Home > Institute Collections > W500 > Tumor- and host-derived heparanase-2 (Hpa2) attenuates tumorigenicity: role of Hpa2 in macrophage polarization and BRD7 nuclear localization. > print

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005     20251118115956.0
024 7 _ |a 10.1038/s41419-024-07262-9
|2 doi
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037 _ _ |a DKFZ-2025-02479
041 _ _ |a English
082 _ _ |a 570
100 1 _ |a Soboh, Soaad
|b 0
245 _ _ |a Tumor- and host-derived heparanase-2 (Hpa2) attenuates tumorigenicity: role of Hpa2 in macrophage polarization and BRD7 nuclear localization.
260 _ _ |a London [u.a.]
|c 2024
|b Nature Publishing Group
336 7 _ |a article
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520 _ _ |a Little attention was given to heparanase 2 (Hpa2) over the last two decades, possibly because it lacks a heparan sulfate (HS)-degrading activity typical of heparanase. Emerging results suggest, nonetheless, that Hpa2 plays a role in human pathologies, including cancer progression where it functions as a tumor suppressor. Here, we examined the role of Hpa2 in cervical carcinoma. We report that high levels of Hpa2 correlate with prolonged survival of cervical carcinoma patients. Strong staining intensity of Hpa2 also correlates with low tumor grade. Overexpression of Hpa2 in SiHa cervical carcinoma cells resulted in tumor xenografts that were two-fold smaller than control tumors. Interestingly, even smaller tumor xenografts were developed by SiHa cells overexpressing the Pro140Arg and Asn543Ile Hpa2 missense mutations that were identified in patients diagnosed with urofacial syndrome (UFS). Utilizing the Ras recruitment system, we identified bromodomain-containing protein 7 (BRD7) to interact with Hpa2 and found that both BRD7 and the Hpa2 mutants are translocated to the cell nucleus in tumors developed by the Pro140Arg and Asn543Ile Hpa2 mutants. Utilizing our newly developed conditional Hpa2-KO mice, we further show that Hpa2 plays a critical role in macrophage polarization; in the absence of Hpa2, macrophages are shifted towards pro-tumorigenic, M2 phenotype. Notably, implanting SiHa cervical carcinoma cells together with Hpa2-KO macrophages promoted tumor growth. These results support, and further expand, the notion that Hpa2 functions as a tumor suppressor, co-operating with another tumor suppressor, BRD7.
588 _ _ |a Dataset connected to CrossRef, PubMed, , Journals: inrepo02.dkfz.de
650 _ 7 |a Glucuronidase
|0 EC 3.2.1.31
|2 NLM Chemicals
650 _ 7 |a heparanase
|0 EC 3.2.1.-
|2 NLM Chemicals
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a Female
|2 MeSH
650 _ 2 |a Glucuronidase: metabolism
|2 MeSH
650 _ 2 |a Glucuronidase: genetics
|2 MeSH
650 _ 2 |a Uterine Cervical Neoplasms: pathology
|2 MeSH
650 _ 2 |a Uterine Cervical Neoplasms: genetics
|2 MeSH
650 _ 2 |a Uterine Cervical Neoplasms: metabolism
|2 MeSH
650 _ 2 |a Macrophages: metabolism
|2 MeSH
650 _ 2 |a Cell Nucleus: metabolism
|2 MeSH
650 _ 2 |a Mice
|2 MeSH
650 _ 2 |a Cell Line, Tumor
|2 MeSH
650 _ 2 |a Carcinogenesis: pathology
|2 MeSH
650 _ 2 |a Carcinogenesis: metabolism
|2 MeSH
650 _ 2 |a Carcinogenesis: genetics
|2 MeSH
700 1 _ |a Vorontsova, Avital
|b 1
700 1 _ |a Farhoud, Malik
|b 2
700 1 _ |a Barash, Uri
|b 3
700 1 _ |a Naroditsky, Inna
|b 4
700 1 _ |a Gross-Cohen, Miriam
|b 5
700 1 _ |a Weissmann, Marina
|b 6
700 1 _ |a Nishioka, Yasuhiko
|b 7
700 1 _ |a Woolf, Adrian S
|b 8
700 1 _ |a Roberts, Neil A
|b 9
700 1 _ |a Shaked, Yuval
|b 10
700 1 _ |a Ilan, Neta
|b 11
700 1 _ |a Vlodavsky, Israel
|b 12
773 _ _ |a 10.1038/s41419-024-07262-9
|g Vol. 15, no. 12, p. 894
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