Selective Activation of Cancer Stem Cells by Size-Specific Hyaluronan in Head and Neck Cancer

Figure 8

A proposed model for oncogenic signaling induced by 200 kDa-HA in the regulation of miRNA-10 production and cancer stem cell (CSC) functions in cells. The binding of 200 kDa-HA (step  1) to cells promotes specific target gene expression (step  2), including stem cell marker (Nanog, Oct-4, KLF-4 and Sox-2) experession (step  3-a). The resultant stem cell marker expression then induces spheres/self-renewal properties and clone formation (differentiation) (step  4-a) contributing to cancer stem cell formation and highly tumorigenic properties (step  5-a). At the same time, the binding of 200 kDa-HA to cells also stimulates miR-10b gene expression/mature miR-10b production (step  3-b) which then stimulates survival protein, IAP (c-IAP1) expression (step  4-b), and HNSCC cell antiapoptosis/survival as well as chemoresistance (step  5-b). Taken together, these findings suggest that HA- (in particular, 200 kDa-HA-) mediated cancer stem cell (CSC) pathways and miR-10b function play a critical role in promoting tumor formation and chemoresistance leading to head and neck cancer progression (step  6).