As a major polysaccharide component of the extracellular matrix, hyaluronan plays essential roles in the organization of tissue architecture and the regulation of cellular functions, such as cell proliferation and migration, through interactions with cell-surface receptors and binding molecules. Metabolic pathways for biosynthesis and degradation tightly control the turnover rate, concentration, and molecular size of hyaluronan in tissues. Despite the relatively simple chemical composition of this polysaccharide, its wide range of molecular weights mediate diverse functions that depend on molecular size and tissue concentration. Genetic engineering and pharmacological approaches have demonstrated close associations between hyaluronan metabolism and functions in many physiological and pathological events, including morphogenesis, wound healing, and inflammation. Moreover, emerging evidence has suggested that the accumulation of hyaluronan extracellular matrix and fragments due to the altered expression of hyaluronan synthases and hyaluronidases potentiates cancer development and progression by remodeling the tumor microenvironment. In addition to the well-known functions exerted by extracellular hyaluronan, recent metabolomic approaches have also revealed that its synthesis can regulate cellular functions via the reprogramming of cellular metabolism. This review highlights the current advances in knowledge on the biosynthesis and catabolism of hyaluronan and describes the diverse functions associated with hyaluronan metabolism.

To investigate the pathophysiological role of fibroblasts in tissue metabolism, we analysed gelatin-...

The hexosamine biosynthetic pathway (HBP) metabolically regulates dynamic cellular events by linking nutrient availability to numerous signaling networks. Significant alterations in the HBP are often associated with cancer pathogenesis. In this study, we investigated the molecular events underlying cancer pathogenesis associated with enhanced HBP flux. Multidimensional analysis of microarray datasets demonstrated up-regulation of genes encoding HBP enzymes in clinical breast cancers and revealed that co-expression of hyaluronan synthase 2 (HAS2) and glutamine:fructose-6-phosphate amidotransferase (GFAT), a rate-limiting enzyme of the HBP, was strongly correlated with a poor prognosis in advanced cancer patients. Consistently with the clinical data, comparative analyses of distinct breast cancer mouse models demonstrated enhancement of the HBP gene expression in primary carcinoma cells, with elevation of Has2 expression and hyaluronan production in aggressive breast cancer cells. The silencing of GFAT reduced CD44^high/CD24^low cancer stem cell (CSC)-like subpopulations, aldehyde dehydrogenase-positive cell populations, and mammosphere size, which were further diminished by gene targeting of Has2. Has2 gene disruption reduced the in vivo growth of aggressive cancer cells and attenuated pro-tumorigenic Akt/GSK3β/β-catenin signaling and cisplatin resistance. Overall protein O-GlcNAcylation was also elevated in association with HBP enhancement in aggressive cancer cells, and the modification exhibited overlapping but distinct roles from the hyaluronan signal in the regulation of CSC-like features. The current data therefore demonstrate that enhanced hexosamine metabolism drives pro-tumorigenic signaling pathways involving hyaluronan and O-GlcNAcylation in aggressive breast cancer.

To investigate the pathophysiological role of matrix metalloproteinase (MMP)‐9 in the skin, we analyzed MMP‐9 expression from human keratinocytes in culture. MMP‐9 and the terminal differentiation marker involucrin were co‐localized in the same keratinocytes with a high concentration of Ca2+, a potent stimulator of differentiation. We identified the novel KRE‐M9 element, further downstream to the previously reported TPA responsive element in the MMP‐9 promoter, and both of these two elements were shown to be important for MMP‐9 transcription and Ca2+ induction. The concomitant upregulation of MMP‐9 and involucrin transcripts was probably due to the very similar gene regulatory elements, KRE‐M9 and KRE‐4, in their respective promoters. These results indicate a novel mechanism of transcriptional regulation for MMP‐9 in the process of keratinization, implying the probable association of apoptosis and differentiation of keratinocytes in epidermal skin tissue.