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Gene Review

HAS3  -  hyaluronan synthase 3

Homo sapiens

Synonyms: HA synthase 3, Hyaluronan synthase 3, Hyaluronate synthase 3, Hyaluronic acid synthase 3
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Disease relevance of HAS3

  • To evaluate the physiological role of human HAS3, expression vectors for this protein were transfected into TSU cells (a prostate cancer cell line), and the phenotypic changes in these cells were examined [1].
  • In our study, colon carcinoma cells isolated from a lymph node metastasis (SW620) produced more pericellular HA and expressed higher levels of HAS3 mRNA compared to cells isolated from a primary colon carcinoma (SW480) [2].
  • Human mesothelial cells, which synthesize large amounts of hyaluronan, express mRNAs encoding all three HAS isoforms, whereas their transformed counterparts, mesothelioma cells, which produce only minute amounts of hyaluronan, express only HAS3 mRNA [3].
  • Human lung fibroblasts and the glioma cell line U-118 MG express only the HAS2 and HAS3 genes [3].
  • Of 20 cases of pulmonary adenocarcinoma, 5 overexpressed HAS1 (25%), 16 of 20 HAS2 (80%), and 4 of 20 HAS3 (20%) [4].

High impact information on HAS3

  • These results suggested that the HAS3-induced overexpression of hyaluronan enhanced tumor cell growth, extracellular matrix deposition, and angiogenesis but was not sufficient to induce metastatic behavior in TSU cells [1].
  • Hyaluronan synthase 3 overexpression promotes the growth of TSU prostate cancer cells [1].
  • Aggressive cells in prostate cancer secrete extracellular hyaluronan (HA) as a result of up-regulated HA synthase enzymes HAS2 and HAS3 [5].
  • The microvilli induced by HAS3 were gradually withered by introduction of an inhibitor of hyaluronan synthesis and rapidly retracted by hyaluronidase digestion, whereas they were not affected by competition with hyaluronan oligosaccharides and disruption of the CD44 gene, suggesting independence of hyaluronan receptors [6].
  • In cells transfected with green fluorescent protein (GFP)-tagged Has3, the dorsal surface was decorated by up to 150 slender, 3-20-microm-long microvillus-type plasma membrane protrusions, which also contained filamentous actin, the hyaluronan receptor CD44, and lipid raft microdomains [6].

Biological context of HAS3

  • These findings suggest that HAS3 gene expression plays a crucial role in the regulation of hyaluronan synthesis in the epidermis [7].
  • To assess functionality, HAS3 expression in SW620 cells was inhibited by transfection with an asHAS3 construct [2].
  • Partial clones facilitated the isolation of genomic and cDNA clones representing the mouse Has3 open reading frame [8].
  • HAS3 was localized to human chromosome 16q22.1 and Has3 to mouse Chr 8 [9].
  • Stimulation of mesothelial cells with platelet-derived growth factor-BB induced an up-regulation of mRNA for HAS2 to a maximum after 6 h of stimulation; HAS1 and HAS3 genes were only induced slightly [3].

Anatomical context of HAS3

  • Furthermore, in situ mRNA hybridization showed that mouse epidermal keratinocytes abundantly expressed HAS3 mRNA from the basal to the granular cell layers, suggesting that HAS3 functions in epidermis [7].
  • Labour-like cyclic mechanical stretch for 24, 36 and 48 h significantly enhanced the secretion of HA, from cultured human uterine cervical fibroblast (CxF) cells, 128.7, 151.4 and 173.2%, respectively, concomitant with a significant augmentation of HAS1 (36, 48 h), HAS2 (24, 36 and 48 h) and HAS3 (48 h) mRNA expression [10].
  • Expression of the mouse Has3 open reading frame in transfected COS-1 cells led to high levels of hyaluronan synthesis, as determined through a classical particle exclusion assay, and by in vitro HA synthase assays [8].
  • MAbs to beta 1 (DH12) and alpha 2 (HAS3) showed positive membrane and cytoplasmic staining of basal cells and luminal epithelial cells [11].
  • Furthermore, we suggest that overexpression of HAS1 and its variants in combination with HAS3 may form an HA matrix around WM cells, thus preventing their elimination by the immune system, and it promotes their migration and may facilitate the spread of disease [12].

