HYAL1 and HYAL2 Inhibit Tumour Growth In Vivo but Not In Vitro

Wang, Fuli; Grigorieva, Elvira V.; Li, Jing‐Feng; Senchenko, V. N.; Pavlova, Tatiana V.; Anedchenko, E. A.; Kudryavtseva, Anna V.; Tsimanis, A. Yu.; Angeloni, Debora; Lerman, Michael I.; Kashuba, Vladimir I.; Klein, George; Zabarovsky, Eugene R.

doi:10.1371/journal.pone.0003031

Cited by 36 publications

(33 citation statements)

References 25 publications

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“…As an enzyme that degrades hyaluronan, HYAL2 is known to be a tumor suppressor gene involved in cell adhesion, cell mobility, chemokinesis, cancer progression, angiogenesis and metastasis. [35][36][37][38][39] Our results also approved the tumor suppressor character of HYAL2 in tissue by observing higher HYAL2 methylation levels in malignant BC tumors than in benign breast tissues (Supporting Information Fig. 3).…”

Section: Discussionsupporting

confidence: 70%

DNA methylation array analyses identified breast cancer‐associated HYAL2 methylation in peripheral blood

Yang

Pfütze

Zucknick

et al. 2014

Intl Journal of Cancer

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Breast cancer (BC) is the leading cause of cancer-related mortality in women worldwide. Changes in DNA methylation in peripheral blood could be associated with malignancy at early stage. However, the BC-associated DNA methylation signatures in peripheral blood were largely unknown. Here, we performed a genome-wide methylation screening and identified a BC-associated differentially methylated CpG site cg27091787 in the hyaluronoglucosaminidase 2 gene (HYAL2) (discovery round with 72 BC case and 24 controls: p 5 2.61 3 10 29 adjusted for cell-type proportions). The substantially decreased methylation of cg27091787 in BC cases was confirmed in two validation rounds (first validation round with 338 BC case and 507 controls: p < 0.0001; second validation round with 189 BC case and 189 controls: p < 0.0001). In addition to cg27091787, the decreased methylation of a 650-bp CpG island shore of HYAL2 was also associated with increased risk of BC. Moreover, the expression and methylation of HYAL2 were inversely correlated with a p-value of 0.006. To note, the BC-associated decreased HYAL2 methylation was replicated in the T-cell fraction (p 5 0.034). The cg27091787 methylation level enabled a powerful discrimination of earlystage BC cases (stages 0 and I) from healthy controls [area under curve (AUC) 5 0.89], and was robust for the detection of BC in younger women as well (age < 50, AUC 5 0.87). Our study reveals a strong association between decreased HYAL2 methylation in peripheral blood and BC, and provides a promising blood-based marker for the detection of early BC.Breast cancer (BC) is the most common cancer and the leading cause of cancer-related mortality among women, 1 with 1.7 million new cases and 522,000 deaths in 2012. 2 In the United States, one in eight women will develop BC in her lifetime. 3 Although therapeutic advances have improved the survival rate, most BC patients still suffer from greatly

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Section: Discussionsupporting

confidence: 70%

DNA methylation array analyses identified breast cancer‐associated HYAL2 methylation in peripheral blood

Yang

Pfütze

Zucknick

et al. 2014

Intl Journal of Cancer

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“…8. At the end of the chain, the inhibitory effect of Hyal2 on cell motility may be relevant to its purported in vivo tumor-suppressive activity (14). Cancer cells deprived of their pericellular coat through hyaluronidase or HA oligosaccharide treatments or through inhibition of hyaluronan export lose much of their capacity to metastasize (58 -61).…”

Section: Discussionmentioning

confidence: 99%

“…Intriguingly, sheep Hyal2 also functions as a cell-entry receptor for oncogenic ovine retroviruses (13), although this function is independent of any HA-degrading activity (8). Recently, expression of HYAL2 and HYAL1 genes has been shown to inhibit tumor growth in vivo without noticeable effect on growth in vitro, suggesting that these hyaluronidases control in some unknown manner tumor-host interactions (14). Hyal2 also anchors tumor growth factor-␤1 to the cell surface and mediates some of its pro-apoptotic effects (15).…”

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confidence: 99%

Two Novel Functions of Hyaluronidase-2 (Hyal2) Are Formation of the Glycocalyx and Control of CD44-ERM Interactions

