Abstract
Androgen receptor (AR) is a key transcription factor playing a critical role in prostate cancer (PCa) initiation and progression. However, the molecular mechanisms of AR action in prostate cancer are not very clear. CXCL13, known as B cell attracting chemokine1 (BCA-1), is a member of CXC chemokine family and relevant to cancer metastasis. This study shows that CXCL13 is an androgen-responsive gene and involved in AR-induced PCa cell migration and invasion. In clinical specimens, expression of CXCL13 in PCa tissues is markedly higher than that in adjacent normal tissues. In cultures, expression of CXCL13 is up-regulated by androgen-AR axis at both mRNA and protein levels. Furthermore, Chip-Seq assay identifies canonical androgen responsive elements (ARE) at CXCL13 enhancer and dual-luciferase reporter assays reveals that the ARE is highly responsive to androgen while mutations of the ARE abolish the reporter activity. Additional chromatin immunoprecipitation (ChIP) assays also identify that the ARE presents androgen responsiveness. In addition, CXCL13 promotes G2/M phase transition by increasing Cyclin B1 levels in PCa cells. Functional studies demonstrate that reducing endogenous CXCL13 expression in LNCaP cells largely weakens androgen-AR axis induced cell migration and invasion. Taken together, our study implicates for the first time that CXCL13 is an AR target gene and involved in AR-mediated cell migration and invasion in primary PCa.
Highlights
Prostate cancer (PCa) is the most commonly diagnosed malignancy and the predominant cause of death from cancer among men in the western countries [1]
We found that levels of CXCL13 were abundant in androgenresponsive LNCaP and CWR22Rv1 cell lines compared to androgen-unresponsive DU145 and PC3 cell lines at both mRNA and protein levels, and the expression of CXCL13 in normal prostate epithelial cell line WPMY-1 was the lowest (Figure 1D and 1E)
In vivo experimental results indicated that CXCL13 promoted androgendependent prostate cancer (PCa) cell growth and enhanced androgendependent subcutaneous xenograft tumor growth in nude mice. Chemokines and their corresponding receptors are primary reported to play a pivotal role in chemoattraction and activation of specific leukocytes in various immunoinflammatory response [37]
Summary
Prostate cancer (PCa) is the most commonly diagnosed malignancy and the predominant cause of death from cancer among men in the western countries [1]. Metastasis is always a primary cause of mortality in prostate cancer even though there have been continual improving techniques and methods in diagnosis and treatment [5]. It is well known that androgen and AR promote PCa cell metastasis, the molecular mechanisms of androgen-mediated cell metastasis remain poorly understood. Increasing evidence suggests that the complex chemokine network plays a key role in cancer cell survival, growth, migration, invasion, proliferation, and apoptosis [10,11,12,13,14]. CXCL12 is approved to be involved in regulating bone marrow metastases in breast cancers and small-cell lung cancer [15, 16], and stimulate cell migration and invasion in ovarian cancer [17]. The effect of CXCL13 on AR-induced PCa cell migration and invasion is still unknown
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