Role of the CXCR4-LASP1 Axis in the Stabilization of Snail1 in Triple-Negative Breast Cancer

Abstract

The CXCL12-CXCR4 axis plays a vital role in many steps of breast cancer metastasis, but the molecular mechanisms have not been fully elucidated. We previously reported that activation of CXCR4 by CXCL12 promotes the nuclear localization of LASP1 (LIM and SH3 protein 1). The nuclear LASP1 then interacts with Snail1 in triple-negative breast cancer (TNBC) cell lines. In this study, we report that the nuclear accumulation and retention of Snail1 was dependent on an increase in nuclear LASP1 levels driven by active CXCR4. The CXCR4-LASP1 axis may directly regulate the stabilization of nuclear Snail1, by upregulating nuclear levels of pS473-Akt, pS9-GSK-3β, A20, and LSD1. Furthermore, the activation of CXCR4 induced association of LASP1 with Snail1, A20, GSK-3β, and LSD1 endogenously. Thus, nuclear LASP1 may also regulate protein-protein interactions that facilitate the stability of Snail1. Genetic ablation of LASP1 resulted in the mislocalization of nuclear Snail1, loss of the ability of TNBC cells to invade Matrigel and a dysregulated expression of both epithelial and mesenchymal markers, including an increased expression of ALDH1A1, a marker for epithelial breast cancer stem-like cells. Our findings reveal a novel role for the CXCR4-LASP1 axis in facilitating the stability of nuclear localized Snail1.

Triptonide Effectively Inhibits Triple-Negative Breast Cancer Metastasis Through Concurrent Degradation Of Twist1 And Notch1 Oncoproteins

“…These data suggest that the effect of triptonide on Snail1 expression may be limited only in the in vitro produced triptonide-resistant HCC1806 cell line, but is uncommon in TNBC cell lines. Of note, overexpression of the transcription factor Snail drives overexpression of various oncogenic and metastatic genes, activates multiple tumorigenic signaling pathways, and promotes EMT, tumorigenesis, cancer metastasis, and drug resistance [42][43][44][45][46][47][48][49][50][51]. Therefore, up-regulation of Snail1 should not be good idea for cancer therapy; instead, suppression of Snail1 should be a sensible strategy for treatment of malignant tumors.…”

“…More recently, Gao B., et al reported that triptonide inhibits TNBC cell tumorigenesis via downregulation of several cancer stem cell-associated genes, up-regulation of Snail1 expression, and induction of a Snail1-associated feedback mechanism for triptonide resistance [37]. Of note, it is wellknown that Smail1 is aberrantly overexpressed in various types of malignant tumors including TNBC [38][39][40][41], overexpression of Snail triggers EMT [40,[42][43][44][45], carcinogenesis [46][47][48][49], and drug resistance [50,51], and is closely associated with poor prognosis in cancer patients [38,41,44,45,48,49]. Accordingly, inhibition of Snail1 in cancer has become a new strategy for developing cancer therapeutics [50][51][52].…”

Roles for growth factors and mutations in metastatic dissemination

“…• The CXCR4-LASP1 axis enhances the stability of nuclear Snail1, to promote invasion of TNBC cells [133]. • CXCL12/CXCR4 promotes invasion of ovarian cancer cells by means of suppressing ARHGAP10 expression [134].…”

The Prognostic and Clinicopathological Significance of LASP1 Expression in Cancer Patients: Systematic Review and Meta-Analysis

“…A total of 2023 cancer patients from 18 included studies concerning LASP1 were included in this study [9][10][11][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29]. The sample size in these studies ranged from 32 to 216.…”

“…The included studies were performed in Asia, Europe and North America, and majority of these studies were conducted in China. Among the 18 eligible studies, 16 studies reported OS [9,11,[15][16][17][18][19][20][21][22][23][24][25][26][27]29], 2 studies reported RFS [20,28], and 13 studies reported clinicopathological parameters [9-11, 15-20, 22, 23, 27, 29]. The included articles varied in their detection regions of LASP1 expression and the cut-off value for LASP1 positive, which might have an effect on the positive rate of LASP1 overexpression.…”