Inhibition of Hyaluronan Synthase-3 Decreases Subcutaneous Colon Cancer Growth by Increasing Apoptosis

Teng, Buwei; Heffler, Melissa; Lai, Eric C. H.; Zhao, Yali; LeVea, Charles; Golubovskaya, Vita M.; BullardDunn, Kelli M.

doi:10.2174/187152011796817655

Cited by 21 publications

(10 citation statements)

References 44 publications

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“…The average size of BxPC-3 HAS3 tumors was 1,905 mm 3 on day 15 after initiation of vehicle treatment while the average size of BxPC-3 tumors was 820 mm 3 (Figures 3(a) and 3(c)). This is consistent with the report that HAS3 overexpression enhances extracellular matrix deposition and tumor growth of prostate cancer cells [45] and that metastatic colon cancer cells have upregulated levels of HAS3 [52]. HAS3 protein level is higher in human ovarian cancer than in normal ovary, and the amount of HAS3-positive cancer cells correlates with hyaluronan accumulation in the stroma [44].…”

Section: Resultssupporting

confidence: 91%

Accumulation of Extracellular Hyaluronan by Hyaluronan Synthase 3 Promotes Tumor Growth and Modulates the Pancreatic Cancer Microenvironment

Kultti

Zhao

Singha

et al. 2014

BioMed Research International

105

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Extensive accumulation of the glycosaminoglycan hyaluronan is found in pancreatic cancer. The role of hyaluronan synthases 2 and 3 (HAS2, 3) was investigated in pancreatic cancer growth and the tumor microenvironment. Overexpression of HAS3 increased hyaluronan synthesis in BxPC-3 pancreatic cancer cells. In vivo, overexpression of HAS3 led to faster growing xenograft tumors with abundant extracellular hyaluronan accumulation. Treatment with pegylated human recombinant hyaluronidase (PEGPH20) removed extracellular hyaluronan and dramatically decreased the growth rate of BxPC-3 HAS3 tumors compared to parental tumors. PEGPH20 had a weaker effect on HAS2-overexpressing tumors which grew more slowly and contained both extracellular and intracellular hyaluronan. Accumulation of hyaluronan was associated with loss of plasma membrane E-cadherin and accumulation of cytoplasmic β-catenin, suggesting disruption of adherens junctions. PEGPH20 decreased the amount of nuclear hypoxia-related proteins and induced translocation of E-cadherin and β-catenin to the plasma membrane. Translocation of E-cadherin was also seen in tumors from a transgenic mouse model of pancreatic cancer and in a human non-small cell lung cancer sample from a patient treated with PEGPH20. In conclusion, hyaluronan accumulation by HAS3 favors pancreatic cancer growth, at least in part by decreasing epithelial cell adhesion, and PEGPH20 inhibits these changes and suppresses tumor growth.

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Section: Resultssupporting

confidence: 91%

Accumulation of Extracellular Hyaluronan by Hyaluronan Synthase 3 Promotes Tumor Growth and Modulates the Pancreatic Cancer Microenvironment

Kultti

Zhao

Singha

et al. 2014

BioMed Research International

105

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“…Of these, 9 were down-regulated after knocking out LSD1, and the remaining 19 were up-regulated (Table 1 and Figure 5C). Interestingly, among these genes, 4 genes, including ADM [41], DKK1 [42], HAS3 [43] and SMURF2 [44], have been reported to be involved in colorectal tumorigenesis. Thus, we tried to find clues from these four for exploring the role of LSD1 in colorectal tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

Lysine-Specific Demethylase 1 (LSD1/KDM1A) Contributes to Colorectal Tumorigenesis via Activation of the Wnt/Β-Catenin Pathway by Down-Regulating Dickkopf-1 (DKK1)

Huang

Song

et al. 2013

PLoS ONE

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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.

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“…Hyaluronan synthase 3 (HAS3) is one of the three HAS isoforms producing HA. HAS3 had been investigated in many cancers [16][17][18][19][20][21]38]. No study, however, has found consistent results of HAS3 effects on different cancer types.…”

Section: Discussionmentioning

confidence: 99%

“…It is true that some studies have linked HAS3 to the promotion of tumor Fig. 3 Kaplan-Meier plots demonstrates the prognostic significances of HAS3 immunoexpression for diseasespecific survival and metastasisfree survival in UTUC (a, b) and UBUC (c, d), respectively growth or to overexpression in cancer compared to a normal organ [16,17,[19][20][21]. Contrariwise, other research has suggested that HAS3 is significantly reduced in premalignancy or malignancy compared to its benign counterparts [18,38].…”

Section: Discussionmentioning

confidence: 99%

“…Other investigators have analyzed the connection between the expression of HAS3-one of the three isoforms of hyaluronan synthases (HAS), a membrane-bound enzyme that produces the glycosaminoglycan hyaluronan using UDP-α-N-acetyl-D-glucosamine and UDP-α-D-glucuronate as substrates-and many cancers, including UBUC. None, however, have specifically examined HAS3 expression in UTUC [15][16][17][18][19][20][21]. Our aim is to address this absence.…”

Section: Introductionmentioning

confidence: 99%

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HAS3 underexpression as an indicator of poor prognosis in patients with urothelial carcinoma of the upper urinary tract and urinary bladder

Chang

Liang

et al. 2015

Tumor Biol.

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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.

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Inhibition of Hyaluronan Synthase-3 Decreases Subcutaneous Colon Cancer Growth by Increasing Apoptosis

Cited by 21 publications

References 44 publications

Accumulation of Extracellular Hyaluronan by Hyaluronan Synthase 3 Promotes Tumor Growth and Modulates the Pancreatic Cancer Microenvironment

Accumulation of Extracellular Hyaluronan by Hyaluronan Synthase 3 Promotes Tumor Growth and Modulates the Pancreatic Cancer Microenvironment

Lysine-Specific Demethylase 1 (LSD1/KDM1A) Contributes to Colorectal Tumorigenesis via Activation of the Wnt/Β-Catenin Pathway by Down-Regulating Dickkopf-1 (DKK1)

HAS3 underexpression as an indicator of poor prognosis in patients with urothelial carcinoma of the upper urinary tract and urinary bladder

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