Heparanase 2 (Hpa2) attenuates the growth of human sarcoma

Knani, Ibrahim; Yanku, Yifat; Gross-Cohen, Miriam; Ilan, Neta; Vlodavsky, Israël

doi:10.1016/j.matbio.2022.09.003

Cited by 7 publications

(18 citation statements)

References 81 publications

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“…The expression level of the HPSE2 gene is low in most malignant cell lines [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ]. Likewise, RMPI-8226 cells expressed a very low, but detectable level of HPSE2 and there was no effect to electrical pulse and transfection with an empty plasmid.…”

Section: Resultsmentioning

confidence: 99%

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Effect of HPSE and HPSE2 SNPs on the Risk of Developing Primary Paraskeletal Multiple Myeloma

Ostrovsky

Beider

Magen

et al. 2023

Cells

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Multiple myeloma (MM) is a plasma cell malignancy that is accompanied by hypercalcemia, renal failure, anemia, and lytic bone lesions. Heparanase (HPSE) plays an important role in supporting and promoting myeloma progression, maintenance of plasma cell stemness, and resistance to therapy. Previous studies identified functional single nucleotide polymorphisms (SNPs) located in the HPSE gene. In the present study, 5 functional HPSE SNPs and 11 novel HPSE2 SNPs were examined. A very significant association between two enhancer (rs4693608 and rs4693084), and two insulator (rs4364254 and rs4426765) HPSE SNPs and primary paraskeletal disease (PS) was observed. SNP rs657442, located in intron 9 of the HPSE2 gene, revealed a significant protective association with primary paraskeletal disease and lytic bone lesions. The present study demonstrates a promoting (HPSE gene) and protective (HPSE2 gene) role of gene regulatory elements in the development of paraskeletal disease and bone morbidity. The effect of signal discrepancy between myeloma cells and normal cells of the tumor microenvironment is proposed as a mechanism for the involvement of heparanase in primary PS. We suggest that an increase in heparanase-2 expression can lead to effective suppression of heparanase activity in multiple myeloma accompanied by extramedullary and osteolytic bone disease.

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Section: Resultsmentioning

confidence: 99%

“…The role of Hpa2 in the development of cancer is not well understood. However, heparanase-2 inhibits heparanase enzymatic activity [ 23 ] and appears to function as a tumor suppressor [ 19 , 24 , 25 , 26 , 27 , 28 , 29 ]. The role of heparanase-2 in multiple myeloma has not been elucidated.…”

Section: Introductionmentioning

confidence: 99%

Effect of HPSE and HPSE2 SNPs on the Risk of Developing Primary Paraskeletal Multiple Myeloma

Ostrovsky

Beider

Magen

et al. 2023

Cells

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“…54 Clinically, it was found that localization of Hpa2 in the cell nucleus was associated with low-stage tumors. 54…”

Section: Sarcomamentioning

confidence: 99%

Impact of heparanase‐2 (Hpa2) on cancer and inflammation: Advances and paradigms

Vlodavsky,

Hilwi,

Kayal

et al. 2024

The FASEB Journal

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HPSE2, the gene‐encoding heparanase 2 (Hpa2), is mutated in urofacial syndrome (UFS), a rare autosomal recessive congenital disease attributed to peripheral neuropathy. Hpa2 lacks intrinsic heparan sulfate (HS)‐degrading activity, the hallmark of heparanase (Hpa1), yet it exhibits a high affinity toward HS, thereby inhibiting Hpa1 enzymatic activity. Hpa2 regulates selected genes that promote normal differentiation, tissue homeostasis, and endoplasmic reticulum (ER) stress, resulting in antitumor, antiangiogenic, and anti‐inflammatory effects. Importantly, stress conditions induce the expression of Hpa2, thus establishing a feedback loop, where Hpa2 enhances ER stress which, in turn, induces Hpa2 expression. In most cases, cancer patients who retain high levels of Hpa2 survive longer than patients bearing Hpa2‐low tumors. Experimentally, overexpression of Hpa2 attenuates the growth of tumor xenografts, whereas Hpa2 gene silencing results in aggressive tumors. Studies applying conditional Hpa2 knockout (cHpa2‐KO) mice revealed an essential involvement of Hpa2 contributed by the host in protecting against cancer and inflammation. This was best reflected by the distorted morphology of the Hpa2‐null pancreas, including massive infiltration of immune cells, acinar to adipocyte trans‐differentiation, and acinar to ductal metaplasia. Moreover, orthotopic inoculation of pancreatic ductal adenocarcinoma (PDAC) cells into the pancreas of Hpa2‐null vs. wild‐type mice yielded tumors that were by far more aggressive. Likewise, intravenous inoculation of cancer cells into cHpa2‐KO mice resulted in a dramatically increased lung colonization reflecting the involvement of Hpa2 in restricting the formation of a premetastatic niche. Elucidating Hpa2 structure–activity‐relationships is expected to support the development of Hpa2‐based therapies against cancer and inflammation.

