A Pro-Tumorigenic Effect of Heparanase 2 (Hpa2) in Thyroid Carcinoma Involves Its Localization to the Nuclear Membrane

Margulis, Itai; Naroditsky, Inna; Gross-Cohen, Miriam; Ilan, Neta; Vlodavsky, Israël; Doweck, Ilana

doi:10.3389/fonc.2021.645524

Cited by 4 publications

(3 citation statements)

References 32 publications

(64 reference statements)

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“…Intriguingly, HPSE‐2 aggregates on the nucleus membrane of cells. Its nuclear membrane localization occurs primarily in metastatic papillary thyroid carcinoma and was linked to an increased number of positive lymph nodes collected at the time of surgery (Margulis et al, 2021). However, how HPSE translocations to the nucleus is unclear, there are different mechanisms have been proposed: (1) nuclear localization of HPSE is associated with cell differentiation (Kobayashi et al, 2006).…”

Section: Overview Of Hpsementioning

confidence: 99%

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Potential roles of heparanase in cancer therapy: Current trends and future direction

Yang

Yuan

Zhou

et al. 2023

Journal Cellular Physiology

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Heparanase (HPSE; heparanase‐1) is an endo‐β‐glucuronidase capable of degrading the carbohydrate moiety of heparan sulfate proteoglycans, thus modulating and facilitating the remodeling of the extracellular matrix and basement membrane. HPSE activity is strongly associated with major human pathological complications, including but not limited to tumor progress and angiogenesis. Several lines of literature have shown that overexpression of HPSE leads to enhanced tumor growth and metastatic transmission, as well as poor prognosis. Gene silencing of HPSE or treatment of tumor with compounds that block HPSE activity are shown to remarkably attenuate tumor progression. Therefore, targeting HPSE is considered as a potential therapeutical strategy for the treatment of cancer. Intriguingly, recent findings disclose that heparanase‐2 (HPSE‐2), a close homolog of HPSE but lacking enzymatic activity, can also regulate antitumor mechanisms. Given the pleiotropic roles of HPSE, further investigation is in demand to determine the precise mechanism of regulating action of HPSE in different cancer settings. In this review, we first summarize the current understanding of HPSE, such as its structure, subcellular localization, and tissue distribution. Furthermore, we systematically review the pro‐ and antitumorigenic roles and mechanisms of HPSE in cancer progress. In addition, we delineate HPSE inhibitors that have entered clinical trials and their therapeutic potential.

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Section: Overview Of Hpsementioning

confidence: 99%

“…Intriguingly, HPSE-2 aggregates on the nucleus membrane of cells. Its nuclear membrane localization occurs primarily in metastatic papillary thyroid carcinoma and was linked to an increased number of positive lymph nodes collected at the time of surgery (Margulis et al, 2021).…”

Section: Shteingauz Et Al Consistently Identified the Presence Of Hpsementioning

confidence: 99%

Potential roles of heparanase in cancer therapy: Current trends and future direction

Yang

Yuan

Zhou

et al. 2023

Journal Cellular Physiology

View full text Add to dashboard Cite

show abstract

“…HPSE2 codes for heparanase-2 ( McKenzie et al, 2000 ), also known as Hpa2, which inhibits endoglycosidase activity of the classic heparanase ( Levy-Adam et al, 2010 ). Although subject to secretion ( Levy-Adam et al, 2010 ; Beaman et al, 2022 ), heparanase-2 has also been detected in the perinuclear membrane ( Margulis et al, 2021 ), suggesting yet-to-be defined functions there. The biology of heparanase-2 has been most studied in relation to oncology.…”

Section: Introductionmentioning

confidence: 99%

Human HPSE2 gene transfer ameliorates bladder pathophysiology in a mutant mouse model of urofacial syndrome

