Disease relevance of HAS2

• The rapidly growing osteosarcoma cells contained almost exclusively HAS2 message [1].
• HAS2 mapped outside the predicted critical region delineated for the Langer-Giedion syndrome and can thus be excluded as a candidate gene for this genetic syndrome [2].
• In the 33 ovarian cancer cases, 12 cases had positive expression of HAS1, 21 cases had positive expression of HAS2 and 11 cases had positive expression of HAS3 [3].
• Differences in the expression pattern of HAS1, HAS2, and HAS3 mRNA by cytokines suggest that these three isoforms are independently and differentially regulated, and each isoform of HAS may have a different role in arthritic joint disease [4].
• Coexpression of Hyal1 with HAS2 diminished HA retention but restored growth kinetics, supporting a possible combined role for excess HA synthesis and processing in maximizing unrestricted growth of prostate cancer cells [5].

High impact information on HAS2

• Of the 3 Has isoforms, Has1 mRNA was expressed predominantly in myeloma bmMPCs, with expression 7.6-fold greater than Has2 [6].
• Inhibition of HAS2 did not alter the expression of the other HAS isoforms, whereas hyaluronidase (HYAL2) and the hyaluronan receptor, CD44, were significantly down-regulated [7].
• The importance of HAS2 expression in highly invasive breast cancer was characterized by the antisense inhibition of HAS2 (ASHAS2) [7].
• The effect of HAS2 inhibition on cell proliferation, migration, hyaluronan metabolism, and receptor status was characterized in vitro, whereas the effect on tumorigenicity and metastasis was established in vivo [7].
• Aggressive cells in prostate cancer secrete extracellular hyaluronan (HA) as a result of up-regulated HA synthase enzymes HAS2 and HAS3 [5].

Biological context of HAS2

• In 5'-rapid amplification of cDNA ends analysis of purified mRNA from human renal epithelial proximal tubular cells, we detected an extended sequence for HAS2 exon 1, relocating the transcription initiation site 130 nucleotides upstream of the reference HAS2 mRNA sequence, GenBank accession number NM_005328 [8].
• In the present study, we analyzed the HAS2 promoter region [8].
• Upon transfection with full-length HAS2 or HAS3, the non-adherent LNCaP cells retained pericellular HA and adhered to BMECs [9].
• HASNT is transcribed from the opposite strand of the HAS2 gene locus and is represented by several independent expressed sequence tags in human [10].
• Alignment of human, murine, and equine genomic DNA sequences upstream of the repositioned HAS2 exon 1 provided evidence for the evolutionary conservation of specific transcription factor binding sites [8].

Anatomical context of HAS2

• HAS2 mRNA was usually predominant in chondrocytes, whereas synovial cells contained increased amounts of HAS1 [1].
• HAS usage in uncultured cartilage and synovial tissues was similar to that in the cultured cells, with HAS2 message being the predominant species in cartilage and HAS1 usually being the predominant species in synovium [1].
• 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 [11].
• Furthermore, HAS1 and HAS2 exhibited differential expression in VECs and non-VECs populating intraocular proliferative membranes [12].
• Human lung fibroblasts and the glioma cell line U-118 MG express only the HAS2 and HAS3 genes [13].

Associations of HAS2 with chemical compounds

• More importantly, two tyrosine kinase inhibitors mimicked the effect of leflunomide in that both blocked IL-1beta-induced HAS1 activation without affecting HAS2 or HAS3 [14].
• RESULTS: Hydrocortisone and dexamethasone suppressed HAS2 and HAS3 mRNAs accumulation concentration-dependently [15].
• In order to define the role of cell-associated hyaluronan in cartilage matrix retention, human articular chondrocytes as well as cartilage slices were treated with phosphorothioate oligonucleotides comprised of sequence antisense to the mRNA of human HA synthase-2 (HAS-2) [16].
• Nuclear run-off experiments showed a 70% suppression of HAS2 gene transcription in nuclei from DEX-treated fibroblasts, which is unlikely to fully explain the rapid 50--80-fold reduction in message levels [17].
• The addition of IL-1 beta or 25 mmol/L D-glucose also increased HA generation in HK-2 cells and was associated with the induction of HAS2 mRNA [18].

Regulatory relationships of HAS2

• CONCLUSION: This study demonstrates, to our knowledge for the first time, that increased HA synthesis in response to either IL-1 beta or elevated 25 mmol/L D-glucose is associated with NF-kappa B-activated transcription of HAS2 [18].
• 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 [19].
• Hyaluronan synthesis was probed by identifying the isotypes of hyaluronan synthase (HAS) expressed in periodontal fibroblasts as HAS-2 and HAS-3 and the effect of EMD on the levels of mRNA for each enzyme was monitored by reverse transcription polymerase chain reaction (RTPCR) [20].
• HAS2 mRNA levels were also stimulated by a selective prostacyclin receptor (IP) agonist, cicaprost (10 nmol/L), prostaglandin E(2) (10 nmol/L), and the EP(2) receptor agonist, butaprost (1 micromol/L) [21].
• CONCLUSION: These data demonstrate that IL-1alpha stimulates HAS-2 at the same time as it inhibits the expression of aggrecan [22].

Other interactions of HAS2

• PC3M-LN4 cells stably transfected with antisense HAS2 and HAS3 failed to form pericellular matrices [9].
• The over-expression of HAS2, Hyal-2 and CD44 is implicated in the invasiveness of breast cancer [23].
• By small interfering RNA against HAS2, it was shown that HAS2 mediated HA synthesis is critically involved in cell cycle progression through G1/S phase and SMC proliferation [24].
• Culture with NCCM caused an up-regulation of aggrecan, versican, and HAS-2 gene expression [25].
• Bovine disc-derived chondrocytes were cultured with serum-deficient medium (DMEM) and NCCM and assayed for the effect of tissue culture conditions on aggrecan, versican, and HAS-2 gene expression [25].

Analytical, diagnostic and therapeutic context of HAS2

• Collectively, our data suggest that natural antisense mRNAs of HAS2 are able to regulate HAS2 mRNA levels and hyaluronan biosynthesis in a cell culture model system and may have an important and novel regulatory role in the control of HAS2, HA biosynthesis, and HA-dependent cell functions in vivo [10].
• This treatment resulted in time-dependent inhibition of HAS-2 mRNA expression, as measured by quantitative RT-PCR, and a significant loss of cell-associated HA staining [16].
• The expression of HAS1 mRNA was not significantly affected by either cytokine, and HAS2 mRNA expression was undetectable under either basal or cytokine-stimulated conditions by northern blot using total RNA [26].
• Real-time PCR results showed that several genes such as hyaluronan synthase 2 (HAS2), TNF-alpha-induced protein 6 (TNFAIP6) and IL-8 were matched with the array results with statistical significance [27].
• HA histochemistry utilized a biotinylated HA binding peptide (n = 15), while HA synthase (HAS) immunohistochemistry utilized an antibody recognizing HAS1, HAS2 HAS3 (n = 24) [28].

References