GLI1 orchestrates CXCR4/CXCR7 signaling to enhance migration and metastasis of breast cancer cells

Abstract

The up-regulation of chemokine receptors CXCR4 and CXCR7 impacts on the distant metastasis and prognosis of breast cancer, though knowledge about the regulatory mechanism of their expressions is limited. Meanwhile, the GLI transcription factors of Hedgehog signaling have been reported to play a pivotal role in the development and progression of many types of human cancer. In breast cancer, the increased expression of GLI1 correlated with metastasis and unfavorable overall prognosis, though its molecular mechanism is also not fully understood. Based on our findings that GLI1 enhanced the lung metastasis of breast cancer cells in a mouse model system, we comprehensively screened for genes up-regulated by GLI1 in breast cancer cells, and as such identified CXCR4, CXCR7/ACKR3, and actin-binding protein LCP1/L-PLASTIN, all of which have been reported to be involved in CXCL12-stimulating signaling. In breast cancer cells, we found that GLI1 and GLI2 up-regulated these expressions, while treatment with GLI-specific inhibitor GANT61 reduced the expressions. As for CXCR4, we confirmed it as a direct target of GLI1 through the reporter assay and the chromatin immunoprecipitation assay. We also found that GLI1 enhanced CXCL12-induced ERK phosphorylation and cell migration, both of which were blocked by either CXCR4-specific inhibitor or knockdown of CXCR7 or LCP1. These evidences suggest an indispensable role of GLI1 in the migration and metastasis of breast cancer cells through CXCL12/CXCR4 signaling enhancement.

Genetic deletion of genes in the cerebellar rhombic lip lineage can stimulate compensation through adaptive reprogramming of ventricular zone-derived progenitors

“…Furthermore, SDF1 is required to maintain GCPs in the outer EGL and to make them more permissive to SHH-dependent proliferation by inhibiting cAMP or PKA activity (46). Furthermore, SHH signaling induces the transcription of Cxcr4 and Cxcr7 , which contain GLI binding sites in their promoters (49). We propose that in Atoh1-Gli2 CKOs a subset of PCL NEPs are able to express CRE protein after integrating in the EGL, and the subsequent deletion of GLI2 protein reduces the expression of CXCR4, leading to migration of proliferating NEP-derive GCP-like cells back into the cerebellar cortex.…”

Breast cancer lung metastasis: Molecular biology and therapeutic implications

“…85 Inaquma et al demonstrated that the glioma-associated oncogene homolog 1 (GLI1) transcription factor enhances lung metastasis of breast cancer cells in a mouse model via its interaction of CXCL12-CXCR4 axis. 86 FOXC1, a transcription factor that is normally overexpressed in BLBC, could directly induce CXCR4 expression by activating its promoter in endothelial cells thereby controlling angiogenesis in breast cancer. 87 Furthermore, FOXC1 controls the cancer stem cell (CSC) properties enriched in BLBC cells via activation of Smoothened (SMO)-independent Gli2 activation.…”

Regulation of Hedgehog Signaling in Cancer by Natural and Dietary Compounds

“…Zerumbone, a sesquiterpene identified from the subtropical ginger Zingiber zerumbet , was reported to suppress the expression of CXCR4, a direct target of Gli1 involved in migration and metastasis of breast cancer cells . These results suggest that zerumbone may regulate metastasis through Gli1/CXCR4 in breast cancer.…”

“…Tumors metastasize by invading the basement membrane, extravasating into circulatory system including lymph and blood vessels, and intravasating to distant locations . Gli1 was found to directly bind the promoter region of human chemokine receptor 4 (CXCR4) gene and stimulate ERK phosphorylation in breast cancer which results in cellular invasiveness and metastasis . Further, TNF‐α induced Gli1 expression increased the migration and invasion of breast cancer cells by activating MMP‐9 .…”