Abstract
A prerequisite condition prior to metastasis is the dramatic production of transforming growth factor beta (TGF‐β), hyaluronan and hyaluronidases by cancer cells. Here it is determined that knockdown of tumor suppressor WWOX (also known as WOX1 or FOR) significantly upregulates the expression of hyaluronidases Hyal‐1 and Hyal‐2 and enhances the metastatic potential cancer cells in vivo. In contrast, overexpressed WWOX suppresses the expression of Hyal‐1 and Hyal‐2 and cell migration in vivo. Hyaluronan binds membrane Hyal‐2, followed by recruiting WWOX and Smad4, and then the Hyal‐2/WWOX/Smad4 complex relocating to the nuclei. Overly activated SMAD responsive element causes apoptosis. Small interfering RNA (siRNA)‐targeting WWOX abolished overexpressed Smad4‐mediated apoptosis. Notably, stimulating membrane Hyal‐2 with a specific antibody or modified hyaluronan induces anticancer response in vivo. Together, hyaluronan invokes a novel signal pathway that causes activation of WWOX and Smad4 from membrane Hyal‐2, and this may invoke an innate mechanism in blocking cancer growth.Support or Funding InformationAHA, DoD and MOST, Taiwan
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