Gene Summary

Gene:HAS3; hyaluronan synthase 3
Summary:The protein encoded by this gene is involved in the synthesis of the unbranched glycosaminoglycan hyaluronan, or hyaluronic acid, which is a major constituent of the extracellular matrix. This gene is a member of the NODC/HAS gene family. Compared to the proteins encoded by other members of this gene family, this protein appears to be more of a regulator of hyaluronan synthesis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2010]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:hyaluronan synthase 3
Source:NCBIAccessed: 11 March, 2017


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: HAS3 (cancer-related)

Katona É, Juhász T, Somogyi CS, et al.
PP2B and ERK1/2 regulate hyaluronan synthesis of HT168 and WM35 human melanoma cell lines.
Int J Oncol. 2016; 48(3):983-97 [PubMed] Free Access to Full Article Related Publications
Hyaluronan (HA) is the major glycosaminoglycan component of the extracellular matrix in either normal or malignant tissues and it may affect proliferation, motility and differentiation of various cell types. Three isoforms of plasma membrane-bound hyaluronan synthases (HAS 1, 2 and 3) secrete and simultaneously bind pericellular HA. HAS enzymes are subjects of post-translational protein phosphorylation which is believed to regulate their enzymatic activity. In this study, we investigated the HA homeostasis of normal human epidermal melanocytes, HT168 and WM35 human melanoma cell lines and melanoma metastases. HAS2 and HAS3 were detected in all the samples, while the expression of HAS1 was not detectable in any case. Malignant tissue samples and melanoma cell lines contained extra- and intracellular HA abundantly but not normal melanocytes. Applying HA as a chemoattractant facilitated the migration of melanoma cells in Boyden chamber. The amount of HA was reduced upon the inhibition of calcineurin with cyclosporine A (CsA), while the inhibition of ERK1/2 with PD098059 elevated it in both cell lines. The signals of Ser/Thr phosphoproteins at 57 kD were stronger after CsA treatment, while a markedly weaker signal was detected upon inhibition of the MAPK pathway. Our results suggest opposing effects of the two investigated enzymes on the HA homeostasis of melanoma cells. We propose that the dephosphorylation of HAS enzymes targeted by PP2B augments HA production, while their phosphorylation by the activity of MAPK pathway reduces HA synthesis. As the expression of the HA receptor RHAMM was also significantly enhanced by PD098059, the MAPK pathway exerted a complex attenuating effect on HA signalling in the investigated melanoma cells. This observation suggests that the application of MAPK-ERK pathway inhibitors requires a careful therapeutic design in melanoma treatment.

Cheng XB, Kohi S, Koga A, et al.
Hyaluronan stimulates pancreatic cancer cell motility.
Oncotarget. 2016; 7(4):4829-40 [PubMed] Free Access to Full Article Related Publications
Hyaluronan (HA) accumulates in pancreatic ductal adenocarcinoma (PDAC), but functional significance of HA in the aggressive phenotype remains unknown. We used different models to investigate the effect of HA on PDAC cell motility by wound healing and transwell migration assay. Changes in cell motility were examined in 8 PDAC cell lines in response to inhibition of HA production by treatment with 4-methylumbelliferone (4-MU) and to promotion by treatment with 12-O-tetradecanoyl-phorbol-13-acetate (TPA) or by co-culture with tumor-derived stromal fibroblasts. We also investigated changes in cell motility by adding exogenous HA. Additionally, mRNA expressions of hyaluronan synthases and hyaluronidases were examined using real time RT-PCR. Inhibition of HA by 4-MU significantly decreased the migration, whereas promotion of HA by TPA or co-culture with tumor-derived fibroblasts significantly increased the migration of PDAC cells. The changes in HA production by these treatments tended to be associated with changes in HAS3 mRNA expression. Furthermore, addition of exogenous HA, especially low-molecular-weight HA, significantly increased the migration of PDAC cells. These findings suggest that HA stimulates PDAC cell migration and thus represents an ideal therapeutic target to prevent invasion and metastasis.

Kohi S, Sato N, Cheng XB, et al.
A novel epigenetic mechanism regulating hyaluronan production in pancreatic cancer cells.
Clin Exp Metastasis. 2016; 33(3):225-30 [PubMed] Related Publications
Pancreatic ductal adenocarcinoma (PDAC) is characterized by an abundant stroma enriched with hyaluronan (HA), a major component of extracellular matrix known to play a critical role in tumor progression. The mechanisms that regulate HA synthesis in PDAC are poorly understood. To investigate whether DNA methylation and HA production from PDAC cells are associated, we studied the effect of 5-aza-2'-deoxycitidine (5-aza-dC), an inhibitor of DNA methylation, or DNA methyltransferase 1 (DNMT1) knockdown by small interfering RNA, on the HA production from PDAC cells. HA production into the conditioned medium was evaluated in PDAC cells treated with 5-aza-dC or DNMT1 knockdown. mRNA expression of HA synthase (HAS) genes was investigated by real-time RT-PCR. Treatment of PDAC cells with 5-aza-dC led to a significant increase in the HA production (up to 2.5-fold increase) in all 4 cell lines tested. This enhanced HA production by 5-aza-dC treatment was accompanied by increased mRNA expression of HAS2 and HAS3. Furthermore, increased HA production and HAS2/HAS3 mRNA expression was also observed in PDAC cells by knockdown of DNMT1. These findings provide evidence, for the first time, that epigenetic mechanism is involved in the regulation of HA synthesis in PDAC cells.

Takabe P, Bart G, Ropponen A, et al.
Hyaluronan synthase 3 (HAS3) overexpression downregulates MV3 melanoma cell proliferation, migration and adhesion.
Exp Cell Res. 2015; 337(1):1-15 [PubMed] Related Publications
Malignant skin melanoma is one of the most deadly human cancers. Extracellular matrix (ECM) influences the growth of malignant tumors by modulating tumor cells adhesion and migration. Hyaluronan is an essential component of the ECM, and its amount is altered in many tumors, suggesting an important role for hyaluronan in tumorigenesis. Nonetheless its role in melanomagenesis is not understood. In this study we produced a MV3 melanoma cell line with inducible expression of the hyaluronan synthase 3 (HAS3) and studied its effect on the behavior of the melanoma cells. HAS3 overexpression expanded the cell surface hyaluronan coat and decreased melanoma cell adhesion, migration and proliferation by cell cycle arrest at G1/G0. Melanoma cell migration was restored by removal of cell surface hyaluronan by Streptomyces hyaluronidase and by receptor blocking with hyaluronan oligosaccharides, while the effect on cell proliferation was receptor independent. Overexpression of HAS3 decreased ERK1/2 phosphorylation suggesting that inhibition of MAP-kinase signaling was responsible for these suppressive effects on the malignant phenotype of MV3 melanoma cells.

