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Carcinogenesis Advance Access originally published online on January 3, 2008
Carcinogenesis 2008 29(2):282-290; doi:10.1093/carcin/bgm259
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Androgen receptor regulates CD168 expression and signaling in prostate cancer

Shi-Lung Lin, Donald Chang, Angela Chiang and Shao-Yao Ying*

Department of Cell and Neurobiology, Keck School of Medicine, BMT-403, University of Southern California, 1333 San Pablo Street, Los Angeles, CA 90033, USA

* To whom correspondence should be addressed. Tel: +1 323 442 1856; Fax: +1 323 442 3466; Email: sying{at}usc.edu

Dysregulation of the androgen receptor (AR) and its signaling in the prostate often occurs during normal aging or after androgen ablation, consequently leading to the development of hormone-refractory prostate cancer (HRPC). Hyaluronan (HA) plays an important role in this transformation of androgen-independent cancer. Previous studies have shown that activation of the receptor for hyaluronan-mediated motility, CD168, was correlated with the Gleason’s score, cancer stage, transformation and metastasis in >90% of HRPC patients. However, the relationship between loss of AR dependency and HA-mediated CD168 signaling remains unclear. We report here that AR regulates normal CD168 expression and its downstream signaling in androgen-dependent (AD) prostatic epithelial cell lines. Furthermore, we observed that the concurrent treatments of HA and dihydrotestosterone (DHT), a native androgen, significantly promoted the tumorigenicity of AD prostate cancer cell lines, which showed elevated rates of cell proliferation, invasion and metastasis to the human bone marrow endothelial cell layer. Inhibition of CD168 downstream Rho-activated protein kinases completely prevented this type of tumorigenicity. These findings suggest that the interaction of androgen and AR is essential for regulating HA-mediated cancer progression via the CD168/ROCK signal transduction pathway and also indicate that the loss of AR regulation not only causes CD168 overexpression but it also activates HA-mediated CD168 signaling in malignant cancer progression and metastasis of HRPC.

Abbreviations: AD, androgen dependent; AI, androgen independent; AR, androgen receptor; CaP, prostate cancer; DHT, dihydrotestosterone; GEO, gene expression omnibus; HA, hyaluronan; hBMEC, human bone marrow endothelial cell; HRPC, hormone-refractory prostate cancer; IHC, immunohistochemical; miRNA, microRNA; mRNA, messenger RNA; NCBI, National Center for Biotechnology Information; NIH, National Institutes of Health; PI3K, phosphatidylinositol-(3,4,5)P3 kinase; RHAMM, receptor for hyaluronan-mediated motility; ROCK/ROK, Rho-activated protein kinase

Received July 5, 2007; revised November 5, 2007; accepted November 8, 2007.


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