Unlike the intense research effort devoted to exploring the significance of heparanase in cancer, very little attention was given to Hpa2, a close homolog of heparanase. Here, we explored the role of Hpa2 in breast cancer. Unexpectedly, we found that patients endowed with high levels of Hpa2 exhibited a higher incidence of tumor metastasis and survived less than patients with low levels of Hpa2. Immunohistochemical examination revealed that in normal breast tissue, Hpa2 localizes primarily in the cell nucleus. In striking contrast, in breast carcinoma, Hpa2 expression is not only decreased but also loses its nuclear localization and appears diffuse in the cell cytoplasm. Importantly, breast cancer patients in which nuclear localization of Hpa2 is retained exhibited reduced lymph-node metastasis, suggesting that nuclear localization of Hpa2 plays a protective role in breast cancer progression. To examine this possibility, we engineered a gene construct that directs Hpa2 to the cell nucleus (Hpa2-Nuc). Notably, overexpression of Hpa2 in breast carcinoma cells resulted in bigger tumors, whereas targeting Hpa2 to the cell nucleus attenuated tumor growth and tumor metastasis. RNAseq analysis was performed to reveal differentially expressed genes (DEG) in Hpa2-Nuc tumors vs. control. The analysis revealed, among others, decreased expression of genes associated with the hallmark of Kras, beta-catenin, and TNF-alpha (via NFkB) signaling. Our results imply that nuclear localization of Hpa2 prominently regulates gene transcription, resulting in attenuation of breast tumorigenesis. Thus, nuclear Hpa2 may be used as a predictive parameter in personalized medicine for breast cancer patients.

Maram Hilwi, Katherina Shulman, Inna Naroditsky, Sari Feld, Miriam Gross-Cohen, Ilanit Boyango, Soaad Soboh, Olga Vornicova, Malik Farhoud, Preeti Singh, Gil Bar-Sela, Hadassah Goldberg, Martin Götte, Andrew D. Sharrocks, Yaoyong Li, Ralph D. Sanderson, Neta Ilan & Israel Vlodavsky (2024). Cell Death & Disease volume 15, Article number: 232. DOI: 10.1038/s41419-024-06596-8

A free version of this article can be found here. 

The following publications received funding by EU Marie Skłodowska-Curie Actions (MSCA) project No.101086322 (HEPINIB).

Ovarian cancer (OC) is the eighth cancer both in prevalence and mortality in women and represents the deadliest female reproductive cancer. Due to generally vague symptoms, OC is frequently diagnosed only at a late and advanced stage, resulting in high mortality. The tumor extracellular matrix and cellular matrix receptors play a key role in the pathogenesis of tumor progression. Syndecans are a family of four transmembrane heparan sulfate proteoglycans (PG), including syndecan-1, -2, -3, and -4, which are dysregulated in a myriad of cancers, including OC. Many clinicopathological studies suggest that these proteins are promising diagnostic and prognostic biomarkers for OC. Furthermore, functions of the syndecan family in the regulation of cellular processes make it an interesting pharmacological target for anticancer therapies.

Oto J, Le QK, Schäfer SD, Kiesel L, Marí-Alexandre J, Gilabert-Estellés J, Medina P, Götte M. Role of Syndecans in Ovarian Cancer: New Diagnostic and Prognostic Biomarkers and Potential Therapeutic Targets. Cancers (Basel). 2023 Jun 9;15(12):3125. doi: 10.3390/cancers15123125. PMID: 37370735; PMCID: PMC10295974.

There is a free full text of this article available under Role of Syndecans in Ovarian Cancer: New Diagnostic and Prognostic Biomarkers and Potential Therapeutic Targets - PMC (nih.gov)

Syndecan-1 (Sdc-1) upregulation is associated with poor prognosis in breast cancer. Sdc-1 knockdown results in reduced angiogenesis and the dysregulation of tissue factor (TF) pathway constituents. Here, we evaluate the regulatory mechanisms and functional consequences of the Sdc-1/TF-axis using Sdc-1 knockdown and overexpression approaches in MCF-7 and MDA-MB-231 breast cancer cells. Gene expression was analyzed by means of qPCR. Thrombin generation and cell migration were detected. Cell-cycle progression and apoptosis were investigated using flow cytometry. In MDA-MB-231 cells, IL6, IL8, VEGF, and IGFR-dependent signaling affected TF pathway expression depending on Sdc-1. Notably, Sdc-1 depletion and TF pathway inhibitor (TFPI) synergistically affected PTEN, MAPK, and STAT3 signaling. At the functional level, the antiproliferative and pro-apoptotic effects of TFPI depended on Sdc-1, whereas Sdc-1’s modulation of cell motility was not affected by TFPI. Sdc-1 overexpression in MCF-7 and MDA-MB-231 cells led to increased TF expression, inducing a procoagulative phenotype, as indicated by the activation of human platelets and increased thrombin formation. A novel understanding of the functional interplay between Sdc-1 and the TF pathway may be compatible with the classical co-receptor role of Sdc-1 in cytokine signaling. This opens up the possibility of a new functional understanding, with Sdc-1 fostering coagulation and platelet communication as the key to the hematogenous metastatic spread of breast cancer cells.