Chang IW, Liang PI, Li CC, et al.
HAS3 underexpression as an indicator of poor prognosis in patients with urothelial carcinoma of the upper urinary tract and urinary bladder.
Tumour Biol. 2015; 36(7):5441-50 [PubMed] Related Publications
Via data mining a published transcriptomic database of UBUC (GSE31684), we discovered hyaluronan synthase-3 (HAS3) as the most significant gene stepwise downregulated from early tumorigenesis to progression among those associated with hyaluronan synthase activity (GO:0050501). We consequently analyzed HAS3 protein expression and their association with clinicopathological factors and survival in our well-characterized cohort of urothelial carcinoma of upper urinary tract (UTUC) and urinary bladder (UBUC). HAS3 expression was assessed by immunohistochemistry and evaluated by using H score method in 295 UBUCs and 340 UTUCs, respectively. HAS3 protein expression statuses were further correlated with clinicopathological parameters and evaluated the prognostic significance for disease-specific survival (DSS) and metastasis-free survival (MeFS). HAS3 protein underexpression was significantly associated with advanced pT status, nodal metastasis, high histological grade, vascular invasion, and frequent mitoses in both groups of UCs. HAS3 underexpression not only predicted poorer DSS and MeFS with univariate analysis, but also indicated dismal DSS and MeFS in multivariate analysis. HAS3 underexpression is associated with advanced tumor stage and adverse pathological features, as well as implies inferior clinical outcomes for both groups of patients with UTUCs and UBUCs, suggesting its critical role in tumor progression in UCs and may serve as a prospective prognostic biomarker and a novel therapeutic target in UCs.

di Martino E, Kelly G, Roulson JA, Knowles MA
Alteration of cell-cell and cell-matrix adhesion in urothelial cells: an oncogenic mechanism for mutant FGFR3.
Mol Cancer Res. 2015; 13(1):138-48 [PubMed] Related Publications
UNLABELLED: Activating mutations of FGFR3 are a common and early event in bladder cancer. Ectopic expression of mutant FGFR3 in normal urothelial cells has both pro-proliferative and antiapoptotic effects at confluence, suggesting that mutant cells are insensitive to cell-cell contact inhibition. Herein, detailed analysis revealed that these cells have reduced cell-cell adhesion, with large intercellular spaces observable at confluence, and diminished cell-substrate adhesion to collagen IV, collagen I, and fibronectin. These phenotypic alterations are accompanied by changes in the expression of genes involved in cell adhesion and extracellular matrix remodeling. Silencing of endogenous mutant FGFR3 in bladder cancer cells induced converse changes in transcript levels of CDH16, PLAU, MMP10, EPCAM, TNC, and HAS3, confirming them as downstream gene targets of mutant FGFR3. Overexpression of EPCAM, HAS3, and MMP10 transcripts was found in a large fraction of primary bladder tumors analyzed, supporting their key role in bladder tumorigenesis in vivo. However, no correlation was found between their protein and/or mRNA expression and FGFR3 mutation status in tumor specimens, indicating that these genes may be targeted by several converging oncogenic pathways. Overall, these results indicate that mutant FGFR3 favors the development and progression of premalignant bladder lesions by altering key genes regulating the cell-cell and cell-matrix adhesive properties of urothelial cells.
IMPLICATIONS: The ability of mutant FGFR3 to drive transcriptional expression profiles involved in tumor cell adhesion suggests a mechanism for expansion of premalignant urothelial lesions.

Adamia S, Kriangkum J, Belch AR, Pilarski LM
Aberrant posttranscriptional processing of hyaluronan synthase 1 in malignant transformation and tumor progression.
Adv Cancer Res. 2014; 123:67-94 [PubMed] Related Publications
It is becoming increasingly apparent that splicing defects play a key role in cancer, and that alterations in genomic splicing elements promote aberrant splicing. Alternative splicing increases the diversity of the human transcriptome and increases the numbers of functional gene products. However, dysregulation that leads to aberrant pre-mRNA splicing can contribute to cancer. Hyaluronan (HA), known to be an important component of cancer progression, is synthesized by hyaluronan synthases (HASs). In cancer cells, hyaluronan synthase 1 (HAS1) pre-mRNA is abnormally spliced to generate a family of aberrant splice variants (HAS1Vs) that synthesize extracellular and intracellular HA. HAS1Vs are clinically relevant, being found almost exclusively in malignant cells. Expression of aberrant HAS1Vs predicts poor survival in multiple myeloma. In this review, we summarize the unusual properties of HAS1Vs and their relationship to cancer. HAS1Vs form heterogeneous multimers with normally spliced HAS1 as well as with each other and with HAS3. Aberrant variants of HAS1 synthesize HA. Extracellular HA synthesized by HAS1Vs is likely to promote malignant spread. We speculate that synthesis of intracellular HA plays a fundamental and early role in oncogenesis by promoting genetic instability and the emergence of viable cancer variants that lead to aggressive disease.

Ricciardelli C, Ween MP, Lokman NA, et al.
Chemotherapy-induced hyaluronan production: a novel chemoresistance mechanism in ovarian cancer.
BMC Cancer. 2013; 13:476 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Hyaluronan (HA) an important component of the extracellular matrix, has been linked to tumor progression and drug resistance in several malignancies. However, limited data is available for ovarian cancer. This study investigated the role of hyaluronan (HA) and a potential link between the HA-CD44 pathway and membrane ATP binding cassette (ABC) transporter proteins in ovarian cancer chemoresistance.
METHODS: We investigated the ability of HA to block the cytotoxic effects of the chemotherapy drug carboplatin, and to regulate the expression of ABC transporters in ovarian cancer cells. We also examined HA serum levels in ovarian cancer patients prior to and following chemotherapy and assessed its prognostic relevance.
RESULTS: HA increased the survival of carboplatin treated ovarian cancer cells expressing the HA receptor, CD44 (OVCAR-5 and OV-90). Carboplatin significantly increased expression of HAS2, HAS3 and ABCC2 and HA secretion in ovarian cancer cell conditioned media. Serum HA levels were significantly increased in patients following platinum based chemotherapy and at both 1st and 2nd recurrence when compared with HA levels prior to treatment. High serum HA levels (>50 μg/ml) prior to chemotherapy treatment were associated with significantly reduced progression-free (P = 0.014) and overall survival (P = 0.036). HA production in ovarian cancer cells was increased in cancer tissues collected following chemotherapy treatment and at recurrence. Furthermore HA treatment significantly increased the expression of ABC drug transporters (ABCB3, ABCC1, ABCC2, and ABCC3), but only in ovarian cancer cells expressing CD44. The effects of HA and carboplatin on ABC transporter expression in ovarian cancer cells could be abrogated by HA oligomer treatment. Importantly, HA oligomers increased the sensitivity of chemoresistant SKOV3 cells to carboplatin.
CONCLUSIONS: Our findings indicate that carboplatin chemotherapy induces HA production which can contribute to chemoresistance by regulating ABC transporter expression. The HA-CD44 signaling pathway is therefore a promising target in platinum resistant ovarian cancer.

