Size-dependent regulation of Snail2 by hyaluronan: Its role in cellular invasion

Abstract

Hyaluronan (HA) induces changes in cellular behavior that are crucial during both embryonic development and cancer progression. However, the biological effects of varying sizes of HA and the signal transduction mechanisms that these polymers may activate remain unclear. In this study, we demonstrate that pulse stimulation of mouse embryonic fibroblasts with high-molecular-weight (HMW) HA, but not HA of lower molecular sizes, leads to increases in Snail2 protein which are dependent on NFkappaB activity. Involvement of CD44, the main HA receptor, in these responses was determined by use of a CD44 blocking antibody and CD44 siRNA. Both the blockade and silencing of CD44 significantly abrogate the increases in nuclear factor kappaB (NFkappaB) activity and Snail2 protein following HMW-HA stimulation. Furthermore, we show that HMW-HA induces cellular invasion and that inhibition of CD44, Snail2, or NFkappaB significantly decreases this response. These studies elucidate a novel HA/Snail2 functional connection through CD44 and NFkappaB that is important for the induction of cellular invasion and is dependent on HA size.

ATDC induces an invasive switch in KRAS-induced pancreatic tumorigenesis

“…In addition to our data showing upregulation of CD44 by ATDC, it has previously been shown that CD44 is a switch for EMT and that YFP + pancreatic epithelial cells undergoing EMT in vivo in the KPCY model expressed CD44 (Kim et al 2008;Afify et al 2009;Brown et al 2011;Jung et al 2011;Rhim et al 2012). Furthermore, many studies have shown that knockdown of CD44 or the use of CD44-blocking antibodies inhibited EMT and invasion (Kim et al 2008;Afify et al 2009;Craig et al 2009;Bhat-Nakshatri et al 2010;Brown et al 2011;Provenzano et al 2012;Li et al 2014). Using qRT-PCR and immunostaining analysis, we observed that CD44 was significantly up-regulated in PanIN lesions and PDA arising in AKC mice compared with KC lesions, while CD44 was not significantly expressed in age-matched wild-type mice, ATDC mice, or KC and AKC littermates prior to PanIN formation ( Fig.…”

Hyaluronic Acid Promotes Angiogenesis by Inducing RHAMM-TGFβ Receptor Interaction via CD44-PKCδ

“…HA can be cleaved by hyaluronidases into small oligosaccharides which have been shown to exert distinct biological activity relative to their high-molecular-weight counterparts (West and Kumar, 1989;West et al, 1985). High molecular weight (HMW) HA (900-1200 kDa), but not low molecular weight form of HA, induces the Snail2 protein via NF-κB to enhance the invasion potential of mouse embryo fibroblasts (Craig et al, 2009). …”

Hyaluronan fragments as mediators of inflammation in allergic pulmonary disease

“…RHAMM deficient fibroblasts are defective in CD44-mediated ERK signaling, demonstrating a role of RHAMM in CD44 signaling and fibroblast migration (Tolg et al, 2006). A recent study also reported a role of HMM HA in promoting fibroblast invasion by increasing snail2 expression (Craig et al, 2009). …”