Soboh Soaad, Vorontsova Avital, Farhoud Malik, Barash Uri, Naroditsky Inna, Gross-Cohen Miriam, Weissmann Marina, Nishioka Yasuhiko, Woolf Adrian S, Roberts Neil A, Shaked Yuval, Ilan Neta, Vlodavsky Israel
Technion Integrated Cancer Center, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
Cell Death Dis. 2024 Dec 18;15(12):894. doi: 10.1038/s41419-024-07262-9.
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.
在过去二十年里，人们对乙酰肝素酶2（Hpa2）的关注较少，这可能是因为它缺乏乙酰肝素酶典型的硫酸乙酰肝素（HS）降解活性。然而，新出现的结果表明，Hpa2在人类疾病中发挥作用，包括在癌症进展中它作为一种肿瘤抑制因子发挥功能。在此，我们研究了Hpa2在宫颈癌中的作用。我们报告称，Hpa2的高水平与宫颈癌患者的生存期延长相关。Hpa2的强染色强度也与低肿瘤分级相关。在SiHa宫颈癌细胞中过表达Hpa2导致肿瘤异种移植瘤比对照肿瘤小两倍。有趣的是，在被诊断患有面泌尿综合征（UFS）的患者中鉴定出的Pro140Arg和Asn543Ile Hpa2错义突变的SiHa细胞产生了甚至更小的肿瘤异种移植瘤。利用Ras招募系统，我们鉴定出含溴结构域蛋白7（BRD7）与Hpa2相互作用，并发现BRD7和Hpa2突变体在由Pro140Arg和Asn543Ile Hpa2突变体形成的肿瘤中都转移到细胞核。利用我们新开发的条件性Hpa2基因敲除小鼠，我们进一步表明Hpa2在巨噬细胞极化中起关键作用；在没有Hpa2的情况下，巨噬细胞向促肿瘤的M2表型转变。值得注意的是，将SiHa宫颈癌细胞与Hpa2基因敲除巨噬细胞一起植入促进了肿瘤生长。这些结果支持并进一步扩展了Hpa2作为肿瘤抑制因子发挥作用并与另一种肿瘤抑制因子BRD7协同作用的观点。
