Profile of sphingolipid-related genes and its association with prognosis highlights sphingolipid metabolism in oral cancer

Article type: Research Article

Authors: da Silva, Gabriel^a | de Matos, Leandro Luongo^{b; c} | Kowalski, Luiz Paulo^{c; d} | Kulcsar, Marco^b | Leopoldino, Andreia Machado^{a; *}

Affiliations: [a] Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, SP, Brazil | [b] Head and Neck Surgery Department, Instituto do Câncer do Estado de São Paulo, University of São Paulo Medical School (LIM28), SP, Brazil | [c] Surgery Department, Faculdade Israelita de Ciências da Saúde Albert Einstein, SP, Brazil | [d] Department of Head and Neck Surgery and Otorhinolaryngology, A. C. Camargo Cancer Center, SP, Brazil

Correspondence: [*] Corresponding author: Andreia Machado Leopoldino, Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. do Café s/n, 14040-903 Ribeirão Preto, SP, Brazil. E-mail: andreiaml@usp.br.

Abstract: BACKGROUND: Sphingolipids are bioactive lipids that play a role in cancer development. However, the clinical role of sphingolipid (SPL)-related genes in oral cancer (OC) remains not fully understood. OBJECTIVE: This study, aimed to examine the mRNA expression of 14 sphingolipid-related genes in oral cancer patients and their implication with clinicopathological features and prognosis. METHODS: qPCR analysis was performed in 50 OC tissues and their matched surgical margins. Next, Kaplan-Meier, Cox regression, and Receiver operating characteristics (ROC) analysis were applied to evaluate the impact of sphingolipid-related genes expression on the prognosis of OC. RESULTS: The genes SET, ACER3, SK1 and S1PR5 were predominantly up-regulated, while ABCG2, S1PR1, ABCB1 and SPNS2 were down-regulated in OC patients. Analyzing the Cancer Genome Atlas Head-Neck Squamous Cell Carcinoma (TCGA-HNSC) data, which are predominantly composed of OC samples, these genes displayed a similar profile. In OC patients, high levels of SK1 were associated with lymph node metastasis, extracapsular invasion, desmoplasia, locoregional relapse, and disease status. Low levels of SPNS2 were associated with lymph node metastasis, perineural invasion, and disease status. Furthermore, OC and HNSC patients with higher SK1 expression demonstrated shorter disease-free survival (p= 0.0037; p= 0.0087), whereas those with lower SPNS2 expression exhibited shorter overall survival (p= 0.051; p= 0.0012). High levels of ACER3 and low levels of S1PR1 were associated with shorter disease-free and overall survival in HNSC patients. CONCLUSION: Several sphingolipid-related genes are deregulated in OC at the mRNA level and are associated with clinicopathological features and presented potencial for the prediction of poor prognosis in OC patients.

Keywords: Sphingolipid, oral squamous cell carcinoma, head and neck cancer, gene expression, survival

DOI: 10.3233/CBM-203100

Journal: Cancer Biomarkers, vol. 32, no. 1, pp. 49-63, 2021