Huang Z, Li S, Song W, et al.
Lysine-specific demethylase 1 (LSD1/KDM1A) contributes to colorectal tumorigenesis via activation of the Wnt/β-catenin pathway by down-regulating Dickkopf-1 (DKK1) [corrected].
PLoS One. 2013; 8(7):e70077 [PubMed] Free Access to Full Article Related Publications
We collected paired samples of tumor and adjacent normal colorectal tissues from 22 patients with colorectal carcinoma to compare the differences in the expression of lysine specific demethylase 1 (LSD1) in these two tissues. The results showed that in 19 paired samples (86.4%), LSD1 is more highly expressed in tumor tissue than in normal tissue. To explore the role of LSD1 in colorectal tumorigenesis, we used somatic cell gene targeting to generate an LSD1 knockout (KO) HCT 116 human colorectal cancer cell line as a research model. The analysis of phenotypic changes showed that LSD1 KO colorectal cancer cells are less tumorigenic, both in vivo and in vitro. The differential expression analysis of the cells by mRNA sequencing (RNA-Seq) yielded 2,663 differentially expressed genes, and 28 of these genes had highly significant differences (Q <0.01). We then selected the 4 colorectal cancer-related genes ADM, DKK1, HAS3 and SMURF2 for quantitative real-time PCR verification. The results showed that the differences in the expression of ADM, DKK1 and HAS3 were consistent with those measured using the RNA-Seq data. As DKK1 was the gene with the most significant differential expression, we analyzed the key proteins of the DKK1-related Wnt/β-catenin signaling pathway and found that, after knocking out LSD1, the amount of free β-catenin translocated to the nucleus was significantly reduced and that the transcription of the signaling pathway target gene c-Myc was down-regulated. Our studies show that LSD1 activates the Wnt/β-catenin signaling pathway by down-regulating the pathway antagonist DKK1, which may be one of the mechanisms leading to colorectal tumorigenesis.

Rilla K, Oikari S, Jokela TA, et al.
Hyaluronan synthase 1 (HAS1) requires higher cellular UDP-GlcNAc concentration than HAS2 and HAS3.
J Biol Chem. 2013; 288(8):5973-83 [PubMed] Free Access to Full Article Related Publications
Mammals have three homologous genes encoding proteins with hyaluronan synthase activity (Has1-3), all producing an identical polymer from UDP-N-acetylglucosamine and UDP-glucuronic acid. To compare the properties of these isoenzymes, COS-1 cells, with minor endogenous hyaluronan synthesis, were transfected with human Has1-3 isoenzymes. HAS1 was almost unable to secrete hyaluronan or form a hyaluronan coat, in contrast to HAS2 and HAS3. This failure of HAS1 to synthesize hyaluronan was compensated by increasing the cellular content of UDP-N-acetyl glucosamine by ∼10-fold with 1 mm glucosamine in the growth medium. Hyaluronan synthesis driven by HAS2 was less affected by glucosamine addition, and HAS3 was not affected at all. Glucose-free medium, leading to depletion of the UDP-sugars, markedly reduced hyaluronan synthesis by all HAS isoenzymes while raising its concentration from 5 to 25 mm had a moderate stimulatory effect. The results indicate that HAS1 is almost inactive in cells with low UDP-sugar supply, HAS2 activity increases with UDP-sugars, and HAS3 produces hyaluronan at high speed even with minimum substrate content. Transfected Has2 and particularly Has3 consumed enough UDP-sugars to reduce their content in COS-1 cells. Comparison of different human cell types revealed ∼50-fold differences in the content of UDP-N-acetylhexosamines and UDP-glucuronic acid, correlating with the expression level of Has1, suggesting cellular coordination between Has1 expression and the content of UDP-sugars.

Heffler M, Golubovskaya VM, Conroy J, et al.
FAK and HAS inhibition synergistically decrease colon cancer cell viability and affect expression of critical genes.
Anticancer Agents Med Chem. 2013; 13(4):584-94 [PubMed] Free Access to Full Article Related Publications
Focal adhesion kinase (FAK), hyaluronan (HA), and hyaluronan synthase-3 (HAS3) have been implicated in cancer growth and progression. FAK inhibition with the small molecule inhibitor Y15 decreases colon cancer cell growth in vitro and in vivo. HAS3 inhibition in colon cancer cells decreases FAK expression and activation, and exogenous HA increases FAK activation. We sought to determine the genes affected by HAS and FAK inhibition and hypothesized that dual inhibition would synergistically inhibit viability. Y15 (FAK inhibitor) and the HAS inhibitor 4-methylumbelliferone (4-MU) decreased viability in a dose dependent manner; viability was further inhibited by treatment with Y15 and 4-MU in colon cancer cells. HAS inhibited cells treated with 2 μM of Y15 showed significantly decreased viability compared to HAS scrambled cells treated with the same dose (p < 0.05) demonstrating synergistic inhibition of viability with dual FAK/HAS inhibition. Microarray analysis showed more than 2-fold up- or down-regulation of 121 genes by HAS inhibition, and 696 genes by FAK inhibition (p < 0.05) and revealed 29 common genes affected by both signaling. Among the genes affected by FAK or HAS3 inhibition were genes, playing role in apoptosis, cell cycle regulation, adhesion, transcription, heatshock and WNT pathways. Thus, FAK or HAS inhibition decreases SW620 viability and affects several similar genes, which are involved in the regulation of tumor survival. Dual inhibition of FAK and HAS3 decreases viability to a greater degree than with either agent alone, and suggests that synergistic inhibition of colon cancer cell growth can result from affecting similar genetic pathways.

Tamada Y, Takeuchi H, Suzuki N, et al.
Cell surface expression of hyaluronan on human ovarian cancer cells inversely correlates with their adhesion to peritoneal mesothelial cells.
Tumour Biol. 2012; 33(4):1215-22 [PubMed] Related Publications
Eight of 15 human ovarian carcinoma cell lines were shown to express high levels of hyaluronan (HA) on their surfaces. The role of cell surface HA in its adhesion to mesothelial cells, which is potentially involved in peritoneal dissemination, was evaluated. Three human ovarian carcinoma cell lines, ES-2, MH, and KF cells, were repeatedly sorted into variant cell lines with high levels of cell surface HA (ES-2/HA+7, MH/HA+7, and KF/HA+7) and with low cell surface HA (ES-2/HA-7, MH/HA-7, and KF/HA-7). The ability of these cells to adhere to peritoneal mesothelial cells was compared. ES-2/HA+7, MH/HA+7, and KF/HA+7 cells were less adherent to mesothelial cells than the ES-2/HA-7, MH/HA-7, and KF/HA-7 cells. On ovarian carcinoma cells, high cell surface HA levels seem to inversely correlate with their capacity to adhere and disseminate to the peritoneum. Considering that peritoneum implantation is the primary ovarian cancer complication, HA cell surface expression may be considered a property associated with a less aggressive phenotype, which is contrary to the general perception that HA expression is associated with malignant progression.

