SET and sphingolipids in head and neck squamous cell carcinoma: signaling, targets and antiumoral therapy

• Grant number: 16/19103-2
• Support Opportunities: Research Projects - Thematic Grants
• Start date: July 01, 2018
• End date: June 30, 2024
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Andréia Machado Leopoldino
• Grantee: Andréia Machado Leopoldino
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated researchers: Carlos Curti ; Luciana Oliveira de Almeida ; Luiz Carlos Conti de Freitas ; Norberto Peporine Lopes
• Associated research grant(s): 23/01454-7 - Crispr screen to identify miRNAs associated with sphingosine kinase 2 and response to therapies in Oral Cancer, AP.R
• Associated scholarship(s): 24/02645-3 - Extracellular vesicles, sphingolipids and factors derived from oral epidermoid and tumor cells in differentiating macrophages into M1 and M2 subtypes, BP.MS; 23/12049-6 - Study of sphingolipids and other types of biomolecules in different biological samples, BP.TT; 22/07171-4 - Investigation of control of histone chaperones by sphingosine kinase 2/S1P and its impact on the biogenesis of oral squamous cell carcinoma, BP.PD; + associated scholarships 23/01878-1 - Studies of sphingolipids in biological samples and biological models, BP.TT; 22/14844-5 - Study of sphingosine kinase 1 and 2 proteins in the response to hypoxia and reoxygenation in an oral keratinocyte lineage model, BP.IC; 22/10740-0 - Study of potential mechanism of regulation of microRNAs by sphingosine kinase 2, BP.DR; 22/05115-0 - Analyses of sphingolipids and other biomolecules in different biological samples and models, BP.TT; 21/03732-9 - Characterization of Sig-1R in the immune and metabolic response of sphingolipids as a chemoresistant factor in oral cavity cancer, BP.PD; 19/22663-8 - Candidate biomarkers selection of human oral cancer by mass spectrometry coupled to high-performance liquid chromatography, BP.PD; 20/00101-5 - Different experimental strategies and approaches for the study of molecular markers in cancer, BP.TT; 18/17480-9 - Study of SET and sphingolipids in head and neck cancer: signaling, targets and antitumor therapy, BP.PD; 18/14225-8 - Study of sphingosine kinase 2 and set proteins in sphingolipids signaling in Head and Neck Cancer, BP.DD - associated scholarships

Abstract

Despite the reached breakthrough in the treatment of some cancer types, the search for new therapeutic targets and antitumor therapy strategies to overcome tumor metastases, relapse, and resistance to therapy, is required. The present research proposal aims to identify evidences on the role of SET protein regarding sphingolipid signaling pathway, as well as the sphingolipids role, in head and neck squamous cell carcinoma (HNSCC). This approach can identify new therapeutic targets that may lead to new anticancer treatments. Several experimental approaches will be employed either in vitro or in vivo. We will perform studies in human cell lines, tumor samples, and serum of patients with cancer. In addition, different methods will be used to achieve the proposed goals, such as (i) sphingolipid analysis by mass spectrometry, (ii) post translational modifications of proteins by Western blotting, (iii) cell distribution of proteins by immunohistochemistry, immunofluorescence or Western blotting (subcellular fractionation), (iv) RNA and miRNAs quantification by real-time PCR, (v) DNA sequencing, (vi) RNA interference using either siRNA or shRNA, (vii) ectopic expression using vectors containing cDNAs of interest, (viii) flow cytometry for cell cycle analysis and characterization of cell types using antibodies, (ix) angiogenesis using HUVEC cells, and (x) cell viability, invasion and clonogenic assays. These studies, in addition to the tumor formation in nude mice using the xenograft model of human tumor cell lines and murine carcinoma cell lines in syngeneic mouse model, can both improve the knowledge on sphingolipid signaling in head and neck cancer and led to new mechanistic/therapeutic approaches for cancer. (AU)

