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has1

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Official Full Name
hyaluronan synthase 1
Background
Hyaluronan or hyaluronic acid (HA) is a high molecular weight unbranched polysaccharide synthesized by a wide variety of organisms from bacteria to mammals, and is a constituent of the extracellular matrix. It consists of alternating glucuronic acid and N-acetylglucosamine residues that are linked by beta-1-3 and beta-1-4 glycosidic bonds. HA is synthesized by membrane-bound synthase at the inner surface of the plasma membrane, and the chains are extruded through pore-like structures into the extracellular space. It serves a variety of functions, including space filling, lubrication of joints, and provision of a matrix through which cells can migrate. HA is actively produced during wound healing and tissue repair to provide a framework for ingrowth of blood vessels and fibroblasts. Changes in the serum concentration of HA are associated with inflammatory and degenerative arthropathies such as rheumatoid arthritis. In addition, the interaction of HA with the leukocyte receptor CD44 is important in tissue-specific homing by leukocytes, and overexpression of HA receptors has been correlated with tumor metastasis. HAS1 is a member of the newly identified vertebrate gene family encoding putative hyaluronan synthases, and its amino acid sequence shows significant homology to the hasA gene product of Streptococcus pyogenes, a glycosaminoglycan synthetase (DG42) from Xenopus laevis, and a recently described murine hyaluronan synthase.
Synonyms
HA synthase 1; HAS; HAS1; HAS1_HUMAN; HuHAS1; Hyaluronan synthase 1; Hyaluronate synthase 1; Hyaluronic acid synthase 1

Recent Research Progress

Hyaluronan synthase 1 (HAS1) is one of three isoenzymes responsible for cellular hyaluronan synthesis. Since the role of HAS1, with lower enzymatic activities, in hyaluronic acid production appears to be insignificant compared to the other two isoenzymes HAS2 and HAS3, there is limited interest in HAS1. However, both expression and activity of HAS1 are induced by pro-inflammatory factors like interleukins and cytokines, suggesting its involvement in inflammatory conditions. Specially, HAS1 is upregulated in states associated with inflammation, like osteoarthritis, and infectious lung disease. What’s more, the full-length and splice variants of HAS1 are expressed in malignant tumors such as bladder cancer, prostate cancer, multiple myeloma, and malignant mesothelioma. Although the enzymatic activity of HAS1 is significantly lower under normal conditions, it may be an important factor as the case of inflammation and cancer.

HAS1 as a Predictor of Cancer Progression

HAS1 is associated with a number of tumor progression and prognosis. Studies have indicated that increased expression of HAS1 is associated with ovarian cancer, colon cancer, Waldenstrm macroglobulinemia, and multiple myeloma. In multiple myeloma and Waldenström’s macroglobulinemia, the occurrence of HAS1 splice variants, rather than the full length HAS1, is related to cancer prognosis. HAS1 expression is also increased in bladder cancer, correlating with increased hyaluronan levels. In bladder cancer, HAS1 has been shown to modulate HA and CD44 levels, affecting tumor growth and progression. Recently, HAS1 and HA staining have been found to be associated with breast cancer cells, and HAS1 was associated with estrogen receptor negative, HER2 positive, high recurrence rate, and short overall survival. In serous ovarian tumors, HAS1 has been shown to be very low or totally absent, whereas HAS2 and HAS3 mRNA or staining levels are not elevated compared to normal ovaries or benign tumors. Interestingly, the levels of HAS1 and HAS2 are decreased in melanomas, correlating with reduced hyaluronan content and poor overall survival in these tumors.

HAS1 as a Mediator in Inflammation

Many recent results suggest HAS1 may play a pivotal role in inflammation. Growth factors and pro-inflammatory cytokines like TGF-β, IL-1β, and TNF-α, which stimulate inflammatory cells, also induce the expression of HAS1 and Has1. Expression of HAS1 is also upregulated in response to prostaglandins. Therefore, Has1/HAS1 up-regulation has been noted in many diseases associated with inflammation such as human osteoarthritis, murine infectious lung disease, and human rheumatoid arthritis. Interestingly, the expression of both HAS1 and HAS2 was reduced in the synovium of patients with osteoarthritis or rheumatoid arthritis compared to healthy controls. Moreover, elevated HAS1 expression is observed in oral lichen planus, which is a chronic inflammatory disease of the oral mucosa. It is worth noting that in oral lichen planus the increased HAS1 expression is detected in the basal layers of the epithelium, which is the most affected, inflamed area in lichen planus. Coincidentally, studies have shown that rheumatoid arthritis (RA) seems to have a subtle connection with HAS. In synoviocytes isolated from RA patients, HAS1 responds readily to pro-inflammatory cytokines like IL-1β and TGF-β. In addition to its role in rheumatoid inflammation, altered HAS1 levels contribute to other inflammation-related states. In murine models of asthma, Has1 mRNA is increased at an early stage, but decreased later. Taken together, HAS1 seems to be fundamentally involved in the inflammation.

References:

  1. Siiskonen H, et al. Hyaluronan synthase 1 (HAS1) produces a cytokine-and glucose-inducible, CD44-dependent cell surface coat. Experimental Cell Research, 2014, 320(1):153-163.
  2. Chan D D, et al. Deficiency of hyaluronan synthase 1 (Has1) results in chronic joint inflammation and widespread intra-articular fibrosis in a murine model of knee joint cartilage damage [J]. Osteoarthritis & Cartilage, 2015, 23(11):1879-1889.
  3. Kramer M W, et al. Association of hyaluronic acid family members (HAS1, HAS2, and HYAL‐1) with bladder cancer diagnosis and prognosis [J]. Cancer, 2015, 117(6):1197-1209.
  4. Siponen M, et al. Altered Expression of HA, HAS1-2 and HYAL1-2 in Oral Lichen Planus [J]. Oral Surgery Oral Medicine Oral Pathology & Oral Radiology, 2015, 44(6):401-409.
  5. Nguyen N, et al. Human hyaluronic acid synthase-1 promotes malignant transformation via epithelial-to-mesenchymal transition, micronucleation and centrosome abnormalities. Cell Communication and Signaling, 2017.