Heparanase confers a growth advantage to differentiating murine embryonic stem cells, and enhances oligodendrocyte formation

Xiong, Anqi; Kundu, Soumi; Forsberg, Maud; Xiong, Yi; Bergström, Tobias; Paavilainen, Tanja; Kjellén, Lena; Li, Jinping; Forsberg-Nilsson, Karin

doi:10.1016/j.matbio.2016.11.007

Cited by 16 publications

(8 citation statements)

References 54 publications

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“…Several studies have reported that ERK and Akt signaling were downstream of HPSE to facilitate cell proliferation. Differentiating Hpse-transgenic embryonic stem cells showed a higher growth rate, and overexpression of HPSE enhanced Erk and Akt phosphorylation in neural stem and progenitor cells [15]. The level of phosphorylated ERK and Akt was also found increased with HPSE transfection and decreased after HPSE knockdown in this study, which suggested that ERK and Akt were a part of HPSE signaling to mediate cell proliferation.…”

Section: Discussionsupporting

confidence: 64%

Expression of heparanase regulates cell proliferation, apoptosis, migration and invasion in vitro in papillary thyroid carcinoma cells with multiple signaling pathways involved

Yang¹,

Zhang²,

Chang³

et al. 2019

Preprint

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Background Heparanase (HPSE) is an endo-β-D-glucuronidase, which is found overexpressed in various human cancers. The purpose of our work was to investigate the possible role of HPSE and the involved signaling molecules in the development of papillary thyroid carcinoma. Methods In this study, the expression plasmid of HPSE and RNA interference with shRNA specific for HPSE were used to elucidate the effects of HPSE on proliferation, apoptosis, migration and invasion in papillary thyroid carcinoma cells of B-CPAP. The probable downstream signaling molecules of HPSE were also explored. Results The results showed that upregulation of HPSE significantly promoted cell proliferation, migration and invasion of B-CPAP cells, and interfered with cell apoptosis. On the contrary, knockdown of HPSE exhibited the opposite effects. Compared with the parental cells, HPSE silencing cells showed attenuated capabilities of proliferation, migration and invasion, yet the apoptotic rate of transfected cells was increased. The activations of various signaling molecules correlated with cell biological behavior were found to be regulated by HPSE upregulation or knockdown. Conclusions Our results suggested that HPSE probably contributed to the progression and metastasis of papillary thyroid carcinoma, which were associated with multiple signaling pathways. HPSE could be a potent molecular target for the therapeutic strategy of papillary thyroid carcinoma.

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Section: Discussionsupporting

confidence: 64%

Expression of heparanase regulates cell proliferation, apoptosis, migration and invasion in vitro in papillary thyroid carcinoma cells with multiple signaling pathways involved

Yang¹,

Zhang²,

Chang³

et al. 2019

Preprint

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“…The harvested cells were first incubated on a 10‐cm Petri dish for 60 minutes at 37°C to remove mixed astrocytes and microglia. After this, the purified OPCs (5 × 10 5 cells per well) were plated on a 6‐multiwell culture dish with poly‐L‐lysine (PLL) and cultured in proliferating medium (OPCM)‐containing platelet‐derived growth factor‐AA (PDGF‐AA) and neurotrophin‐3 (NT‐3) for 1 day or in differentiating medium (OPCDM) containing thyroid hormone for 4 days. After treating with OPCM for 1 day, the purity of OPCs was assessed by oligodendrocyte transcription factor 2 (Olig2), a widely used marker for OPCs, and 4′‐6‐diamidino‐2‐phenylindole (DAPI), a nuclear marker of all cells.…”

Section: Methodsmentioning

confidence: 99%

Complement C3a induces axonal hypomyelination in the periventricular white matter through activation of WNT/β‐catenin signal pathway in septic neonatal rats experimentally induced by lipopolysaccharide