Associations of HAS3 with chemical compounds


Regulatory relationships of HAS3

  • In contrast to the activatory effect on HAS1, TGF-beta dose-dependently suppresses HAS3 mRNA [16].
  • HAS1 mRNA was upregulated by transforming growth factor-beta and HAS3 mRNA was upregulated by interleukin-1beta and somewhat by tumor necrosis factor-alpha in the RA cells [17].
  • In addition, at 24 h mRNA for HA synthase 2 was expressed in all samples whereas mRNA for HA synthase 3 was only expressed in strained cells [18].

Other interactions of HAS3


Analytical, diagnostic and therapeutic context of HAS3


  1. Hyaluronan synthase 3 overexpression promotes the growth of TSU prostate cancer cells. Liu, N., Gao, F., Han, Z., Xu, X., Underhill, C.B., Zhang, L. Cancer Res. (2001) [Pubmed]
  2. Hyaluronan synthase-3 is upregulated in metastatic colon carcinoma cells and manipulation of expression alters matrix retention and cellular growth. Bullard, K.M., Kim, H.R., Wheeler, M.A., Wilson, C.M., Neudauer, C.L., Simpson, M.A., McCarthy, J.B. Int. J. Cancer (2003) [Pubmed]
  3. Expression of human hyaluronan synthases in response to external stimuli. Jacobson, A., Brinck, J., Briskin, M.J., Spicer, A.P., Heldin, P. Biochem. J. (2000) [Pubmed]
  4. Hyaluronan synthase expression in pleural malignant mesotheliomas. Kanomata, N., Yokose, T., Kamijo, T., Yonou, H., Hasebe, T., Itano, N., Kimata, K., Ochiai, A. Virchows Arch. (2005) [Pubmed]
  5. Concurrent expression of hyaluronan biosynthetic and processing enzymes promotes growth and vascularization of prostate tumors in mice. Simpson, M.A. Am. J. Pathol. (2006) [Pubmed]
  6. Hyaluronan synthesis induces microvillus-like cell surface protrusions. Kultti, A., Rilla, K., Tiihonen, R., Spicer, A.P., Tammi, R.H., Tammi, M.I. J. Biol. Chem. (2006) [Pubmed]
  7. Hyaluronan synthase 3 regulates hyaluronan synthesis in cultured human keratinocytes. Sayo, T., Sugiyama, Y., Takahashi, Y., Ozawa, N., Sakai, S., Ishikawa, O., Tamura, M., Inoue, S. J. Invest. Dermatol. (2002) [Pubmed]
  8. Molecular cloning and characterization of a cDNA encoding the third putative mammalian hyaluronan synthase. Spicer, A.P., Olson, J.S., McDonald, J.A. J. Biol. Chem. (1997) [Pubmed]
  9. Chromosomal localization of the human and mouse hyaluronan synthase genes. Spicer, A.P., Seldin, M.F., Olsen, A.S., Brown, N., Wells, D.E., Doggett, N.A., Itano, N., Kimata, K., Inazawa, J., McDonald, J.A. Genomics (1997) [Pubmed]
  10. Cyclic mechanical stretch augments hyaluronan production in cultured human uterine cervical fibroblast cells. Takemura, M., Itoh, H., Sagawa, N., Yura, S., Korita, D., Kakui, K., Kawamura, M., Hirota, N., Maeda, H., Fujii, S. Mol. Hum. Reprod. (2005) [Pubmed]
  11. Expression of integrin subunits in the human infant breast correlates with morphogenesis and differentiation. Anbazhagan, R., Bartkova, J., Stamp, G., Pignatelli, M., Gusterson, B., Bartek, J. J. Pathol. (1995) [Pubmed]
