Background: Overexpression of aspartate β-hydroxylase (ASPH) in human tumors contributes to their progression by stimulating cell proliferation, migration, and invasion. Several signaling pathways affected by ASPH have been identified, but the high number of potential targets of ASPH hydroxylation suggests that additional mechanisms may be involved. This study was performed to reveal new targets of ASPH signaling. Methods: The effect of ASPH on the oncogenicity of three mouse tumor cell lines was tested using proliferation assays, transwell assays, and spheroid invasion assays after inhibition of ASPH with the small molecule inhibitor MO-I-1151. ASPH was also deactivated with the CRISPR/Cas9 system. A transcriptomic analysis was then performed with bulk RNA sequencing and differential gene expression was evaluated. Expression data were verified by quantitative PCR and immunoblotting. Results: Inhibition or abrogation of ASPH reduced proliferation of the cell lines and their migration and invasiveness. Among the genes with differential expression in more than one cell line, two members of the lymphocyte antigen 6 (Ly6) family, Ly6a and Ly6c1, were found. Their downregulation was confirmed at the protein level by immunoblotting, which also showed their reduction after ASPH inhibition in other mouse cell lines. Reduced production of the Ly6D and Ly6K proteins was shown after ASPH inhibition in human tumor cell lines. Conclusions: Since increased expression of Ly6 genes is associated with the development and progression of both mouse and human tumors, these results suggest a novel mechanism of ASPH oncogenicity and support the utility of ASPH as a target for cancer therapy.

• Klíčová slova
• ASPH inhibitor, Ly6 family, RNA sequencing, Tumorigenesis,
• Publikační typ
• časopisecké články MeSH

The epithelial-mesenchymal plasticity, in tight association with stemness, contributes to the mammary gland homeostasis, evolution of early neoplastic lesions and cancer dissemination. Focused on cell surfaceome, we used mouse models of pre-neoplastic mammary epithelial and cancer stem cells to reveal the connection between cell surface markers and distinct cell phenotypes. We mechanistically dissected the TGF-β family-driven regulation of Sca-1, one of the most commonly used adult stem cell markers. We further provided evidence that TGF-β disrupts the lineage commitment and promotes the accumulation of tumor-initiating cells in pre-neoplastic cells.

• MeSH
• ataxin-1 metabolismus   MeSH
• epitelo-mezenchymální tranzice genetika   MeSH
• epitelové buňky patologie   MeSH
• experimentální nádory mléčných žláz genetika   patologie   MeSH
• lidé MeSH
• mléčné žlázy zvířat patologie   MeSH
• myši MeSH
• nádorové buněčné linie transplantace   MeSH
• nádorové kmenové buňky patologie   MeSH
• nádory prsu genetika   patologie   MeSH
• plasticita buňky genetika   MeSH
• receptor erbB-2 genetika   MeSH
• regulace genové exprese u nádorů MeSH
• rekombinantní proteiny genetika   metabolismus   MeSH
• signální transdukce genetika   MeSH
• transformující růstový faktor beta genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ataxin-1 MeSH
• Atxn1 protein, mouse MeSH Prohlížeč
• Erbb2 protein, mouse MeSH Prohlížeč
• receptor erbB-2 MeSH
• rekombinantní proteiny MeSH
• transformující růstový faktor beta MeSH