Urakawa H, Nishida Y, Knudson W, et al.
Therapeutic potential of hyaluronan oligosaccharides for bone metastasis of breast cancer.
J Orthop Res. 2012; 30(4):662-72 [PubMed] Related Publications
Hyaluronan (HA) oligosaccharides were reported to have suppressive effects on various malignant tumors via disruption of receptor HA interactions. However, no studies have focused on the effects of HA oligosaccharides on bone metastasis of breast cancer. In this study, we clarified the effective size of HA oligosaccharides required to inhibit cell growth in the highly invasive breast cancer cell line, MDA-MB-231 cells. Based on the results of cell growth assay, we subsequently analyzed the effects of HA tetrasaccharides, HA decasaccharides, and high molecular weight HA on the other breast cancer cell behaviors in vitro and breast cancer bone metastasis in vivo. HA decasaccharides significantly inhibited cell growth, motility, and invasion, whereas tetrasaccharides did not. HAS2 mRNA expression was altered after the treatment with both tetrasaccharides and decasaccharides. Phosphorylation of Akt was suppressed after 1 h treatment with HA decasaccharides, and the effect was partially reversed by anti-CD44 monoclonal antibody. In vivo, local application of HA decasaccharides inhibited the expansion of osteolytic lesions in tibia on soft X-rays using mouse bone metastasis model of breast cancer. Histological analysis revealed HA accumulation in bone metastatic lesions was perturbed by decasaccharides. These results suggest that HA oligosaccharides suppressed progression of bone metastasis in breast cancer via interruption of endogenous HA-CD44 interaction, and as such, can be a novel therapeutic candidate to limit bone metastasis of breast cancer.

Chi A, Shirodkar SP, Escudero DO, et al.
Molecular characterization of kidney cancer: association of hyaluronic acid family with histological subtypes and metastasis.
Cancer. 2012; 118(9):2394-402 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Molecular profiling of renal cell carcinomas (RCCs) may improve the distinction between oncocytoma and malignant RCC subtypes and aid in early detection of metastasis. The hyaluronic acid (HA) family includes HA synthases (HAS1, HAS2, HAS3), hyaluronidases (HYAL-1, HYAL-2, HYAL-3, HYAL-4, PH20, HYAL-P1), and HA receptors (CD44s, CD44v, RHAMM). HA family members promote tumor growth and metastasis. The authors evaluated the expression of HA family members in kidney specimens.
METHODS: By using quantitative polymerase chain reaction, mRNA levels of 12 HA family members were measured in tumor specimens obtained from 86 consecutive patients undergoing nephrectomy; 80 of them also provided normal specimens. Mean and median follow-up were 15.2 ± 8.8 and 13.8 months. RCC specimens included clear cell RCC: 65; papillary: 10; chromophobe: 5; oncocytoma: 6; metastasis positive: 17.
RESULTS: Median HAS1, CD44s, and RHAMM transcript levels were elevated 3- to 25-fold in clear cell RCC and papillary and chromophobe tumors when compared with normal tissues. HYAL-4, CD44s, and RHAMM levels were elevated 4- to 12-fold in clear cell RCC and papillary tumors when compared with oncocytomas; only HYAL-4 levels distinguished between chromophobe and oncocytoma (P = .009). CD44s and RHAMM levels were significantly higher in tumors <4 cm (510 ± 611 and 19.6 ± 20.8, respectively) when compared with oncocytoma (46.4 ± 20 and 3.8 ± 2.5; P ≤ .006). In univariate and multivariate analyses, CD44s (P < .0001), RHAMM (P < .0001), stage, tumor size, and/or renal vein involvement were significantly associated with metastasis. The combined CD44s + RHAMM marker had 82% sensitivity and 86% specificity to predict metastasis.
CONCLUSIONS: CD44s and RHAMM levels distinguish between oncocytoma and RCC subtypes regardless of tumor size and are potential predictors of RCC metastasis.

Twarock S, Freudenberger T, Poscher E, et al.
Inhibition of oesophageal squamous cell carcinoma progression by in vivo targeting of hyaluronan synthesis.
Mol Cancer. 2011; 10:30 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Oesophageal cancer is a highly aggressive tumour entity with at present poor prognosis. Therefore, novel treatment options are urgently needed. Hyaluronan (HA) is a polysaccharide present in the matrix of human oesophageal squamous cell carcinoma (ESCC). Importantly, in vitro ESCC cells critically depend on HA synthesis to maintain the proliferative phenotype. The aim of the present study is (1) to study HA-synthase (HAS) expression and regulation in human ESCC, and (2) to translate the in vitro results into a mouse xenograft model of human ESCC to study the effects of systemic versus tumour targeted HAS inhibition on proliferation and distribution of tumour-bound and stromal hyaluronan.
METHODS: mRNA expression was investigated in human ESCC biopsies by semiquantitative real-time RT PCR. Furthermore, human ESCC were xenografted into NMRI nu/nu mice. The effects on tumour progression and morphology of 4-methylumbelliferone (4-MU), an inhibitor of HA-synthesis, and of lentiviral knock down of HA-synthase 3 (HAS3), the main HAS isoform in the human ESCC tissues and the human ESCC cell line used in this study, were determined. Tumour progression was monitored by calliper measurements and by flat-panel detector volume computed tomography (fpVCT). HA content, cellular composition and proliferation (Ki67) were determined histologically.
RESULTS: mRNA of HAS isoform 3 (HAS3) was upregulated in human ESCC biopsies and HAS3 mRNA was positively correlated to expression of the epidermal growth factor (EGF) receptor. EGF was also proven to be a strong inductor of HAS3 mRNA expression in vitro. During the course of seven weeks, 4-MU inhibited progression of xenograft tumours. Interestingly, remodelling of the tumour into a more differentiated phenotype and inhibition of cell proliferation were observed. Lentiviral knockdown of HAS3 in human ESCC cells prior to xenografting mimicked all effects of 4-MU treatment suggesting that hyaluronan produced by ESCC is accountable for major changes in tumour environment in vivo.
CONCLUSIONS: Systemic inhibition of HA-synthesis and knockdown of tumour cell HAS3 cause decreased ESCC progression accompanied by tumour stroma remodelling and may therefore be used in novel approaches to ESCC therapy.