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“…Furthermore, patients that retain high levels of Hpa2 survived longer than patients bearing Hpa2‐low tumors 105,107–109,113 . Experimentally, overexpression of Hpa2 attenuated the growth of tumor xenografts, whereas Hpa2 gene silencing resulted in bigger tumors 106–109,111,114,115 . This is best demonstrated by gene editing of Hpa2 in pharyngeal FaDu cells applying the CRISPR technology.…”

Section: Hpa2—a New Player In the Heparanase Fieldmentioning

confidence: 99%

“…105 2015-Overexpression of HPSE2 attenuates tumor growth, whereas HPSE2 gene silencing promotes tumorigenesis. [106][107][108][109][110][111][112][113][114][115] 2016-Hpa2 protects against sepsis, endotoxemia, renal inflammation, and Covid-19. [116][117][118] 2018-Hpa2 functions as a natural inhibitor of Hpa1, emphasizing the significance of a proper Hpa1/Hpa2 ratio in tissue hemostasis.…”

Section: Nonenzymatic Activitiesmentioning

confidence: 99%

Heparanase—A single protein with multiple enzymatic and nonenzymatic functions

Vlodavsky,

Kayal,

Hilwi

et al. 2023

Proteoglycan Research

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Heparanase (Hpa1) is expressed by tumor cells and cells of the tumor microenvironment and functions extracellularly to remodel the extracellular matrix (ECM) and regulate the bioavailability of ECM‐bound factors, augmenting, among other effects, gene transcription, autophagy, exosome formation, and heparan sulfate (HS) turnover. Much of the impact of heparanase on tumor progression is related to its function in mediating tumor‐host crosstalk, priming the tumor microenvironment to better support tumor growth, metastasis, and chemoresistance. The enzyme appears to fulfill some normal functions associated, for example, with vesicular traffic, lysosomal‐based secretion, autophagy, HS turnover, and gene transcription. It activates cells of the innate immune system, promotes the formation of exosomes and autophagosomes, and stimulates signal transduction pathways via enzymatic and nonenzymatic activities. These effects dynamically impact multiple regulatory pathways that together drive tumor growth, dissemination, and drug resistance as well as inflammatory responses. The emerging premise is that heparanase expressed by tumor cells, immune cells, endothelial cells, and other cells of the tumor microenvironment is a key regulator of the aggressive phenotype of cancer, an important contributor to the poor outcome of cancer patients and a valid target for therapy. So far, however, antiheparanase‐based therapy has not been implemented in the clinic. Unlike heparanase, heparanase‐2 (Hpa2), a close homolog of heparanase (Hpa1), does not undergo proteolytic processing and hence lacks intrinsic HS‐degrading activity, the hallmark of heparanase. Hpa2 retains the capacity to bind heparin/HS and exhibits an even higher affinity towards HS than heparanase, thus competing for HS binding and inhibiting heparanase enzymatic activity. It appears that Hpa2 functions as a natural inhibitor of Hpa1 regulates the expression of selected genes that maintain tissue hemostasis and normal function, and plays a protective role against cancer and inflammation, together emphasizing the significance of maintaining a proper balance between Hpa1 and Hpa2.

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Heparanase 2 (Hpa2) attenuates the growth of human sarcoma

Cited by 7 publications

References 81 publications

Effect of HPSE and HPSE2 SNPs on the Risk of Developing Primary Paraskeletal Multiple Myeloma

Effect of HPSE and HPSE2 SNPs on the Risk of Developing Primary Paraskeletal Multiple Myeloma

Impact of heparanase‐2 (Hpa2) on cancer and inflammation: Advances and paradigms

Heparanase—A single protein with multiple enzymatic and nonenzymatic functions

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