Feedback control of the CXCR7/CXCL11 chemokine axis by estrogen receptor α in ovarian cancer

Abstract

Ovarian cancer (OC) is one of the most intractable diseases, exhibiting tremendous molecular heterogeneity and lacking reliable methods for screening, resulting in late diagnosis and widespread peritoneal dissemination. Menopausal estrogen replacement therapy is a well‐recognized risk factor for OC, but little is known about how estrogen might contribute to this disease at the cellular level. This study identifies chemokine receptor CXCR7/ACKR3 as an estrogen‐responsive gene, whose expression is markedly enhanced by estrogen through direct recruitment of ERα and transcriptional active histone modifications in OC cells. The gene encoding CXCR7 chemokine ligand I‐TAC/CXCL11 was also upregulated by estrogen, resulting in Ser‐118 phosphorylation, activation, and recruitment of estrogen receptor ERα at the CXCR7 promoter locus for positive feedback regulation. Both CXCR7 and CXCL11, but not CXCR3 (also recognized to interact with CXCL11), were found to be significantly increased in stromal sections of microdissected tumors and positively correlated in mesenchymal subtype of OC. Estrogenic induction of mesenchymal markers SNAI1, SNAI2, and CDH2 expression, with a consequent increase in cancer cell migration, was shown to depend on CXCR7, indicating a key role for CXCR7 in mediating estrogen upregulation of mesenchymal markers to induce invasion of OC cells. These findings identify a feed‐forward mechanism that sustains activation of the CXCR7/CXCL11 axis under ERα control to induce the epithelial–mesenchymal transition pathway and metastatic behavior of OC cells. Such interplay underlies the complex gene profile heterogeneity of OC that promotes changes in tumor microenvironment and metastatic acquisition.

What doesn't kill you makes you stranger: Dipeptidyl peptidase-4 (CD26) proteolysis differentially modulates the activity of many peptide hormones and cytokines generating novel cryptic bioactive ligands

“…It was also found that higher levels of CXCL12(5-67) in brain were associated with HIV-1 infection (McQuibban, et al, 2001;Zhang, et al, 2003). The interesting and relevant part, is that this form of cleaved CXCL12(5-67) did not act through CXCR4, the regular receptor for intact CXCL12, but exerted its neurotoxic and immunogenic actions through the chemokine receptor CXCR3, which also shares the ligand CXCL11 with ACKR3, which is promiscuous in being activation-prone by Nterminal modified CXCL11 and CXCL12 (Benhadjeba, et al, 2018;Vergote, et al, 2006). This does not mean that DPP4-cleaved CXCL12 acts through CXCR3, but it reinforces the idea that a proteolytic enzyme can generate a new cryptic ligand to a receptor that was not activated by the intact parent peptide.…”

An Overview of Candidate Therapeutic Target Genes in Ovarian Cancer

“…Moreover, it has been observed that CXCR7 (C-X-C Chemokine Receptor Type 7) and CXCL11 (C-X-C motif chemokine 11) genes are activated by estrogens through the direct recruitment of ERα and this leads to increased migration and invasion of OC cells [ 83 ]. Estrogens are also able to influence the anoikis process by Bit1 involvement.…”

Associations between TAB2 Gene Polymorphisms and Epithelial Ovarian Cancer in a Chinese Population

“…In fact, GWAS have identified several risk loci demonstrating a shared association between breast and ovarian cancer risk [19]. Previous studies have also shown that ESR1 is involved in the development and progression of EOC [30], and genetic susceptibility studies have suggested that polymorphisms in the ER-α gene confer increased risk for EOC [31]. Thus, in line with the present study, it is possible that the association between rs237028 and EOC susceptibility be mediated through the ER signaling pathway.…”