CCL17‐CCR4 axis promotes metastasis via ERK/MMP13 pathway in bladder cancer

Zhao, Hongda; Bo, Qiyu; Wang, Weifen; Wang, Rui; Li, Yan; Chen, Shouzhen; Xia, Yangyang; Wang, Wenfu; Wang, Yong; Zhu, Ke-Cheng; Liu, Lei; Cui, Jianfeng; Wang, Shuai; Liu, Qinggang; Wu, Zonglong; Guo, Hu; Shi, Benkang

doi:10.1002/jcb.27494

Cited by 20 publications

(12 citation statements)

References 27 publications

(46 reference statements)

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“…Stimulation of regulatory T cells with CCL17/CCR4 can phosphorylate ERK1/2,36 and CCR4 up-regulates MMP13 expression through ERK1/2 in colorectal cancer 37. Similarly, Zhao et al, also reported that CCL17/CCR4 axis can induce the metastasis of bladder cancer cells by promoting ERK1/2 signaling and MMP13 expression 19. CXCL12/CXCR4 promoted laryngeal and hypopharyngeal squamous cell carcinoma metastasis through MMP-13-dependent invasion via the ERK1/2 signaling pathway 20.…”

Section: Discussionmentioning

confidence: 92%

“…MMP13 is known to promote BC cell invasion and metastasis and is associated with overall survival of BC patients 18. ERK1/2, as well as its downstream signaling effector MMP13, is some of the mechanism by which CXCL12/CXCR4 or CCL17/CCR4 regulates cell invasion and migration of laryngeal and hypopharyngeal squamous cell carcinoma and bladder cancer 19,20. However, how CCL17 regulates ERK1/2 pathway directly or indirectly remains unclear.…”

Section: Introductionmentioning

confidence: 99%

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<p>Down-regulation of CCL17 in cancer-associated fibroblasts inhibits cell migration and invasion of breast cancer through ERK1/2 pathway</p>

Chen

Yang

et al. 2019

CMAR

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Objective Cancer-associated fibroblasts (CAFs) in the tumor microenvironment are involved in cancer development and progression, including breast cancer (BC). Up-regulation of CCL17 was observed in BC and predicted a decrease in overall survival, suggesting an important role of CCL17 in BC development. Nonetheless, little is known about the role of CCL17 in the interaction between CAFs and BC. Materials and methods Real-time quantitative PCR, Western blot, and enzyme-linked immunosorbent assay were performed to examine C-C motif chemokine ligand 17 (CCL17) and C-C motif chemokine receptor 4 (CCR4) levels in BC tissues and CAFs. Cell proliferation, migration, and invasion of CAFs co-cultured with or without BC cell lines were measured by Cell Counting Kit-8 and Transwell analysis. Expression of CCL17, CCR4, dual specificity phosphatase 6 (DUSP6), matrix metallopeptidase 13 (MMP13), extracellular signal-regulated kinase (ERK) 1/2, and phosphor-ERK1/2 (p-ERK1/2) in BC cell lines co-cultured with or without CAFs was measured by Western blotting. Results We found that BC tissues and CAFs demonstrated higher levels of CCL17 compared with adjacent-normal breast tissues and adjacent-normal fibroblasts (NFs), respectively. CCL17 expression is correlated with lymph nodes, TNM stage and tumor size of BC patients. CCL17 knockdown significantly inhibited CCL17 release, CCR4 expression, and the cell proliferation of CAFs, while CCL17 overexpression demonstrated an inverse effect in NFs. Co-culture with CAFs induced the increases in cell proliferation, migration, invasion, and the expression of CCL17, CCR4, MMP13, and p-ERK1/2 in MCF-7 and MDA-MB-231 cells were markedly reversed by CCL17 knockdown in CAFs. Meanwhile, co-culture with NFs induced the malignant phenotype of MCF-7 cells was markedly enhanced by CCL17 overexpression in NFs. Moreover, DUSP6, a negative regulator of ERK1/2, was dose-dependent decrease in response to recombinant CCL17 and inhibited cell migration, invasion, MMP13 expression, and ERK1/2 activation in MCF-7 cells. Conclusion The findings of this study suggest that CCL17 may function as a novel biomarker as well as potential therapeutic target against BC and CAF-secreted CCL17 promotes BC cell migration and invasion through the DUSP6-dependent ERK1/2 pathway.