Nykopp TK, Rilla K, Tammi MI, et al.
Hyaluronan synthases (HAS1-3) and hyaluronidases (HYAL1-2) in the accumulation of hyaluronan in endometrioid endometrial carcinoma.
BMC Cancer. 2010; 10:512 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Hyaluronan accumulation correlates with the degree of malignancy in many solid tumor types, including malignant endometrial carcinomas. To elucidate the mechanism of hyaluronan accumulation, we examined the expression levels of the hyaluronan synthases (HAS1, HAS2 and HAS3) and hyaluronidases (HYAL1 and HYAL2), and correlated them with hyaluronan content and HAS1-3 immunoreactivity.
METHODS: A total of 35 endometrial tissue biopsies from 35 patients, including proliferative and secretory endometrium (n = 10), post-menopausal proliferative endometrium (n = 5), complex atypical hyperplasia (n = 4), grade 1 (n = 8) and grade 2 + 3 (n = 8) endometrioid adenocarcinomas were divided for gene expression by real-time RT-PCR, and paraffin embedded blocks for hyaluronan and HAS1-3 cytochemistry.
RESULTS: The mRNA levels of HAS1-3 were not consistently changed, while the immunoreactivity of all HAS proteins was increased in the cancer epithelium. Interestingly, HAS3 mRNA, but not HAS3 immunoreactivity, was increased in post-menopausal endometrium compared to normal endometrium (p = 0.003). The median of HYAL1 mRNA was 10-fold and 15-fold lower in both grade 1 and grade 2+3 endometrioid endometrial cancers, as compared to normal endometrium (p = 0.004-0.006), and post-menopausal endometrium (p = 0.002), respectively. HYAL2 mRNA was also reduced in cancer (p = 0.02) and correlated with HYAL1 (r = 0.8, p = 0.0001). There was an inverse correlation between HYAL1 mRNA and the epithelial hyaluronan staining intensity (r = -0.6; P = 0.001).
CONCLUSION: The results indicated that HYAL1 and HYAL2 were coexpressed and significantly downregulated in endometrioid endometrial cancer and correlated with the accumulation of hyaluronan. While immunoreactivity for HASs increased in the cancer cells, tumor mRNA levels for HASs were not changed, suggesting that reduced turnover of HAS protein may also have contributed to the accumulation of hyaluronan.

Tzellos TG, Kyrgidis A, Vahtsevanos K, et al.
Nodular basal cell carcinoma is associated with increased hyaluronan homeostasis.
J Eur Acad Dermatol Venereol. 2011; 25(6):679-87 [PubMed] Related Publications
BACKGROUND: Basal cell carcinoma (BCC) is one of the most frequent forms of malignancy in humans. Although BCC is a tumour of low degree of malignancy, if left untreated, it can be locally aggressive, eat away at tissues and cause ulceration. Nodular is the most common subtype of BCC (>50%). Although apparently non-invasive, micronodular, a certain subgroup of nodular, is likely to recur. Glycosaminoglycans (GAGs), such as hyaluronic acid (HA), are extracellular matrix molecules of high importance in malignant transformation, metastasis and other complex remodelling processes.
OBJECTIVES: To investigate the expression of GAGs and their metabolizing enzymes in nodular BCC, when compared with adjacent healthy human skin tissue specimens.
METHODS: Total GAGs were isolated and purified from nodular BCC and normal adjacent human skin tissue specimens. GAGs were subsequently fractionated by electrophoresis on cellulose acetate membranes and characterized using specific GAG-degrading enzymes. The content of HA in total GAGs was measured using ELISA and the expression of HA synthases (HAS), hyaluronidases (HYAL) and HA receptors (CD44 and receptor hyaluronic acid-mediated motility (RHAMM) was assessed using RT-PCR.
RESULTS: Nodular BCC is associated with increased levels of HA concomitant with upregulation of gene expression of HAS3, HYAL3 and RHAMM, when compared with normal adjacent skin.
CONCLUSION: These results indicate that HA homeostasis in nodular BCC shows distinct features which may be helpful in understanding the complex behaviour of nodular subtype of BCC, thus eventually leading to new treatment strategies.

Chow G, Tauler J, Mulshine JL
Cytokines and growth factors stimulate hyaluronan production: role of hyaluronan in epithelial to mesenchymal-like transition in non-small cell lung cancer.
J Biomed Biotechnol. 2010; 2010:485468 [PubMed] Free Access to Full Article Related Publications
In this study, we investigated the role of hyaluronan (HA) in non-small cell lung cancer (NSCLC) since close association between HA level and malignancy has been reported. HA is an abundant extracellular matrix component and its synthesis is regulated by growth factors and cytokines that include epidermal growth factor (EGF) and interleukin-1beta (IL-1beta). We showed that treatment with recombinant EGF and IL-1beta, alone or in combination with TGF-beta, was able to stimulate HA production in lung adenocarcinoma cell line A549. TGF-beta/IL-1beta treatment induced epithelial to mesenchymal-like phenotype transition (EMT), changing cell morphology and expression of vimentin and E-cadherin. We also overexpressed hyaluronan synthase-3 (HAS3) in epithelial lung adenocarcinoma cell line H358, resulting in induced HA expression, EMT phenotype, enhanced MMP9 and MMP2 activities and increased invasion. Furthermore, adding exogenous HA to A549 cells and inducing HA H358 cells resulted in increased resistance to epidermal growth factor receptor (EGFR) inhibitor, Iressa. Together, these results suggest that elevated HA production is able to induce EMT and increase resistance to Iressa in NSCLC. Therefore, regulation of HA level in NSCLC may be a new target for therapeutic intervention.

Twarock S, Tammi MI, Savani RC, Fischer JW
Hyaluronan stabilizes focal adhesions, filopodia, and the proliferative phenotype in esophageal squamous carcinoma cells.
J Biol Chem. 2010; 285(30):23276-84 [PubMed] Free Access to Full Article Related Publications
Hyaluronan (HA) is a polysaccharide component in the parenchyma and stroma of human esophageal squamous cell carcinoma (ESCC). Clinically, esophageal cancer represents a highly aggressive tumor type with poor prognosis resulting in a 5-year survival rate of 5%. The aim of the present study was the detailed analysis of the role of HA synthesis for ESCC phenotype in vitro using the ESCC cell line OSC1. In OSC1 cells, pericellular HA-matrix surrounding extended actin-dependent filopodia was detected. The small molecule inhibitor of HA synthesis, 4-methylumbelliferone (4-MU, 0.3 mm) caused loss of these filopodia and focal adhesions and inhibited proliferation and migration. In search of the underlying mechanism cleavage of focal adhesion kinase (FAK) was detected by immunoblotting. In addition, displacing HA by an HA-binding peptide (Pep-1, 500 mug/ml) and digestion of pericellular HA by hyaluronidase resulted in cleavage of focal adhesions. Furthermore, real-time reverse transcription PCR revealed that HA synthase 3 (HAS3) > HAS2 are the predominant HA-synthases in OSC1. Lentiviral transduction with shHAS3, and to a lesser extent with shHAS2, reduced intact FAK protein and filopodia as well as proliferation and migration. Furthermore, down-regulation by lentiviral shRNA of RHAMM (receptor of HA-mediated motility) but not CD44 induced loss of filopodia and caused FAK cleavage. In contrast, knockdown of both HA receptors inhibited proliferation and migration of OSC1. In conclusion, HA synthesis and, in turn, RHAMM and CD44 signaling promoted an activated phenotype of OSC1. Because RHAMM appears to support both filopodia, FAK, and the proliferative and migratory phenotype, it may be promising to explore RHAMM as a potential therapeutic target in esophageal cancer.