Huang

Zhang

Lin³

et al. 2019

Brain Pathology

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Neuroinflammation is thought to play a pivotal role in the pathogenesis of periventricular white matter (PWM) damage (PWMD) induced by neonatal sepsis. Because the complement cascade is implicated in inflammatory response, this study was carried out to determine whether C3a is involved in PWMD, and, if so, whether it would induce axonal hypomyelination. Furthermore, we explored if C3a would act through its C3a receptor (C3aR) and thence inhibit maturation of oligodendrocyte precursor cells (OPCs) via the WNT/β-catenin signal pathway. Sprague Dawley (SD) rats aged 1 day were intraperitoneally injected with lipopolysaccharide (LPS) (1 mg/ kg). C3a was upregulated in activated microglia and astrocytes in the PWM up to 7 days after LPS injection. Concomitantly, enhanced C3aR expression was observed in NG2 + oligodendrocytes (OLs). Myelin proteins including CNPase, PLP, MBP and MAG were significantly reduced in the PWM of 28-day septic rats. The number of PLP + and MBP + cells was markedly decreased. By electron microscopy, myelin sheath thickness was thinner and the average g-ratios were higher. This was coupled with an increase in number of NG2 + cells and decreased number of CC1 + cells. Olig1, Olig2 and SOX10 protein expression was significantly reduced in the PWM after LPS injection. Very strikingly, C3aRa administration for the first 7 days could reverse the above-mentioned pathological alterations in the PWM of septic rats. When incubated with C3a, expression of MBP, CNPase, PLP, MAG, Olig1, Olig2, SOX10 and CC1 in primary cultured OPCs was significantly downregulated as opposed to increased NG2. Moreover, WNT/β-catenin signaling pathway was found to be implicated in inhibition of OPCs maturation and differentiation induced by C3a in vitro. As a corollary, it is speculated that C3a in the PWM of septic rats is closely associated with the disorder of OPCs differentiation and maturation through WNT/β-catenin signaling pathway, which would contribute ultimately to axonal hypomyelination. Huang et al C3a induces hypomyelination in the septic brain

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“…Loss-of function studies employing HPSE inhibitors demonstrated that the enzymatic activity of HPSE was key in proliferation and colony formation efficiency of mouse bone marrow-derived mesenchymal stem cells [347]. A growth advantage was imparted upon HPSE-overexpressing mouse embryonic stem cells, which formed larger teratomas when inoculated in vivo [348]. Furthermore, in a study to determine the therapeutic potential of hypoxic preconditioning mesenchymal stem cells (HPC-MSCs), mice injected with HPSE overexpressing HPC-MSCs showed enhanced blood flow recovery on account of the pro-angiogenic properties of HPSE [316].…”

Section: Cancer Cells and Cscsmentioning

confidence: 99%

Heparanase and the hallmarks of cancer

Jayatilleke

Hulett

2020

J Transl Med

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Heparanase is the only mammalian enzyme that cleaves heparan sulphate, an important component of the extracellular matrix. This leads to the remodelling of the extracellular matrix, whilst liberating growth factors and cytokines bound to heparan sulphate. This in turn promotes both physiological and pathological processes such as angiogenesis, immune cell migration, inflammation, wound healing and metastasis. Furthermore, heparanase exhibits non-enzymatic actions in cell signalling and in regulating gene expression. Cancer is underpinned by key characteristic features that promote malignant growth and disease progression, collectively termed the ‘hallmarks of cancer’. Essentially, all cancers examined to date have been reported to overexpress heparanase, leading to enhanced tumour growth and metastasis with concomitant poor patient survival. With its multiple roles within the tumour microenvironment, heparanase has been demonstrated to regulate each of these hallmark features, in turn highlighting the need for heparanase-targeted therapies. However, recent discoveries which demonstrated that heparanase can also regulate vital anti-tumour mechanisms have cast doubt on this approach. This review will explore the myriad ways by which heparanase functions as a key regulator of the hallmarks of cancer and will highlight its role as a major component within the tumour microenvironment. The dual role of heparanase within the tumour microenvironment, however, emphasises the need for further investigation into defining its precise mechanism of action in different cancer settings.

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Heparanase confers a growth advantage to differentiating murine embryonic stem cells, and enhances oligodendrocyte formation

Cited by 16 publications

References 54 publications

Expression of heparanase regulates cell proliferation, apoptosis, migration and invasion in vitro in papillary thyroid carcinoma cells with multiple signaling pathways involved

Expression of heparanase regulates cell proliferation, apoptosis, migration and invasion in vitro in papillary thyroid carcinoma cells with multiple signaling pathways involved

Complement C3a induces axonal hypomyelination in the periventricular white matter through activation of WNT/β‐catenin signal pathway in septic neonatal rats experimentally induced by lipopolysaccharide

Heparanase and the hallmarks of cancer

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