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.
Highlights
Prostate cancer is the second leading type of cancer in men in United States
SLUG upregulated CXCL12 expression in prostate cancer cell lines CXCL12 expression was significantly higher in human prostate cancer tissue than hyperplastic prostate tissues [25], suggesting that CXCL12 has an autocrine regulatory role via its receptor CXCR4 in the regulation of prostate cancer cell migration, invasion, and metastasis [26]
To determine whether CXCL12/CXCR4 axis plays a role in SLUG-mediated migration and invasion of prostate cancer cells in vitro, we first tested if forced expression of SLUG increases CXCL12 expression
Summary
Prostate cancer is the second leading type of cancer in men in United States. In 2010, new cases of prostate cancer were estimated at 217,730, resulting in 32,050 deaths in [1]. The CXCL12/CXCR4 pathway was originally discovered in the immune system to play an important role in cancer cell metastasis [9,10,11,12]. The CXCR4/CXCL12 axis can coordinate metastasis of a variety of cancers, such as bladder [17], breast [18], head and neck [19], ovarian [20], renal cell [21], and prostate [22,23]. SLUG is required for transcriptional and functional regulation of CXCL12 during bone tissue remodeling [24]. SLUG 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
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