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Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

<p>Down-regulation of CCL17 in cancer-associated fibroblasts inhibits cell migration and invasion of breast cancer through ERK1/2 pathway</p>

Chen

Yang

et al. 2019

CMAR

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“…Previous studies have reported that CCR4 regulated the traffic of dendritic cells, recirculated T cells from tissue to draining lymph nodes, and migrated T cells to ectopic lymphoid tissue (24,25). CCR4 has also been found to be expressed in some epithelial cells, such as lung, colon, and bronchial epithelial cells (26,27) and to play an important role in many malignant tumors, including solid and hematological tumors (28)(29)(30).…”

Section: Discussionmentioning

confidence: 99%

CCR4 is a prognostic biomarker and correlated with immune infiltrates in head and neck squamous cell carcinoma

Zhang

Chen

Li³

et al. 2021

Ann Transl Med

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Background: Increased evidence has indicated that the tumour microenvironment plays an essential in the development, treatment and prognosis of head and neck squamous cell carcinoma (HNSC). Recent studies have indicated CC chemokine receptor 4 (CCR4) plays an essential role in tumor invasion and other adverse biological behavior. This study used data from the Cancer Genome Atlas (TCGA) database to explore the role of CCR4 in HNSC and its clinical significance. Methods: The gene expression and clinical data of HNSC patients in the TCGA database were extracted. Gene Expression Profiling Interactive Analysis (GEPIA) was used to analyze the expression of CCR4 in tumor and non-tumor tissue. Kaplan-Meier survival analysis was used to analyze the relationship between CCR4 expression and overall survival rate (OS), disease-specific survival (DSS), and progression-free interval (PFI) in HNSC. A logistic regression model was used to analyze the relationships between various clinical factors and CCR4 expression. Gene Set Enrichment Analysis (GSEA) was used to explore the potential role of CCR4 in HNSC. Additionally, we explored the relationship between CCR4 and immune infiltration.Results: The expression of CCR4 in HNSC was not significantly different from that in normal tissue. The expression level of CCR4 in wild-type TP53 was higher than that in mutant TP53. Cox regression analysis showed the expression level of CCR4 was related to the patient's tumor grade and Tumor-Node-Metastasis (TNM) stage. CCR4 expression level is an independent prognostic factor. CCR4 is positively correlated with immune infiltration and immune checkpoints expression levels. The results of GSEA revealed that the high CCR4 expression group genes were enriched in allograft rejection, inflammatory response, IL-6/JAK/ STAT3 signaling, interferon gamma response, and KRAS signaling up. Low CCR4 expression group genes were enriched in oxidative phosphorylation, MYC targets v1, DNA repair, reactive oxygen species pathway, and P53 pathway. Further, our study indicated CCR4 can also predict the prognosis of radiotherapy patients.Conclusions: Our study found that CCR4 was a prognostic marker related to HNSC immune infiltration, and patients with high expression of CCR4 had a better prognosis.

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“…MMP13 level in ascitic fluid was seemed to be associated with shorter survival. Thus, MMP13 could be a potential prognostic factor and plays an important role in ovarian cancer metastasis [29,30].…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-Inducible Factor-1α (HIF-1α) Promotes Hypoxia-Induced Invasion and Metastasis in Ovarian Cancer by Targeting Matrix Metallopeptidase 13 (MMP13)

Zhang

Yang²,

Lian

et al. 2019

Med Sci Monit

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Background: Hypoxia promotes cancer progression. Hypoxia-inducible factor-1a (HIF-1a) has been reported to enhance tumor invasion and metastasis via activating downstream genes, such as matrix metalloproteinases (MMPs). The purpose of this study was to explore the probable roles of HIF-1a and MMP13 in the invasion and metastasis of ovarian cancer under hypoxic conditions. Material/Methods: The expression of HIF-1a and MMP13 protein were detected with immunohistochemistry staining in ovarian cancer tissues, metastatic lesions, and normal fallopian tissues. Ovarian cancer A2780 cells were cultured under normoxic condition and hypoxic condition. mRNA and protein expression of HIF-1a and MMP13 were detected by RT-PCR and Western blot analysis. The effects of siRNA against HIF-1a on MMP13 expression were examined by RT-PCR and Western blot analysis. Transwell invasion assays were performed to test the invasive ability of A2780 cells. Results: Immunohistochemistry staining showed significantly higher expression of HIF-1a and MMP13 protein in ovarian cancer tissues and metastatic lesions than in normal fallopian tissues. HIF-1a and MMP13 expression were closely related. After exposure to hypoxia, mRNA and protein levels of HIF-1a and MMP13 were upregulated. siRNA effectively inhibited HIF-1a expression and MMP13 expression. The number of invading A2780 cells decreased after HIF-1a was silenced. Conclusions: This study suggests that HIF-1a promotes ovarian cancer cell invasion through a MMP13 mechanism. It might be an effective strategy targeting HIF-1a-MMP13 to inhibit invasion and metastasis of ovarian cancer.

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CCL17‐CCR4 axis promotes metastasis via ERK/MMP13 pathway in bladder cancer

Cited by 20 publications

References 27 publications

<p>Down-regulation of CCL17 in cancer-associated fibroblasts inhibits cell migration and invasion of breast cancer through ERK1/2 pathway</p>

<p>Down-regulation of CCL17 in cancer-associated fibroblasts inhibits cell migration and invasion of breast cancer through ERK1/2 pathway</p>

CCR4 is a prognostic biomarker and correlated with immune infiltrates in head and neck squamous cell carcinoma

Hypoxia-Inducible Factor-1α (HIF-1α) Promotes Hypoxia-Induced Invasion and Metastasis in Ovarian Cancer by Targeting Matrix Metallopeptidase 13 (MMP13)

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