Study of sphingosine kinase 2 in head and neck cancer

Author(s)

Lais Brigliadori Fugio

• Document type: Doctoral Thesis
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Ciências Farmacêuticas de Ribeirão Preto (PCARP/BC)
• Defense date: 2022-03-09

Examining board members

Andréia Machado Leopoldino; Paulo Tambasco de Oliveira; Lays Martin Sobral

• Advisor: Andréia Machado Leopoldino

Abstract

Sphingosine-1-phosphate (S1P) is produced in cells from sphingosine phosphorylation, catalyzed by sphingosine kinase 1 (SK1) and 2 (SK2), and can act in autocrine and intracellular signaling pathways. Changes in the levels of S1P and SK1 and SK2 enzymes are described in several pathologies, such as cancer and autoimmune diseases. Although some sphingolipids and genes associated with their metabolism are being suggested as candidates for biomarkers in oral cancer, there are still questions that need to be clarified to propose them as potential therapeutic targets. Therefore, in this study, we propose to evaluate how different levels of the SK2 protein affect the signaling and biology of oral squamous cells using head and neck squamous cell carcinoma (CECP: HN13 and HN12) and non-tumor oral keratinocyte (NOK-SI) cell lines. Knockdown of SK2 protein in HN13 and NOK-SI cells was performed by stable interference RNA (short hairpin RNA), while stable overexpression was obtained in HN12 and NOK-SI cells using a lentiviral vector containing cDNA for SK2. Our in vitro results showed that SK2 overexpression or knockdown regulated proteins of various signaling pathways in all cell lines, altering different cellular parameters such as histone acetylation, proliferation, autophagy, cell cycle progression, mitochondrial dynamics and cell transformation. Furthermore, experiments in xenograft tumor forming nude BALB/c mice showed that SK2 accumulation in NOK-SI cells induces oncogenic transformation. In HN12 cells, the accumulation of SK2 accentuated their tumorigenic potential, increasing proliferation and tumor growth. Thus, as the accumulation of SK2 itself is capable of inducing the malignant transformation of non-tumor keratinocytes (NOK-SI) and altering several cellular processes, we conclude that SK2 has a relevant role in oral oncogenesis, constituting a potential therapeutic target in head and neck cancer. (AU)

• FAPESP's process: 18/14225-8 - Study of sphingosine kinase 2 and set proteins in sphingolipids signaling in Head and Neck Cancer
• Grantee: Lais Brigliadori Fugio
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)