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

Shingo Inaguma,Miho Riku,Hiroshi Ikeda,Kenji Kasai,Hideaki Ito,Takumi Tsunoda

doi:10.18632/oncotarget.5203

Shingo Inaguma, Miho Riku + Show 4 more

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https://doi.org/10.18632/oncotarget.5203

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Journal: Oncotarget	Publication Date: Sep 16, 2015
Citations: 87	License type: cc-by

Affiliation: Aichi Medical University

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.

Highlights

Breast cancer frequently exhibits distant metastasis to bone, lung, liver, and brain, which worsens morbidity and mortality associated with the disease
We found that the GLI1 expression increased the number of metastatic foci of the lung (Figure 1A, 1B; see Figure 2C for GLI1 expression in 4T1-LucGLI1), indicating the activity of GLI1 had to do with the metastatic potential of breast cancer cells. 4T1-Luc cells expressed a low amount but detectable levels of GLI1
Assuming that GLI1 up-regulates a set of these CXCL12related signaling components in breast cancer cells, we focused our study on CXCR4, CXCR7 and LCP1

Summary

Introduction

Breast cancer frequently exhibits distant metastasis to bone, lung, liver, and brain, which worsens morbidity and mortality associated with the disease. This tissue-specific metastasis has been explained in part by the expression of CXCR4 and its downstream signaling of breast cancer cells. To date, the molecular mechanism of CXCR4 expression has not been fully understood. While transcriptional regulators such as USF/c-myc [7], NFkB [8] and p53 [9] have been reported to contribute to the regulation of CXCR4 expression, they are ubiquitously expressed; estrogen receptor-dependent up-regulation of CXCR4 in breast cancer cells has been reported [10], but it does not account for the fact that a high level expression of CXCR4 predicts a poor prognosis for a “triple-negative” type of breast cancer, which does not express a hormone receptor [3]

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