Nykopp TK, Rilla K, Sironen R, et al.
Expression of hyaluronan synthases (HAS1-3) and hyaluronidases (HYAL1-2) in serous ovarian carcinomas: inverse correlation between HYAL1 and hyaluronan content.
BMC Cancer. 2009; 9:143 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Hyaluronan, a tumor promoting extracellular matrix polysaccharide, is elevated in malignant epithelial ovarian tumors, and associates with an unfavorable prognosis. To explore possible contributors to the accumulation of hyaluronan, we examined the expression of hyaluronan synthases (HAS1, HAS2 and HAS3) and hyaluronidases (HYAL1 and HYAL2), correlated with hyaluronidase enzyme activity hyaluronan content and HAS1-3 immunoreactivity.
METHODS: Normal ovaries (n = 5) and 34 serous epithelial ovarian tumors, divided into 4 groups: malignant grades 1+2 (n = 10); malignant grade 3 (n = 10); borderline (n = 4) and benign epithelial tumors (n = 10), were analyzed for mRNA by real-time RT-PCR and compared to hyaluronidase activity, hyaluronan staining, and HAS1-3 immunoreactivity in tissue sections of the same specimens.
RESULTS: The levels of HAS2 and HAS3 mRNA (HAS1 was low or absent), were not consistently increased in the carcinomas, and were not significantly correlated with HAS protein or hyaluronan accumulation in individual samples. Instead, the median of HYAL1 mRNA level was 69% lower in grade 3 serous ovarian cancers compared to normal ovaries (P = 0.01). The expression of HYAL1, but not HYAL2, significantly correlated with the enzymatic activity of tissue hyaluronidases (r = 0.5; P = 0.006). An inverse correlation was noted between HYAL1 mRNA and the intensity of hyaluronan staining of the corresponding tissue sections (r = -0.4; P = 0.025).
CONCLUSION: The results indicate that in serous epithelial ovarian malignancies HAS expression is not consistently elevated but HYAL1 expression is significantly reduced and correlates with the accumulation of hyaluronan. (233 words).

Golshani R, Lopez L, Estrella V, et al.
Hyaluronic acid synthase-1 expression regulates bladder cancer growth, invasion, and angiogenesis through CD44.
Cancer Res. 2008; 68(2):483-91 [PubMed] Related Publications
Hyaluronic acid (HA) promotes tumor metastasis and is an accurate diagnostic marker for bladder cancer. HA is synthesized by HA synthases HAS1, HAS2, or HAS3. We have previously shown that HAS1 expression in tumor tissues is a predictor of bladder cancer recurrence and treatment failure. In this study, we stably transfected HT1376 bladder cancer cells with HAS1-sense (HAS1-S), HAS1-antisense (HAS1-AS), or vector cDNA constructs. Whereas HAS1-S transfectants produced approximately 1.7-fold more HA than vector transfectants, HA production was reduced by approximately 70% in HAS1-AS transfectants. HAS1-AS transfectants grew 5-fold slower and were approximately 60% less invasive than vector and HAS1-S transfectants. HAS1-AS transfectants were blocked in G(2)-M phase of the cell cycle due to down-regulation of cyclin B1, cdc25c, and cyclin-dependent kinase 1 levels. These transfectants were also 5- to 10-fold more apoptotic due to the activation of the Fas-Fas ligand-mediated extrinsic pathway. HAS1-AS transfectants showed a approximately 4-fold decrease in ErbB2 phosphorylation and down-regulation of CD44 variant isoforms (CD44-v3, CD44-v6, and CD44-E) both at the protein and mRNA levels. However, no decrease in RHAMM levels was observed. The decrease in CD44-v mRNA levels was not due to increased mRNA degradation. Whereas CD44 small interfering RNA (siRNA) transfection decreased cell growth and induced apoptosis in HT1376 cells, HA addition modestly increased CD44 expression and cell growth in HAS1-AS transfectants, which could be blocked by CD44 siRNA. In xenograft studies, HAS1-AS tumors grew 3- to 5-fold slower and had approximately 4-fold lower microvessel density. These results show that HAS1 regulates bladder cancer growth and progression by modulating HA synthesis and HA receptor levels.

Bharadwaj AG, Rector K, Simpson MA
Inducible hyaluronan production reveals differential effects on prostate tumor cell growth and tumor angiogenesis.
J Biol Chem. 2007; 282(28):20561-72 [PubMed] Related Publications
Prostate cancer progression can be predicted in human tumor biopsies by abundant hyaluronan (HA) and its processing enzyme, the hyaluronidase HYAL1. Accumulation of HA is dictated by the balance between expression levels of HA synthases, the enzymes that produce HA polymers, and hyaluronidases, which process polymers to oligosaccharides. Aggressive prostate tumor cells express 20-fold higher levels of the hyaluronan synthase HAS3, but the mechanistic relevance of this correlation has not been determined. We stably overexpressed HAS3 in prostate tumor cells. Adhesion to extracellular matrix and cellular growth kinetics in vitro were significantly reduced. Slow growth in culture was restored either by exogenous addition of hyaluronidase or by stable HYAL1 coexpression. Coexpression did not improve comparably slow growth in mice, however, suggesting that excess hyaluronan production by HAS3 may alter the balance required for induced tumor growth. To address this, we used a tetracycline-inducible HAS3 expression system in which hyaluronan production could be experimentally controlled. Adjusting temporal parameters of hyaluronan production directly affected growth rate of the cells. Relief from growth suppression in vitro but not in vivo by enzymatic removal of HA effectively uncoupled the respective roles of hyaluronan in growth and angiogenesis, suggesting that growth mediation is less critical to establishment of the tumor than early vascular development. Collectively results also imply that HA processing by elevated HYAL1 expression in invasive prostate cancer is a requirement for progression.

Bourguignon LY, Gilad E, Peyrollier K
Heregulin-mediated ErbB2-ERK signaling activates hyaluronan synthases leading to CD44-dependent ovarian tumor cell growth and migration.
J Biol Chem. 2007; 282(27):19426-41 [PubMed] Related Publications
Heregulin (HRG)-induced cell responses are mediated by the ErbB family of tyrosine kinase receptors. In this study we have investigated HRG activation of ErbB2, extracellular signal-regulated kinase (ERK) signaling, and their role in regulating hyaluronan synthase (HAS) activity in human ovarian tumor cells (SK-OV-3.ipl cells). Immunological and biochemical analyses indicate that ErbB2, ErbB3, and ErbB4 are all expressed in SK-OV-3.ipl cells and that ErbB4 (but not ErbB3) is physically linked to ErbB2 following HRG stimulation. Furthermore, our data indicate that the HRG-induced ErbB2.ErbB4 complexes stimulate ErbB2 tyrosine kinase, which induces both ERK phosphorylation and kinase activity. The activated ERK then increases the phosphorylation of HAS1, HAS2, and HAS3. Consequently, all three HAS isozymes are activated resulting in hyaluronan (HA) production. Because HRG-mediated HAS isozyme phosphorylation/activation can be effectively blocked by either AG825 (an ErbB2 inhibitor) or thiazolidinedione compound (an ERK blocker), we conclude that ErbB2-ERK signaling and HAS isozyme phosphorylation/HA production are functionally coupled in SK-OV-3.ipl cells. HRG also promotes HA- and CD44-dependent oncogenic events (e.g. CD44-Cdc42 association, p21-activated kinase 1 activation, and p21-activated kinase 1-filamin complex formation) and tumor cell-specific behaviors in an ErbB2-ERK signaling-dependent manner. Finally, we have found that the down-regulation of HAS isozyme expression (by transfecting cells with HAS1/HAS2/HAS3-specific small interfering RNAs) not only inhibits HRG-mediated HAS phosphorylation/activation and HA production but also impairs CD44-specific Cdc42-PAK1/filamin signaling, cytoskeleton activation and tumor cell behaviors. Taken together, these findings clearly indicate that HRG activation of ErbB2-ERK signaling modulates HAS phosphorylation/activation and HA production leading to CD44-mediated oncogenic events and ovarian cancer progression.

