SLUG promotes prostate cancer cell migration and invasion via CXCR4/CXCL12 axis

Abstract

BackgroundSLUG is a zinc-finger transcription factor of the Snail/Slug zinc-finger family that plays a role in migration and invasion of tumor cells. Mechanisms by which SLUG promotes migration and invasion in prostate cancers remain elusive.MethodsExpression level of CXCR4 and CXCL12 was examined by Western blot, RT-PCR, and qPCR analyses. Forced expression of SLUG was mediated by retroviruses, and SLUG and CXCL12 was downregulated by shRNAs-expressing lentiviruses. Migration and invasion of prostate cancer were measured by scratch-wound assay and invasion assay, respectively.ResearchWe demonstrated that forced expression of SLUG elevated CXCR4 and CXCL12 expression in human prostate cancer cell lines PC3, DU145, 22RV1, and LNCaP; conversely, reduced expression of SLUG by shRNA downregulated CXCR4 and CXCL12 expression at RNA and protein levels in prostate cancer cells. Furthermore, ectopic expression of SLUG increased MMP9 expression and activity in PC3, 22RV1, and DU-145 cells, and SLUG knockdown by shRNA downregulated MMP9 expression. We showed that CXCL12 is required for SLUG-mediated MMP9 expression in prostate cancer cells. Moreover, we found that migration and invasion of prostate cancer cells was increased by ectopic expression of SLUG and decreased by SLUG knockdown. Notably, knockdown of CXCL12 by shRNA impaired SLUG-mediated migration and invasion in prostate cancer cells. Lastly, our data suggest that CXCL12 and SLUG regulate migration and invasion of prostate cancer cells independent of cell growth.ConclusionWe provide the first compelling evidence that upregulation of autocrine CXCL12 is a major mechanism underlying SLUG-mediated migration and invasion of prostate cancer cells. Our findings suggest that CXCL12 is a therapeutic target for prostate cancer metastasis.

Induction of Slug by Chronic Exposure to Single-Walled Carbon Nanotubes Promotes Tumor Formation and Metastasis

“…54 In this study, we focused mainly on the functional role of SWCNT-induced Slug upregulation in tumorigenesis and metastasis. Consistent with the previous findings by our group and others, 20,37,44,49,50,57 the present study shows that Slug is essential for the aggressive phenotype of BSW cells in vitro and is responsible for BSW-induced tumor growth and metastasis in vivo . To our knowledge, this is the first demonstration of the effect of chronic CNT exposure on EMT activation and the role of Slug in the process.…”

Convergence of oncogenic and hormone receptor pathways promotes metastatic phenotypes

“…Further investigation of relative CDH1 transcript levels in LN-vector (LN-vec), LN-SLUG polyclonal, and LN-SLUG (clonal) cell lines showed no significant changes in CDH1 expression (Supplemental Figure 4A), supporting the notion that Slug regulated phenotypes are independent of changes in E-cadherin levels or localization. Similarly, the expression of several other targets of Slug implicated in prometastatic phenotypes (derived from mouse models) (41)(42)(43) demonstrated an insensitivity to Slug expression (Supplemental Figure 4B). Collectively, these data implicate Slug as an obligate effector of cyclin D1b function and provide evidence of CDH1-independent Slug functions.…”

SLUG: Critical regulator of epithelial cell identity in breast development and cancer

“…[2][3][4][5][6][7][8] Additionally, SNAIL family members are aberrantly expressed in a variety of cancers where they regulate a diverse number of processes ranging from tumor cell invasion and metastasis to cell survival and proliferation. 2,[9][10][11][12][13][14][15] Proteins of the SNAIL family share a similar structural organization. The carboxy terminus contains 4 to 6 C 2 H 2 zinc finger motifs, which facilitate the protein's direct binding to DNA.…”