CXCL1-LCN2 paracrine axis promotes progression of prostate cancer via the Src activation and epithelial-mesenchymal transition

Abstract

Background Mechanisms driving the progression of castration-resistant prostate cancer are believed to relate substantially to the tumor microenvironment. However, the cross-talks between tumor epithelial cell, stromal cells, and immune cells are yet to be fully elucidated. The present study aims to determine the role of chemokine and neutrophil derived cytokine paracrine axis in mediating the interaction between tumor cells, stromal myofibroblasts, and neutrophils in the tumor microenvironment of prostate cancer. Methods To identify myofibroblasts and neutrophil derived specific proteins affecting progression of prostate cancer, bioinformatics analyses were firstly performed in independent human prostate cancer gene expression data sets from the GEO data bank. Expression of stromal myofibroblasts secretory chemokine CXCL1 and neutrophil derived cytokine LCN2 was evaluated in prostate tissues via immunohistochemistry assay. We further investigated the effect of CXCL1 and LCN2 on prostate cancer using in vivo and in vitro models, and explored the underlying signal transduction pathways. Results A CXCL1-LCN2 paracrine network was confirmed in prostate cancer tissue samples, which was correlated with the biochemical recurrence of prostate cancer. Of note, CXCL1-LCN2 axis activates Src signaling, triggers the epithelial-mesenchymal transition (EMT), consequently promotes the migration of prostate cancer cells, leading to enhanced tumor metastasis. Conclusions Our findings may provide enhanced insight into the interactions of carcinoma-stromal cells and immune cells linked to prostate cancer progression, wherein CXCL1-LCN2 axis is a key contributor to prostate cancer cells migration. These data indicate tumor microenvironment and Src signaling pathway may be potential therapeutic targets of prostate cancer treatment.

Chemokines and their Receptors: Multifaceted Roles in Cancer Progression and Potential Value as Cancer Prognostic Markers

“…Interestingly, various chemokines have been implicated to contribute to EMT progression in cancer cells. EMT can be induced by CXCL8 and its receptors through overexpression of the transcription factor Brachyury [141], CCL2 with the enhancement of Snail expression [142], the CXCL6/CXCR1/2 axis via the PI3K/AKT and Wnt/β-catenin pathways [143], and the CXCL1/LCN2 paracrine axis with the activation of Src signalling [144]. In addition, NF-κB is associated with the EMT induced by CCL5 and CCL18 [145,146].…”

<p>Low-Dose Radiation Promotes Invasion and Migration of A549 Cells by Activating the CXCL1/NF-κB Signaling Pathway</p>

“…Recent studies have reported that CXCL1 is a key molecule leading to EMT and plays an important role in the development of various malignancies and metastasis. 22,23 Moreover, its high expression is associated with poor prognosis. 23 In this study, we showed for the first time that low-dose radiation can significantly upregulate the expression of CXCL1.…”

Identification of critical pathways and potential therapeutic targets in Poorly differentiated duodenal papilla adenocarcinoma

“…Lipocalin 2 (LCN2) is a secreted glycoprotein of lipocalin superfamily that is an important innate immunity component against bacterial pathogens and various cellular stress (19). Abnormal expression of LCN2 plays an extremely important role in the epithelial-to-mesenchymal transition process, angiogenesis, and cell migration and invasion in several cancers by involving multiple signaling pathways (20). A lot of research has indicated that LCN2 is correlated with high-grade malignancy, relapse proneness, metastasis and poor prognosis in epithelial-derived tumors (21).…”