Li Y, Li L, Brown TJ, Heldin P
Silencing of hyaluronan synthase 2 suppresses the malignant phenotype of invasive breast cancer cells.
Int J Cancer. 2007; 120(12):2557-67 [PubMed] Related Publications
Accumulation of hyaluronan has been demonstrated in the peritumoral breast cancer stroma and nests of tumor cells. In this study, we have quantified the production of hyaluronan and the expression of mRNAs encoding hyaluronan synthesizing (HAS) and hyaluronan degrading (HYAL) enzymes in a panel of breast cancer cell lines. The analysis revealed that highly invasive breast cancer cells produce high amounts of hyaluronan and express preferentially HAS2 mRNA, whereas less invasive breast cancer cells produce low amount of hyaluronan and express HAS1 and HYAL1 mRNAs. We explored the importance of HAS2 expression for breast cancer tumorigenicity, by specifically silencing the HAS2 gene using RNA interference (RNAi)-mediated suppression in the invasive breast cancer cell line Hs578T. This led to a less aggressive phenotype of the breast tumor cells, as assessed by cell growth, both in anchorage-dependent and anchorage-independent cultures. siRNA-mediated knock down of HAS2 in Hs578T breast tumor cells led to an up-regulation of HAS1, HAS3 and HYAL1 mRNAs, resulting in only a 50% decrease in the net hyaluronan production; however, the synthesized hyaluronan was of lower size and more polydisparse compared to control siRNA-treated cells. Interestingly, Hs578T cells deprived of HAS2 migrated only half as efficiently as HAS2 expressing cells through cell-free areas in a culture wounding assay and through Transwell polycarbonate membrane as well as invaded a Matrigel layer. These results imply that alterations in HAS2 expression and endogenously synthesized hyaluronan affect the malignant phenotype of Hs578T breast cancer cells.

Golshani R, Hautmann SH, Estrella V, et al.
HAS1 expression in bladder cancer and its relation to urinary HA test.
Int J Cancer. 2007; 120(8):1712-20 [PubMed] Related Publications
Hyaluronic acid (HA) levels are elevated in bladder cancer tissues and regulate tumor growth and progression. Urinary HA levels measured by the HA test are an accurate marker for bladder cancer. In cells, HA is synthesized by one of the 3 HA-synthase(s) i.e., HAS1, HAS2 and HAS3. In this study, we examined HAS1 expression in bladder cancer cells and tissues. Real-time RT-PCR and northern blot analyses showed that HAS1 transcript levels are elevated 5- to 10-fold in bladder cancer tissues, when compared with normal tissues (p < 0.001). Among the 3 HAS1 splice variants, only HAS1-va was expressed in bladder tissues, but the expression was significantly lower than the wild type HAS1 transcript. Increased HAS1 expression in bladder tumor tissues correlated with increased tissue HA levels (p < 0.001). Size of the large HA species (2.0 x 10(6) D) present in bladder tissues was consistent with the size of the HA polymer synthesized by HAS1. The amount of HA produced by bladder cancer cell lines correlated with the expression of HAS1 protein. Immunohistochemical analyses of bladder tumor tissues showed that HAS1 and HA expression had 79-88% sensitivity and 83.3-100% specificity. Both HAS1 and HA expression in bladder cancer tissues correlated with a positive HA urine test (p < 0.001). HAS1 expression correlated with tumor recurrence, prior treatment (p < 0.05) and possibly disease progression (p = 0.058). Therefore, elevated HAS1 expression in bladder tumor tissues contributes to a positive HA urine test and may have some prognostic potential.

Tofuku K, Yokouchi M, Murayama T, et al.
HAS3-related hyaluronan enhances biological activities necessary for metastasis of osteosarcoma cells.
Int J Oncol. 2006; 29(1):175-83 [PubMed] Related Publications
Several studies have suggested that increased production of hyaluronan (HA) is associated with metastatic behavior in various malignant tumors. To our knowledge, HA molecular weights required for metastasis are still unsolved in osteosarcoma. We examined the size of HA and hyaluronan synthase (HAS) isoforms related to biological functions required for metastasis in the LM8 stably highly metastatic osteosarcoma cell line. We found that HA of molecular weight which HAS3 produces enhanced biological functions related to metastasis such as cell proliferation, invasion, and degradation of extracellular matrix. Moreover, cell proliferation and invasion were inhibited by suppressing the activity of HAS3 expressed in LM8 cells, using hyaluronan synthase suppressor, 4-methylumbelliferone (MU). HA with the molecular weight related to HAS2 was the most adherent to CD44 in LM8 cells, suggesting that HAS2 may play an important role in pericellular coat formation. These results suggest that HAS3-related HA enhances crucial biological activities necessary for metastasis and that HAS2-related HA offers an advantageous environment for osteosarcoma cells.

Udabage L, Brownlee GR, Nilsson SK, Brown TJ
The over-expression of HAS2, Hyal-2 and CD44 is implicated in the invasiveness of breast cancer.
Exp Cell Res. 2005; 310(1):205-17 [PubMed] Related Publications
Within tumors there appears to be an intricate balance between hyaluronan (HA) synthesis and degradation where the invading edges display increased HA metabolism. The metabolism of HA has not been characterized in breast cancer cell lines; therefore, this study quantitatively identifies and characterizes the enzymes responsible for the synthesis and degradation of HA while correlating gene expression to cancer cell invasiveness and HA receptor status. In ten well-established breast cancer cell lines, the expression of the genes for each hyaluronan synthase (HAS) and hyaluronidase (Hyal) isoform was quantitated using real-time and reverse transcriptase polymerase chain reaction (PCR). The synthesis and degradation rates of hyaluronan were determined by ELISA, while quantitation of HA receptors, CD44 and RHAMM was performed by comparative Western blotting. The molecular weight of HA synthesized by each HAS isoform and the degradation products of each hyaluronidase were characterized by size exclusion chromatography. It was demonstrated that highly invasive cell lines preferentially expressed the HAS2 and Hyal-2 isoforms, while less invasive cells expressed HAS3 and Hyal-3. There was a correlation between elevated levels of HA synthesis, CD44 expression and cancer cell migration thereby highlighting the pivotal role that HA metabolism plays in the aggressive breast cancer phenotype.

