Hyaluronan stimulates transformation of androgen-independent prostate cancer

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Abstract
Interaction between extracellular matrices and cancer cell receptors frequently alters signal transduction pathways, leading to malignant transformation and metastasis. Hyaluronan (HA) is a tumor promoter and enhancer in transformation of androgen-independent (AI) prostate cancer (CaP); however, the signal transduction pathway involved in this mechanism remains unclear. We report here that HA-mediated CD168, a receptor for HA-mediated motility, and its downstream signal molecules, including ROK1, Gab-1, PI3K•p110α and eIF4E3, accelerate the progression of AI rather than androgen-dependent CaP and enhance AI cell invasion and metastasis in human bone marrow endothelial layers. MicroRNA-based small hairpin RNA-mediated suppression of ROK1 can reverse the malignant role of CD168 signaling in human AI CaP PC3 and DU145 cells. This differential activation of ROK–PI3K signaling in AI CaP cells may provide clues to shed light on some mechanisms of cancer relapse after androgen ablation. These findings reveal a novel signal transduction mechanism for matrix-mediated cancer transformation and metastasis in hormone-refractory CaP.

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