Duterme

Mertens-Strijthagen

Tammi

et al. 2009

Journal of Biological Chemistry

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It has long been predicted that the members of the hyaluronidase enzyme family have important non-enzymatic functions. However, their nature remains a mystery. The metabolism of hyaluronan (HA), their major enzymatic substrate, is also enigmatic. To examine the function of Hyal2, a glycosylphosphatidylinositol-anchored hyaluronidase with intrinsically weak enzymatic activity, we have compared stably transfected rat fibroblastic BB16 cell lines with various levels of expression of Hyal2. These cell lines continue to express exclusively the standard form (CD44s) of the main HA receptor, CD44. Hyal2, CD44, and one of its main intracellular partners, ezrin-radixin-moesin (ERM), were found to co-immunoprecipitate. Functionally, Hyal2 overexpression was linked to loss of the glycocalyx, the HA-rich pericellular coat. This effect could be mimicked by exposure of BB16 cells either to Streptomyces hyaluronidase, to HA synthesis inhibitors, or to HA oligosaccharides. This led to shedding of CD44, separation of CD44 from ERM, reduction in baseline level of ERM activation, and markedly decreased cell motility (50% reduction in a wound healing assay). The effects of Hyal2 on the pericellular coat and on CD44-ERM interactions were inhibited by treatment with the Na ؉ /H ؉ exchanger-1 inhibitor ethyl-N-isopropylamiloride. We surmise that Hyal2, through direct interactions with CD44 and possibly some pericellular hyaluronidase activity requiring acidic foci, suppresses the formation or the stability of the glycocalyx, modulates ERMrelated cytoskeletal interactions, and diminishes cell motility. These effects may be relevant to the purported in vivo tumorsuppressive activity of Hyal2.

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“…The tumorigenicity of each cell line was tested by subcutaneous injection of 10 4 cells in three 4-week-old female SCID mice, as described previously (Wang et al, 2008). Tumor growth in animals was checked twice a week, if tumor formation was observed, tumors were measured using calipers.…”

Section: In Vivo Tumor Growth Analysismentioning

confidence: 99%

The RASSF8 candidate tumor suppressor inhibits cell growth and regulates the Wnt and NF-κB signaling pathways

et al. 2010

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The Ras-assocation domain family (RASSF) of tumor suppressor proteins until recently contained six proteins named RASSF1-6. Recently, four novel family members, RASSF7-10, have been identified by homology searches for RA-domain-containing proteins. These additional RASSF members are divergent and structurally distinct from RASSF1-6, containing an N-terminal RA domain and lacking the Sav/RASSF/Hpo (SARAH) domain. Here, we show that RASSF8 is ubiquitously expressed throughout the murine embryo and in normal human adult tissues. Functionally, RNAi-mediated knockdown of RASSF8 in non-small-cell lung cancer (NSCLC) cell lines, increased anchorage-independent growth in soft agar and enhanced tumor growth in severe combined immunodeficiency (SCID) mice. Furthermore, EdU staining of RASSF8-depleted cells showed growth suppression in a manner dependent on contact inhibition. We show that endogenous RASSF8 is not only found in the nucleus, but is also membrane associated at sites of cell-cell adhesion, co-localizing with the adherens junction (AJ) component b-catenin and binding to E-cadherin. Following RASSF8 depletion in two different lung cancer cell lines using alternative small interfering RNA (siRNA) sequences, we show that AJs are destabilized and E-cadherin is lost from the cell membrane. The AJ components b-catenin and p65 are also lost from sites of cell-cell contact and are relocalized to the nucleus with a concomitant increase in b-catenin-dependent and nuclear factorjB (NF-jB)-dependent signaling following RASSF8 depletion. RASSF8 may also be required to maintain actin -cytoskeletal organization since immunofluorescence analysis shows a striking disorganization of the actincytoskeleton following RASSF8 depletion. Accordingly, scratch wound healing studies show increased cellular migration in RASSF8-deficient cells. These results implicate RASSF8 as a tumor suppressor gene that is essential for maintaining AJs function in epithelial cells and have a role in epithelial cell migration.

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HYAL1 and HYAL2 Inhibit Tumour Growth In Vivo but Not In Vitro

Cited by 36 publications

References 25 publications

DNA methylation array analyses identified breast cancer‐associated HYAL2 methylation in peripheral blood

DNA methylation array analyses identified breast cancer‐associated HYAL2 methylation in peripheral blood

Two Novel Functions of Hyaluronidase-2 (Hyal2) Are Formation of the Glycocalyx and Control of CD44-ERM Interactions

The RASSF8 candidate tumor suppressor inhibits cell growth and regulates the Wnt and NF-κB signaling pathways

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