Scientific publications

(8)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

SOUSA, LUCAS OLIVEIRA; SOBRAL, LAYS MARTIN; DE ALMEIDA, LUCIANA OLIVEIRA; GARCIA, CRISTIANA BERNADELLI; GREENE, LEWIS JOEL; LEOPOLDINO, ANDREIA MACHADO. SET protein modulates H4 histone methylation status and regulates miR-137 level in oral squamous cell carcinoma. Epigenomics, v. 12, n. 6, p. 475-485, MAR 2020. (10/20384-0, 16/19103-2, 13/10898-4, 13/08135-2)

DA SILVA, GABRIEL; BROCHERS-LACCHINI, FERNANDA COELI; LEOPOLDINO, ANDREIA MACHADO. How do sphingolipids play a role in epigenetic mechanisms and gene expression?. Epigenomics, v. 14, n. 5, p. 4-pg., 2021-12-15. (18/17480-9, 16/19103-2)

DA SILVA, GABRIEL; DE MATOS, LEANDRO LUONGO; KOWALSKI, LUIZ PAULO; KULCSAR, MARCO; LEOPOLDINO, ANDREIA MACHADO. Profile of sphingolipid-related genes and its association with prognosis highlights sphingolipid metabolism in oral cancer. CANCER BIOMARKERS, v. 32, n. 1, p. 49-63, 2021. (16/19103-2, 13/08135-2)

OUCHIDA, AMANDA TOMIE; UYEMURA, VALERIA TUDELLA; QUEIROZ, ANDRE LIMA; BRAUER, VERONICA SOARES; CAVALCANTI-NETO, MARINALDO PACIFICO; SOUSA, LUCAS OLIVEIRA; UYEMURA, SERGIO AKIRA; CURTI, CARLOS; LEOPOLDINO, ANDREIA MACHADO. SET protein accumulation prevents cell death in head and neck squamous cell carcinoma through regulation of redox state and autophagy. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, v. 1866, n. 4, p. 623-637, APR 2019. (09/52228-0, 13/10898-4, 16/19103-2)

GOTO, RENATA NISHIDA; SOBRAL, LAYS MARTIN; STRINGHETTA-PADOVANI, KARINA; GARCIA, CRISTIANA B.; DA SILVA, GABRIEL; VITEK, MICHAEL P.; LEOPOLDINO, ANDREIA MACHADO. Synergic effect of OP449 and FTY720 on oral squamous cell carcinoma. European Journal of Pharmacology, v. 882, SEP 5 2020. (13/00374-8, 13/01355-7, 13/10898-4, 18/17480-9, 16/19103-2, 13/08135-2)

FAEDO, RAQUEL ROMAN; DA SILVA, GABRIEL; DA SILVA, RODRIGO MOREIRA; USHIDA, TATIANE RESENDE; DA SILVA, RICARDO ROBERTO; LACCHINI, RICCARDO; MATOS, LEANDRO LUONGO; KOWALSKI, LUIZ PAULO; LOPES, NOBERTO PEPORINE; LEOPOLDINO, ANDREIA MACHADO. Sphingolipids signature in plasma and tissue as diagnostic and prognostic tools in oral squamous cell carcinoma. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS, v. 1867, n. 1, JAN 2022. (17/18922-2, 18/17480-9, 16/19103-2, 19/05026-4, 18/03278-3)

FUGIO, LAIS BRIGLIADORI; COELI-LACCHINI, FERNANDA B.; LEOPOLDINO, ANDREIA MACHADO. Sphingolipids and Mitochondrial Dynamic. CELLS, v. 9, n. 3, MAR 2020. (18/14225-8, 16/19103-2, 13/08135-2)

PADOVANI, KARINA STRINGHETTA; GOTO, RENATA NISHIDA; FUGIO, LAIS BRIGLIADORI; GARCIA, CRISTIANA BERNADELLI; ALVES, VANI MARIA; BRASSESCO, MARIA SOL; GREENE, LEWIS JOEL; REGO, EDUARDO MAGALHAES; LEOPOLDINO, ANDREIA MACHADO. Crosstalk between hnRNP K and SET in ATRA-induced differentiation in acute promyelocytic leukemia. FEBS OPEN BIO, v. 11, n. 7, p. 2019-2032, JUL 2021. (13/01355-7, 13/00374-8, 13/10898-4, 13/08135-2, 16/19103-2)