The activation of Erk, Akt and Sp1 was detected by western blot and the binding of Sp1 to the MUC1 promoter was determined by ChIP.ResultsThe co-expression of CCR7 and MUC1 was detected in 153 ESCC samples by IHC, and both were correlated with lymph node metastasis, regional lymphatic recurrence and poor prognosis. Correspondingly, increasing levels of MUC1 mRNA and protein were detected in the ESCC cell lines KYSE410 and Eca9706 after treatment with CCL21 in a time- and dose-dependent manner. Furthermore, silencing MUC1 could remarkably suppress the invasion and migration of ESCC cells induced by CCL21. Moreover, heterologous CCR7 promoted the invasion and migration of KYSE150 and up-regulated MUC1 expression. Increasing levels of activated ERK1/2 and Akt were detected in KYSE410 after treating the cells with CCL21, and inhibiting the activation of ERK1/2 but not Akt caused the increased transcription of MUC1. Finally, the phosphorylation of Sp1 induced by ERK1/2 and subsequent increases in the binding of Sp1 to the muc1 promoter at −99/−90 were confirmed to cause the up-regulation of MUC1 induced by CCL21-CCR7.ConclusionsOur findings suggested that MUC1 plays an important role in CCL21-CCR7-induced lymphatic metastasis and may serve as a therapeutic target in ESCC.
Highlights
chemokine receptor type 7 (CCR7) and cell surface associated mucin1 (MUC1) are correlated with lymph node metastasis in Esophageal squamous cell carcinoma (ESCC), but the role of MUC1 in the CCR7-induced lymphatic metastasis and the underlying molecular mechanism is still unclear
Co-expression of CCR7 and MUC1 in ESCC tissue To determine the correlation of CCR7 and MUC1 in ESCC tissue, we detected the expression of CCR7 and MUC1 by IHC in 153 ESCC samples
To further confirm the role of CCR7 in the up-regulation of MUC1 induced by CCL21, we used the specific antibody to block CCR7, and the results showed that blocking CCR7 could significantly suppress the up-regulation of MUC1 Cterminal subunit (MUC1-C) induced by CCL21 (Fig. 2h, i)
Summary
CCR7 and MUC1 are correlated with lymph node metastasis in ESCC, but the role of MUC1 in the CCR7-induced lymphatic metastasis and the underlying molecular mechanism is still unclear. Shi et al Journal of Experimental & Clinical Cancer Research (2015) 34:149 chemokines highly expressed in target organs could attract and capture tumor cells by binding with the chemokine receptors expressed on the surface of tumor cells [6, 7]. As a member of chemokine receptor family, C-C chemokine receptor type 7 (CCR7) is mainly located on the membrane of mature dendritic and T cells, and it could induce the “homing” of dendritic and T cells to the lymph node by binding with its specific ligands CCL19 and CCL21, which are highly expressed in the endothelium of lymphatic vessels and secondary lymph nodes [8, 9]. Studies have identified the upregulation of CCR7 in various types of malignant tumors, such as breast cancer, gastric cancer, and prostate cancer, and have revealed its function in promoting lymph node metastasis [10,11,12]
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