  12. Abnormal expression of hyaluronan synthases in patients with Waldenstrom's macroglobulimenia. Adamia, S., Crainie, M., Kriangkum, J., Mant, M.J., Belch, A.R., Pilarski, L.M. Semin. Oncol. (2003) [Pubmed]
  13. HAS3-related hyaluronan enhances biological activities necessary for metastasis of osteosarcoma cells. Tofuku, K., Yokouchi, M., Murayama, T., Minami, S., Komiya, S. Int. J. Oncol. (2006) [Pubmed]
  14. Expression of hyaluronan synthases in articular cartilage. Hiscock, D.R., Caterson, B., Flannery, C.R. Osteoarthr. Cartil. (2000) [Pubmed]
  15. Synergistic effect of N-acetylglucosamine and retinoids on hyaluronan production in human keratinocytes. Sayo, T., Sakai, S., Inoue, S. Skin pharmacology and physiology. (2004) [Pubmed]
  16. Differential effect of transforming growth factor beta (TGF-beta) on the genes encoding hyaluronan synthases and utilization of the p38 MAPK pathway in TGF-beta-induced hyaluronan synthase 1 activation. Stuhlmeier, K.M., Pollaschek, C. J. Biol. Chem. (2004) [Pubmed]
  17. Differential stimulation of three forms of hyaluronan synthase by TGF-beta, IL-1beta, and TNF-alpha. Oguchi, T., Ishiguro, N. Connect. Tissue Res. (2004) [Pubmed]
  18. The effect of mechanical strain on hyaluronan metabolism in embryonic fibrocartilage cells. Dowthwaite, G.P., Ward, A.C., Flannely, J., Suswillo, R.F., Flannery, C.R., Archer, C.W., Pitsillides, A.A. Matrix Biol. (1999) [Pubmed]
  19. Regulation of hyaluronan synthase gene expression in human periodontal ligament cells by tumour necrosis factor-alpha, interleukin-1beta and interferon-gamma. Ijuin, C., Ohno, S., Tanimoto, K., Honda, K., Tanne, K. Arch. Oral Biol. (2001) [Pubmed]
  20. Pathologic gene expression in adhesive subacromial bursae of human shoulder. Yoshida, M., Funasaki, H., Saito, M., Kajitani, K., Fujii, K. Clin. Orthop. Relat. Res. (2003) [Pubmed]
  21. Expression of hyaluronan synthase messenger ribonucleic acids and their induction by interleukin-1beta in human orbital fibroblasts: potential insight into the molecular pathogenesis of thyroid-associated ophthalmopathy. Kaback, L.A., Smith, T.J. J. Clin. Endocrinol. Metab. (1999) [Pubmed]
  22. Hyaluronan synthase expression in ovarian cancer. Yabushita, H., Noguchi, M., Kishida, T., Fusano, K., Noguchi, Y., Itano, N., Kimata, K., Noguchi, M. Oncol. Rep. (2004) [Pubmed]
  23. Expression of hyaluronan synthase genes in umbilical cord blood stem/progenitor cells. Grskovic, B., Pollaschek, C., Mueller, M.M., Stuhlmeier, K.M. Biochim. Biophys. Acta (2006) [Pubmed]
  24. Molecular cloning of rabbit hyaluronic acid synthases and their expression patterns in synovial membrane and articular cartilage. Ohno, S., Tanimoto, K., Fujimoto, K., Ijuin, C., Honda, K., Tanaka, N., Doi, T., Nakahara, M., Tanne, K. Biochim. Biophys. Acta (2001) [Pubmed]
  25. Expression of hyaluronan synthases and hyaluronidases in the MG63 osteoblast cell line. Adams, J.R., Sander, G., Byers, S. Matrix Biol. (2006) [Pubmed]
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