Heparanase 2 (Hpa2) attenuates tumor growth by inducing Sox2 expression
| Autor: | Neta Ilan, Angel Cid-Arregui, Yifat Yanku, Miriam Gross-Cohen, Ilanit Boyango, Israel Vlodavsky, Ofra Kessler, Uri Barash, Gera Neufeld |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
SOXB1 Transcription Factors Cancer Biology medicine.disease medicine.disease_cause 03 medical and health sciences Cytokeratin 030104 developmental biology 0302 clinical medicine SOX2 Downregulation and upregulation Head and Neck Neoplasms 030220 oncology & carcinogenesis Cancer research medicine Gene silencing Humans Heparanase Heparitin Sulfate Carcinogenesis Molecular Biology Epithelial cell differentiation Glucuronidase |
| Zdroj: | Matrix biology : journal of the International Society for Matrix Biology. 99 |
| ISSN: | 1569-1802 |
| Popis: | The pro-tumorigenic properties of heparanase are well documented, and heparanase inhibitors are being evaluated clinically as anti-cancer therapeutics. In contrast, the role of heparanase 2 (Hpa2), a close homolog of heparanase, in cancer is largely unknown. Previously, we have reported that in head and neck cancer, high levels of Hpa2 are associated with prolonged patient survival and decreased tumor cell dissemination to regional lymph nodes, suggesting that Hpa2 functions to restrain tumorigenesis. Also, patients with high levels of Hpa2 were diagnosed as low grade and exhibited increased expression of cytokeratins, an indication that Hpa2 promotes or maintains epithelial cell differentiation and identity. To reveal the molecular mechanism underlying the tumor suppressor properties of Hpa2, and its ability to induce the expression of cytokeratin, we employed overexpression as well as gene editing (Crispr) approaches, combined with gene array and RNAseq methodologies. At the top of the list of many genes found to be affected by Hpa2 was Sox2. Here we provide evidence that silencing of Sox2 resulted in bigger tumors endowed with reduced cytokeratin levels, whereas smaller tumors were developed by cells overexpressing Sox2, suggesting that in head and neck carcinoma, Sox2 functions to inhibit tumor growth. Notably, Hpa2-null cells engineered by Crispr/Cas 9, produced bigger tumors vs control cells, and rescue of Hpa2 attenuated tumor growth. These results strongly imply that Hpa2 functions as a tumor suppressor in head and neck cancer, involving Sox2 upregulation mediated, in part, by the high-affinity interaction of Hpa2 with heparan sulfate. |
| Databáze: | OpenAIRE |
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