Involvement of hyaluronidases in colorectal cancer

Bouga, Helen; Tsouros, Isidoros; Bounias, Dimitrios; Kyriakopoulou, Dora; Stavropoulos, M.; Papageorgakopoulou, N.; Theocharis, Dimitrios A.; Vynios, Demitrios H.

doi:10.1186/1471-2407-10-499

Cited by 59 publications

(50 citation statements)

References 29 publications

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“…In the current study, we found that the expression levels of HYAL1, HYAL2, and HYAL3 were all significantly elevated in cancer tissues when compared with matched noncancerous tissues from CRC patients. Our results were consistent with previous study showing that HAase activity was higher in colorectal cancerous tissues than in macroscopically normal tissues . After analysis of the association between HAase levels and CRC progression, we found that HYAL1 and HYAL2 were negatively correlated with LN metastasis and TNM stage.…”

Section: Discussionsupporting

confidence: 92%

The suppressive role of HYAL1 and HYAL2 in the metastasis of colorectal cancer

Jin

Zhang

Liu

et al. 2019

J of Gastro and Hepatol

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Background Hyaluronidases (HAases), enzymes that degrade hyaluronan, have been widely investigated in cancer biology. However, whether HAases serve as tumor promoters or suppressors has been controversial in different cancers, and the exact role of HAases in colorectal cancer (CRC) has not been elucidated. Methods The expression levels of HYAL1, HYAL2, and HYAL3 in cancer and corresponding normal tissues from CRC patients were examined via immunohistochemistry. Then the correlation between HAases levels and pathological characteristics of CRC patients was analyzed. To verify the clinical data, HYAL1 and HYAL2 were downregulated or overexpressed in colon cancer cells LOVO and HCT116 to observe their influences on cell invasion and migration. For the mechanism study, we investigated the effects of HYAL1 and HYAL2 on the expression of matrix metalloproteases (MMPs)/tissue inhibitor of metalloproteases (TIMPs) and distribution of F‐actin. Results All the three HAases were abnormally elevated in cancer tissues. Interestingly, HYAL1 and HYAL2, but not HYAL3, were negatively correlated with lymphatic metastasis and TNM stage. When HYAL1 and HYAL2 were knocked down, the invasion and migration abilities of colon cancer cells were accelerated, whereas overexpression of HYAL1 and HYAL2 had the opposite effects. In addition, colon cancer cells with HYAL1 and HYAL2 downregulation showed increased levels of MMP2 and MMP9, decreased levels of TIMP1 and TIMP2, and more intense F‐actin stress fibers. Conclusions Our study suggests that HYAL1 and HYAL2 suppress CRC metastasis through regulating MMPs/TIMPs balance and rearranging F‐actin distribution, further inhibiting invasion and migration of cancer cells.

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Section: Discussionsupporting

confidence: 92%

The suppressive role of HYAL1 and HYAL2 in the metastasis of colorectal cancer

Jin

Zhang

Liu

et al. 2019

J of Gastro and Hepatol

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“…Other HYAL family molecules, PH-20/SPAM1 and HYAL5, can function at neutral pH (11,12). Although there are reports that PH-20/SPAM1 is expressed in some cancers (13)(14)(15), their expression in normal tissues is largely restricted in the testis, and it is unlikely that PH-20/SPAM1 and HYAL5 act as principal extracellular hyaluronidase in a broad range of normal somatic tissues.…”

Section: Hyaluronic Acid (Ha)mentioning

confidence: 99%

A mammalian homolog of the zebrafish transmembrane protein 2 (TMEM2) is the long-sought-after cell-surface hyaluronidase