Hassan N, Bückreiß N, Efing J, Schulz-Fincke M, König P, Greve B, Bendas G, Götte M. The Heparan Sulfate Proteoglycan Syndecan-1 Triggers Breast Cancer Cell-Induced Coagulability by Induced Expression of Tissue Factor. Cells. 2023 Mar 16;12(6):910. doi: 10.3390/cells12060910. PMID: 36980251; PMCID: PMC10047229.

There is a free full text available under Cells | Free Full-Text | The Heparan Sulfate Proteoglycan Syndecan-1 Triggers Breast Cancer Cell-Induced Coagulability by Induced Expression of Tissue Factor (mdpi.com)

Abstract

Alterations in glycoconjugate profiles are thought to promote changes in cell-to-cell and cell-to-intracellular and extracellular scaffold interactions in human disease. The nearly unlimited number of “glycoforms” that may exist in nature are difficult to study due to glycosylation and glycoconjugate modifications being associated with non-genome coded posttranscription and post-translation processes. Specific products generated by glycosylation are dependent on concentration and sub-cellular locations of glycan synthesis and processing enzymes. An indirect “high-throughput” approach to study glycosylation is to characterize glycan processing enzymes (hydrolases and transferases) by single cell sequencing of all cell types in tissue of human diseases. We previously identified TMEM230 as an endoplasmic reticulum (ER) associated protein that regulates NOTCH glycoprotein receptor and ligand signaling in zebrafish blood vessel formation and destructive remodeling capacities of diverse cell types including fibroblast, phagocytic and immune system cells in patients with cancer or granulomatous systemic vasculitis autoimmune disorder. NOTCH signaling represents a paradigm in glycan mediated signal transduction and supports the role of TMEM230 in glycan modifications. The ER initiates the earliest steps of glycoconjugate synthesis, sorting, and trafficking. As blood vessel and tissue remodeling, and Notch signaling are hallmarks of autoimmune disorders, we investigated whether aberrant TMEM230 expression was also associated with changes in expression of glycan processing enzymes in patients with rheumatoid arthritis (RA). In this current study, single cell sequencing analysis supported that TMEM230 expression was downregulated in all cell types associated with synovial tissue of RA patients while glycan processing enzymes were predominantly upregulated. In contrast, TMEM230 was upregulated in patients with high-grade compared to low-grade gliomas as it was N-linked glycosylation (GlcNAc), and glycoprotein and glycosaminoglycan expression. Our collective results support that TMEM230 regulates glycan/glycoconjugate processing enzymes in RA and the expression of protein glycoconjugate in aggressive gliomas. TMEM230 may therefore be a therapeutic target and marker for clinical treatment for glycosylation induced human autoimmunity disorders or cancer.

Elena Angeli, Cinzia Cocola, Edoardo Abeni, Eleonora Piscitelli, Paride Pelucchi, Ettore Mosca, Alice Chiodi, Luca Lerma, Cristiana Balbino, Ileana Zucchi, Mira Palizban, Martin Götte, Alberto Diaspro, Rolland A. Reinbold (2025). Proteoglycan Research, Vol.3 (1). doi: dx.doi.org/10.1002/pgr2.70020

High-grade gliomas (HGGs) and glioblastoma multiforme (GBM) are characterized by a heterogeneous and aggressive population of tissue-infiltrating cells that promote both destructive tissue remodeling and aberrant vascularization of the brain. The formation of defective and permeable blood vessels and microchannels and destructive tissue remodeling prevent efficient vascular delivery of pharmacological agents to tumor cells and are the significant reason why therapeutic chemotherapy and immunotherapy intervention are primarily ineffective. Vessel-forming endothelial cells and microchannel-forming glial cells that recapitulate vascular mimicry have both infiltration and destructive remodeling tissue capacities. The transmembrane protein TMEM230 (C20orf30) is a master regulator of infiltration, sprouting of endothelial cells, and microchannel formation of glial and phagocytic cells. A high level of TMEM230 expression was identified in patients with HGG, GBM, and U87-MG cells. In this study, we identified candidate genes and molecular pathways that support that aberrantly elevated levels of TMEM230 play an important role in regulating genes associated with the initial stages of cell infiltration and blood vessel and microchannel (also referred to as tumor microtubule) formation in the progression from low-grade to high-grade gliomas. As TMEM230 regulates infiltration, vascularization, and tissue destruction capacities of diverse cell types in the brain, TMEM230 is a promising cancer target for heterogeneous HGG tumors. 

Cocola, Cinzia; Abeni, Edoardo; Martino, Valentina; Piscitelli, Eleonora; Pelucchi, Paride; Ettore Mosca, Ettore; Chiodi, Alice; Mohamed, Tasnim; Palizban, Mira; Porta, Giovanni; Palizban, Helga; Nano, Giovanni; Acquati, Francesco; Bruno, Antonino; Greve, Burkhard; Gerovska, Daniela; Magnaghi, Valerio; Mazzaccaro, Daniela; Bertalot, Giovanni; Kehler, James; Balbino, Cristiana; Araúzo-Bravo, Marcos J.; Götte, Martin; Zucchi, Ileana; Reinbold, Rolland A. (2024). INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, ISSN 1422-0067, 25 (7), pp. 396701-396721. DOI: https://doi.org/10.3390/ijms25073967

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