Lopes,

Grenier,

Jarvis

et al. 2024

eLife

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Rare early onset lower urinary tract disorders include defects of functional maturation of the bladder. Current treatments do not target the primary pathobiology of these diseases. Some have a monogenic basis, such as urofacial, or Ochoa, syndrome (UFS). Here, the bladder does not empty fully because of incomplete relaxation of its outflow tract, and subsequent urosepsis can cause kidney failure. UFS is associated with biallelic variants of HPSE2 , encoding heparanase-2. This protein is detected in pelvic ganglia, autonomic relay stations that innervate the bladder and control voiding. Bladder outflow tracts of Hpse2 mutant mice display impaired neurogenic relaxation. We hypothesized that HPSE2 gene transfer soon after birth would ameliorate this defect and explored an adeno-associated viral ( AAV ) vector-based approach. AAV9/HPSE2, carrying human HPSE2 driven by CAG , was administered intravenously into neonatal mice. In the third postnatal week, transgene transduction and expression were sought, and ex vivo myography was undertaken to measure bladder function. In mice administered AAV9/HPSE2 , the transduced genome was detected in pelvic ganglia, where human HPSE2 was also expressed. Moreover, heparanase-2 became detectable in pelvic ganglia of treated mutant mice. On autopsy, untreated mutant mice had distended urinary bladders, consistent with bladder outflow obstruction, but AAV9/HPSE2 - administered mice did not, thus resembling wild-type mice. AAV9/HPSE2 significantly ameliorated impaired neurogenic relaxation of Hpse2 mutant bladder outflow tracts. Impaired neurogenic contractility of mutant detrusor smooth muscle was also significantly ameliorated by AAV9/HPSE2 . These results constitute first steps towards curing UFS, a clinically devastating genetic disease featuring a bladder autonomic neuropathy.

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HumanHPSE2gene transfer ameliorates bladder pathophysiology in a mutant mouse model of urofacial syndrome

Lopes,

Grenier,

Jarvis

et al. 2023

Preprint

View full text Add to dashboard Cite

Rare early onset lower urinary tract disorders include defects of functional maturation of the bladder. Current treatments do not target the primary pathobiology of these diseases. Some have a monogenic basis, such as urofacial, or Ochoa, syndrome (UFS). Here, the bladder does not empty fully because of incomplete relaxation of its outflow tract, and subsequent urosepsis can cause kidney failure. UFS is associated with biallelic variants of HPSE2, encoding heparanase-2. This protein is detected in pelvic ganglia, autonomic relay stations that innervate the bladder and control voiding. Bladder outflow tracts of Hpse2 mutant mice display impaired neurogenic relaxation. We hypothesized that HPSE2 gene transfer soon after birth would ameliorate this defect and explored an adeno-associated viral (AAV) vector-based approach. AAV9/HPSE2, carrying human HPSE2 driven by CAG, was administered intravenously into neonatal mice. In the third postnatal week, transgene transduction and expression were sought, and ex vivo myography was undertaken to measure bladder function. In mice administered AAV9/HPSE2, the transduced genome was detected in pelvic ganglia, where human HPSE2 was also expressed. Moreover, heparanase-2 became detectable in pelvic ganglia of treated mutant mice. On autopsy, untreated mutant mice had distended urinary bladders, consistent with bladder outflow obstruction, but AAV9/HPSE2-administered mice did not, thus resembling wild-type mice. AAV9/HPSE2 significantly ameliorated impaired neurogenic relaxation of Hpse2 mutant bladder outflow tracts. Impaired neurogenic contractility of mutant detrusor smooth muscle was also significantly ameliorated by AAV9/HPSE2. These results constitute first steps towards curing UFS, a clinically devastating genetic disease featuring a bladder autonomic neuropathy.

show abstract

A Pro-Tumorigenic Effect of Heparanase 2 (Hpa2) in Thyroid Carcinoma Involves Its Localization to the Nuclear Membrane

Cited by 4 publications

References 32 publications

Potential roles of heparanase in cancer therapy: Current trends and future direction

Potential roles of heparanase in cancer therapy: Current trends and future direction

Human HPSE2 gene transfer ameliorates bladder pathophysiology in a mutant mouse model of urofacial syndrome

HumanHPSE2gene transfer ameliorates bladder pathophysiology in a mutant mouse model of urofacial syndrome

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