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

Abstract

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.

The Detection of Plasma Soluble Podoplanin of Patients with Breast Cancer and Its Clinical Signification

“…CAF has been reported as a sign of breast cancer recurrence. 33 Our IHC results are consistent with that finding suggesting that infiltration of positive PDPN CAFs can predict poor prognosis. 34 , 35 The expression of PDPN (probably in tumor stroma) was detected in the surgical specimens of 15 out of 40 IDC patients, especially in the patients of late clinical stage who had lymph node metastasis, high expression of Ki67 and sPDPN, and were estrogen receptor- and progesterone receptor-negative.…”

Identification of a Six-Gene Signature for Predicting the Overall Survival of Cervical Cancer Patients

“… 26 Interestingly, many studies have shown that CCL17 can also stimulate cancer cell proliferation and migration. 27 , 28 However, in the present study, the expression of CCL17 was evaluated in CC tissue, and the results showed that lower expression of CCL17 was associated with a poor prognosis in CC patients. 29 , 30 DES encodes a muscle-specific class III intermediate filament that plays a crucial role in maintaining the structure of sarcomeres, interconnecting Z-disks and forming myofibrils.…”

Identification of a Six-gene Signature Predicting Overall Survival for Cervical Cancer

“…Interestingly, many studies also showed that CCL17 can also stimulate cancer cell proliferation and migration [28,29] [30,31]. However, in present study, the expression of CLL17 was evaluated in the cervical cancer tissue and showed lower expression was associated with poor prognosis of cervical caner.…”