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.
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.
Department of Medicine, University of California, San Francisco, USA. lilly.bourguignon@ucsf.edu
Lilly Y W
LY
Bourguignon
Gabriel
G
Wong
Christine A
CA
Earle
Weiliang
W
Xia
D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D018925:Chemokines / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000494:pharmacology*; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D014162:Transfection
C084510:AFAP 110; D018925:Chemokines; D016207:Cytokines; D018960:Hyaluronan Receptors; D008840:Microfilament Proteins; D016328:NF-kappa B; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D006820:Hyaluronic Acid