Yamamoto

Tobisawa

Inubushi

et al. 2017

Journal of Biological Chemistry

140

162

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Edited by Amanda J. Fosang Hyaluronan (HA) is an extremely large polysaccharide (glycosaminoglycan) involved in many cellular functions. HA catabolism is thought to involve the initial cleavage of extracellular high-molecular-weight (HMW) HA into intermediate-size HA by an extracellular or cell-surface hyaluronidase, internalization of intermediate-size HA, and complete degradation into monosaccharides in lysosomes. Despite considerable research, the identity of the hyaluronidase responsible for the initial HA cleavage in the extracellular space remains elusive. HYAL1 and HYAL2 have properties more consistent with lysosomal hyaluronidases, whereas CEMIP/KIAA1199, a recently identified HA-binding molecule that has HA-degrading activity, requires the participation of the clathrincoated pit pathway of live cells for HA degradation. Here we show that transmembrane protein 2 (TMEM2), a mammalian homolog of a protein playing a role in zebrafish endocardial cushion development, is a cell-surface hyaluronidase. Live immunostaining and surface biotinylation assays confirmed that mouse TMEM2 is expressed on the cell surface in a type II transmembrane topology. TMEM2 degraded HMW-HA into ϳ5-kDa fragments but did not cleave chondroitin sulfate or dermatan sulfate, indicating its specificity to HA. The hyaluronidase activity of TMEM2 was Ca 2؉ -dependent; the enzyme's pH optimum is around 6 -7, and unlike CEMIP/ KIAA1199, TMEM2 does not require the participation of live cells for its hyaluronidase activity. Moreover, TMEM2-expressing cells could eliminate HA immobilized on a glass surface in a contact-dependent manner. Together, these data suggest that TMEM2 is the long-sought-after hyaluronidase that cleaves extracellular HMW-HA into intermediate-size fragments before internalization and degradation in the lysosome.Hyaluronic acid (HA) 2 is a glycosaminoglycan composed of repeating disaccharide units of glucuronic acid and N-acetylglucosamine. It is a linear polymer of extremely large molecular mass, often exceeding 10 6 Da (1). The sheer size of HA suggests that cells should have very efficient mechanisms for its metabolism. In fact, one-third of the total body HA, which is estimated to be 15 g in a human with a 70-kg body weight, is thought to be turned over daily (2). In skin, the metabolic halflife of HA is 1 to 1.5 days (3). It is believed that high-molecularweight (HMW) HA (10 6 -10 7 Da) is first degraded extracellularly into intermediate-size fragments of 10 -100 kDa. These are then internalized and degraded to monosaccharides by the combined actions of lysosomal hyaluronidase and exoglucosidases (4). Considering the accumulating evidence for the role of HA degradation in tumor invasion and metastasis (5), identifying the molecule(s) that degrade HA on the cell surface is an important biological issue.The HYAL family molecules have been implicated as the major players in HA catabolism. HYAL1 and HYAL2 are expressed widely and postulated to be the key hyaluronidases involved in HA catabolism in somatic tissues. How...

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“…This phenomenon could be attributable to localization of the free Hyal1 at the primary tumor site rather than in the circulation. A separate study showed that multiple isoforms of Hyal (Hyal1, 2, 3, and PH-20) had increased activity in colorectal cancer patient samples and the expression of Hyal1 and Hyal2 was especially associated with more aggressive stages of cancer (Bouga et al, 2010). …”

Section: : Hyaluronidase Expression In Cancermentioning

confidence: 99%

Emerging Roles for Hyaluronidase in Cancer Metastasis and Therapy

McAtee

Barycki

Simpson³

2014

Advances in Cancer Research

167

140

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Hyaluronidases are a family of five human enzymes that have been differentially implicated in the progression of many solid tumor types, both clinically and in functional studies. Advances in the past five years have clarified many apparent contradictions, (1) by demonstrating that specific hyaluronidases have alternative substrates to hyaluronan (HA) or do not exhibit any enzymatic activity, (2) that high molecular weight HA polymers elicit signaling effects that are opposite those of the hyaluronidase-digested HA oligomers, and (3) that it is actually the combined overexpression of HA synthesizing enzymes with hyaluronidases that confers tumorigenic potential. This review examines the literature supporting these conclusions and discusses novel mechanisms by which hyaluronidases impact invasive tumor cell processes. In addition, a detailed structural and functional comparison of the hyaluronidases is presented with insights into substrate selectivity and potential for therapeutic targeting. Finally, technological advances in targeting hyaluronidase for tumor imaging and cancer therapy are summarized.

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Involvement of hyaluronidases in colorectal cancer

Cited by 59 publications

References 29 publications

The suppressive role of HYAL1 and HYAL2 in the metastasis of colorectal cancer

The suppressive role of HYAL1 and HYAL2 in the metastasis of colorectal cancer

A mammalian homolog of the zebrafish transmembrane protein 2 (TMEM2) is the long-sought-after cell-surface hyaluronidase

Emerging Roles for Hyaluronidase in Cancer Metastasis and Therapy

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