Yabushita H, Kishida T, Fusano K, et al.
Role of hyaluronan and hyaluronan synthase in endometrial cancer.
Oncol Rep. 2005; 13(6):1101-5 [PubMed] Related Publications
The aim of this study was to determine if the immunohistochemical expression of hyaluronan synthase (HAS) and serum levels of hyaluronan correlate with the clinicopathological manifestations of endometrial carcinoma. Sera were obtained from 59 endometrial cancer patients and 22 post-menopausal healthy women. Concentration of hyaluronan in sera was measured by an inhibitory ELISA using a hyaluronan-binding protein. Tissues obtained from 59 endometrial cancer patients were immunostained by the avidin-biotin-peroxidase complex method using anti-HAS1, anti-HAS2, anti-HAS3 and anti-CD44 antibody. A section was defined as having positive expression when >50% of the tumor cells were intensely stained. The expression of HAS1 was related to the depth of myometrial invasion, histological grade and lymph-vascular space involvement, but the expression of HAS2 and HAS3 was unrelated to these parameters. CD44 expression occurred more frequently in the HAS2- or HAS3-positive groups than in the HAS2- or HAS3-negative groups, and the expression of HAS1 was unrelated to CD44 expression. Serum levels of hyaluronan were higher in the endometrial cancer group than in the healthy control group, and increased with depth of myometrial invasion, histological grade and lymph-vascular space involvement. Serum hyaluronan levels were higher in the HAS1-positive group than in the HAS1-negative group, but the expression of HAS2 and HAS3 was unrelated to serum hyaluronan levels. HAS1 expression and an increase in serum hyaluronan in endometrial cancer may be associated with disease progression through myometrial invasion and lymph-vascular space involvement.

Adamia S, Maxwell CA, Pilarski LM
Hyaluronan and hyaluronan synthases: potential therapeutic targets in cancer.
Curr Drug Targets Cardiovasc Haematol Disord. 2005; 5(1):3-14 [PubMed] Related Publications
Current models of oncogenesis describe cancer as a progression of genetic mutations in a tumor cell mass. However, tumors are more than a clonal expansion of malignant cells. Tumors are heterogeneous, with a complex 3D structure, analogous to organs comprised of different tissues. In a tumor mass, the component cell types interact with each other and with their microenvironment by exchanging information through cell-cell interactions and/or through interactions with the extracellular matrix (ECM). These synergetic interactions facilitate tumor progression. Furthermore, tumor invasion and metastatic development are accomplished through the breakdown of ECM. Disruption of ECM promotes abnormal inter- and/or intra- cellular signaling, leading to dysregulation of cell proliferation, growth and cytoskeleton reorganization. The disruption of the ECM in turn promotes the overproduction of growth factors, which induce elevated epithelial cell proliferation and other abnormalities including carcinogenesis. In this review we will demonstrate that hyaluronan (HA), a core component of ECM, contributes to certain types of cancer development. Additional to extracellular HA, intracellular and nuclear forms of HA have been detected. Intracellular HA is involved in cell signaling, whereas nuclear HA could promote chromatin condensation and thus facilitate mitosis. HA molecules are synthesized by hyaluronan synthases (HASs)-HAS1, HAS2 and HAS3 enzymes. Dysregulation of HAS genes results in abnormal production of HA and promotion of abnormal biological processes such as transformation and metastasis. The function of HASs appears to be cell and tissue specific. HAS1 maintains a low, basal level of HA. HAS2 is involved in embryonic and cardiac cushion morphogenesis and subsequent development through cell migration and invasion. HAS2 stimulates cell proliferation and angiogenesis. HAS3 appears to favor the malignant phenotype in many types of malignancies. However, the exact function of HAS isoenzymes and their role in cell signaling remains to be elucidated. A better understanding of HA and HASs may facilitate the design of novel therapeutic strategies to counter presumptive cancer-promoting effects of microenvironmental components.

Untergasser G, Gander R, Lilg C, et al.
Profiling molecular targets of TGF-beta1 in prostate fibroblast-to-myofibroblast transdifferentiation.
Mech Ageing Dev. 2005; 126(1):59-69 [PubMed] Related Publications
The development of age-related proliferative disorders of the prostate gland is supported by transdifferentiation and cellular senescence processes in the stroma. Both processes are involved in remodeling of stromal tissue, as observed in benign prostatic hyperplasia (BPH), and in "reactive stroma" adjacent to prostate cancer (PCa). It has been assumed that TGF-beta1 plays a key role in the aging prostate by inducing premature senescence and favoring myofibroblast differentiation. Therefore, we evaluated the stromal cell phenotypes of human primary adult prostatic fibroblasts (n=3) and the molecular and cellular mechanisms of growth arrest after treatment with TGF-beta1 and of in vitro cellular senescence. Microarray analysis, quantitative PCR, immunofluorescence and western blot revealed that cellular senescence and transdifferentiation of fibroblasts have distinct underlying mechanisms, pathways and gene and protein expression profiles in human PrSCs. In clear contrast to senescent cells, TGF-beta1-treated cells morphologically transdifferentiated into myofibroblasts with dense cytoskeletal fibers and increased expression of smooth muscle cell alpha-actin, calponin and tenascin. TGF-beta1 induced neither expression of senescence-associated markers nor genes involved in terminal growth arrest, such as senescence-associated beta-galactosidase and cyclin-dependent kinase (cdk) inhibitors p16(Ink4A) and p21(Cip1) but increased p15(Ink4B) protein expression. Differentiation inhibitor (Id-1) protein level down-regulation was observed under both conditions. Genes specifically up-regulated by transdifferentiation but not by cellular senescence of PrSCs were metalloproteinase 1 tissue inhibitor (Timp1), transgelin (Tagln), gamma 2 actin (Actg2), plasminogen activator inhibitor 1 (Serpinel), insulin-like growth factor binding protein 3 (Igfbp3), parathyroid hormone-like hormone (Pthlp), Tgfb-1, four and a half LIM domains 2 (Fhl-2), hydrogen peroxide-inducible clone 5 (Hic5) and cartilage oligomeric matrix protein (Comp). Other genes, such as Cdc28 protein kinase 1 (Cks1b), v-myb myeloblastosis viral oncogene homolog (MybL2), pyruvate kinase, muscle 2 (Pkm2) and Forkhead box M1 (FoxM1), were down-regulated only upon TGF-beta1 treatment but not by cellular senescence. Pyruvate dehydrogenase kinase 3 (Pdk3) and connective tissue growth factor (Ctgf) were up-regulated and hyaluronan synthase 3 (Has3) down-regulated under both conditions. Moreover, GageC1, a prostate/testis-specific protein overexpressed in symptomatic BPH and PCa was induced in transdifferentiated stromal cells. Genes such as GageC1 could be promising targets for therapeutic inhibitors of stromal tissue remodeling and progression of BPH and PCa.

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