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Hyal‐2 antibody mediates cancer suppression via Hyal‐2/WWOX/Smad4 signaling
Author(s) -
Chang NanShan,
Su WanPei,
Wang WanJen
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.897.29
Subject(s) - cancer research , biology , smad , receptor , cancer cell , internalization , antibody , signal transduction , microbiology and biotechnology , cancer , immunology , biochemistry , genetics
We have discovered that cell surface hyaluronidase Hyal‐2 can act a cognate receptor for transforming growth factor beta (TGF‐b) in type II TGF‐b receptor (TbRII)‐negative cells (JBC 284:16049‐59, 2009). TbRII is the major receptor for the canonical TGF‐b/Smad signaling. The TGF‐b1/Hyal‐2 complex recruits tumor suppressors WWOX (also named WOX1 or FOR) and Smad4 for translocating to the nucleus and activates the SMAD‐regulated promoter. Here, we found that injection of Hyal‐2 IgG antibody in immune competent BALB/c and immunodeficient nude and NOD‐SCID mice resulted in protection of these mice against the growth of inoculated breast cancer cells and many other types of cancer cells (inhibition by 80‐100%), suggesting a novel lineage of immune response is activated to run against cancer growth in immune deficient mice. A portion of WWOX is localized on the cell surface by itself or physically interacts with membrane Hyal‐2. Additionally, specific suppression of an N‐terminal phosphorylation site in WWOX abolishes cancer cell homing and growth in the liver and lung in mice. Together, Hyal‐2 antibody causes internalization of membrane Hyal‐2 and a specific phosphorylated form of surface WWOX that elicits an anticancer response and prevents caner cell metastasis and homing in vivo. (Supported in part by DoD, USA and MOST and NHRI, Taiwan)