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Interaction of low molecular weight hyaluronan with CD44 and toll-like receptors promotes the actin filament-associated protein 110-actin binding and MyD88-NFκB signaling leading to proinflammatory cytokine/chemokine production and breast tumor invasion.

Abstract
Both high and low molecular weight hyaluronan (HMW-HA vs. LMW-HA) exist in various tissues and cells. In this study, we investigated LMW-HA-mediated CD44 interaction with Toll-like receptors (TLRs), the actin filament-associated protein (AFAP-110), and a myeloid differentiation factor (MyD88) in breast tumor cells (MDA-MB-231 cells). Our data indicate that LMW-HA (but not HMW-HA) preferentially stimulates a physical association between CD44 and TLRs followed by a concomitant recruitment of AFAP-110 and MyD88 into receptor-containing complexes in breast tumor cells. LMW-HA-activated AFAP-110 then binds to filamentous actin (F-actin) resulting in MyD88/nuclear factor-κB (NF-κB) nuclear translocation, NF-κB-specific transcription, and target gene [interleukine 1β and interleukine-8 (IL-1β and IL-8)] expression. These signaling events lead to proinflammatory cytokine/chemokine production in the breast tumor cells. AFAP-110-F-actin (activated by LMW-HA) also promotes tumor cell invasion. Downregulation of AFAP-110 or MyD88 by transfecting breast tumor cells with AFAP-110 siRNA or MyD88 siRNA, respectively not only blocks the ability of LMW-HA to stimulate AFAP-110-actin function, but also impairs MyD88-NF-κB nuclear translocation and NF-κB transcriptional activation. Consequently, both IL-1β/IL-8 production and tumor cell invasion are impaired. Taken together, these findings suggest that LMW-HA plays an important role in CD44-TLR-associated AFAP-110-actin interaction and MyD88-NF-κB signaling required for tumor cell behaviors, which may contribute to the progression of breast cancer.
AuthorsLilly Y W Bourguignon, Gabriel Wong, Christine A Earle, Weiliang Xia
JournalCytoskeleton (Hoboken, N.J.) (Cytoskeleton (Hoboken)) Vol. 68 Issue 12 Pg. 671-93 (Dec 2011) ISSN: 1949-3592 [Electronic] United States
PMID22031535 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
CopyrightCopyright © 2011 Wiley Periodicals, Inc.
Chemical References
  • AFAP 110
  • Chemokines
  • Cytokines
  • Hyaluronan Receptors
  • Microfilament Proteins
  • NF-kappa B
  • Phosphoproteins
  • RNA, Small Interfering
  • Hyaluronic Acid
Topics
  • Animals
  • Breast Neoplasms (drug therapy, genetics, metabolism, pathology)
  • Cell Line, Tumor
  • Cell Movement (physiology)
  • Chemokines (biosynthesis, genetics, metabolism)
  • Cytokines (biosynthesis, genetics, metabolism)
  • Female
  • Humans
  • Hyaluronan Receptors (genetics, metabolism)
  • Hyaluronic Acid (pharmacology)
  • Microfilament Proteins (genetics, metabolism)
  • NF-kappa B (biosynthesis, genetics, metabolism)
  • Phosphoproteins (genetics, metabolism)
  • RNA, Small Interfering (genetics, metabolism)
  • Rats
  • Signal Transduction
  • Transfection

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