title: 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.
authors.affiliation: Department of Pathology, Aichi Medical University School of Medicine, Nagakute, Aichi 480-1195, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Inaguma
authors.affiliation: Department of Pathology, Aichi Medical University School of Medicine, Nagakute, Aichi 480-1195, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Riku
authors.affiliation: Department of Pathology, Aichi Medical University School of Medicine, Nagakute, Aichi 480-1195, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Ito
authors.affiliation: Department of Pathology, Aichi Medical University School of Medicine, Nagakute, Aichi 480-1195, Japan.
authors.forename: Takumi
authors.initials: T
authors.lastname: Tsunoda
authors.affiliation: Department of Pathology, Aichi Medical University School of Medicine, Nagakute, Aichi 480-1195, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ikeda
authors.affiliation: Department of Pathology, Aichi Medical University School of Medicine, Nagakute, Aichi 480-1195, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kasai
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D049109:Cell Proliferation / Q000502:physiology; D005260:Female; D006801:Humans; D009362:Neoplasm Metastasis; D054387:Receptors, CXCR / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D000071676:Zinc Finger Protein GLI1
chemical_list: C501896:ACKR3 protein, human; C527276:CXCR4 protein, human; C400551:GLI1 protein, human; D054387:Receptors, CXCR; D019718:Receptors, CXCR4; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1
keywords: CXCR4; CXCR7; GLI1; breast cancer; migration