CXCL1 derived from tumor-associated macrophages promotes breast cancer metastasis via activating NF-κB/SOX4 signaling

Abstract

Tumor-associated macrophages (TAMs) have been implicated in the promotion of breast cancer growth and metastasis, and multiple TAM-secreted cytokines have been identified associating with poor clinical outcomes. However, the therapeutic targets existing in the loop between TAMs and cancer cells are still required for further investigation. Here in, cytokine array validated that C-X-C motif chemokine ligand 1 (CXCL1) is the most abundant chemokine secreted by TAMs, and CXCL1 can promote breast cancer migration and invasion ability, as well as epithelial–mesenchymal transition in both mouse and human breast cancer cells. QPCR screening further validated SOX4 as the highest responsive gene following CXCL1 administration. Mechanistic study revealed that CXCL1 binds to SOX4 promoter and activates its transcription via NF-κB pathway. In vivo breast cancer xenografts demonstrated that CXCL1 silencing in TAMs results in a significant reduction in breast cancer growth and metastatic burden. Bioinformatic analysis and clinical investigation finally suggested that high CXCL1 expression is significantly correlated with breast cancer lymph node metastasis, poor overall survival and basal-like subtype. Taken together, our results indicated that TAMs/CXCL1 promotes breast cancer metastasis via NF-κB/SOX4 activation, and CXCL1-based therapy might become a novel strategy for breast cancer metastasis prevention.

XIAOPI formula inhibits the pre-metastatic niche formation in breast cancer via suppressing TAMs/CXCL1 signaling

“…However, our previous findings demonstrated that CXCL1 acts as the highest chemokine secreted by TAMs isolated from breast cancer [16,41]. Moreover, CXCL1 silencing in TAMs was found to inhibit breast cancer growth and lung metastasis via inhibiting NF-κB/SOX4 signaling in both murine and human models [42]. Similar results were also observed in other malignancies.…”

PTEN deletion drives aberrations of DNA methylome and transcriptome in different stages of prostate cancer

“…However, the role of CXCL1 in prostate-specific PTEN KO-induced PCa progression has been poorly investigated. 41 Also, targeting IL-6 and TIMP4 interactions with a CXCL1 monoclonal antibody offers a novel strategy to F I G U R E 7 Validation of the mRNA changes observed for selected genes and their regulation by PTEN loss. 39 Increased CXCL1 protein levels were present in high-grade malignancies, in which it was associated with higher-grade prostate tumors.…”

“…40 Increasing evidence shows that TAMs/ CXCL1 promotes breast cancer metastasis via NF-κB/ SOX4 activation, and CXCL1-based therapy might become a novel strategy for breast cancer metastasis prevention. 41 Also, targeting IL-6 and TIMP4 interactions with a CXCL1 monoclonal antibody offers a novel strategy to therapeutically manage prostate and bladder cancers. 42 A recent study showed that obese patients with PCa have increased epithelial CXCL1 expression.…”

Alternative polyadenylation is a determinant of oncogenic Ras function

“…In addition, mining of our RNAseq dataset revealed expression changes in EMT-related genes upon CFIm25 depletion, especially in the KRAS mutant cells, including increased TGF-b2 expression, reduced Occludin, and significant upregulation of multiple EMTassociated chemokines ( Supplementary Fig. 7b), providing more evidence that CFIm25 regulates EMT [50][51][52] .…”