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
✍ Scribed by Lilly Y. W. Bourguignon; Gabriel Wong; Christine A. Earle; Weiliang Xia
- Publisher
- Wiley (John Wiley & Sons)
- Year
- 2011
- Tongue
- English
- Weight
- 796 KB
- Volume
- 68
- Category
- Article
- ISSN
- 1949-3584
- DOI
- 10.1002/cm.20544
No coin nor oath required. For personal study only.
✦ Synopsis
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. © 2011 Wiley Periodicals, Inc.