Oncotarget | Sphingomyelin phosphodiesterase 3 methylation and silencing in oral squamous cell carcinoma results in increased migration and invasion and altered stress response


Oncotarget Volume 11 Issue 5: While lentivirus-induced overexpression of SMPD3 in cell models of oral dysplasia and OSCC did not significantly alter proliferation, it did decrease migration and invasion and increased resistance to the epidermal growth factor receptor inhibitor erlotinib.

These results suggest that SMPD3 downregulation is a common event in OSCC progression and may promote the spread of tumor cells.

Dr. Cathie Garnis from the Department of Integrative Oncology at British Columbia Cancer Research Centre as well as the Division of Otolaryngology at the Department of Surgery at the University of British Columbia said in their Oncotarget Research Article, "Oral squamous cell carcinoma (OSCC) is among the most commonly diagnosed cancer types in the world, with over 300,000 new cases and 145,000 deaths attributed to the disease worldwide each year."

Ceramide plays a complex role in the cell by altering the composition of lipid rafts and impinging on various signaling pathways.

Figure 1: Methylation of the  SMPD3 promoter CpG island is increased in oral dysplasia and cancer tissues compared with normal tissues.

Figure 1: Methylation of the SMPD3 promoter CpG island is increased in oral dysplasia and cancer tissues compared with normal tissues. The mean β-value for CpGs within the SMPD3 promoter CpG island across patient-matched samples was measured for normal, dysplastic, and carcinoma in situ/oral squamous cell carcinoma tissues from each of 10 patients. Bars represent the mean and standard deviation. Significance was determined using a one-way ANOVA with post-hoc Tukey's multiple comparisons test. **P < 0.01. ***P < 0.001. Abbreviations: ns, not significant; CIS/OSCC, carcinoma in situ/oral squamous cell carcinoma.

Initial studies on the role of ceramide found that it induced apoptosis and inhibited the cell cycle in leukemic cells, suggesting a tumor-suppressive role.

For instance, ceramide accumulation following nSMase2 activation that was triggered by oxidative stress resulted in apoptosis of human airway epithelial cells, whereas activation of the same enzyme protected neuroblastoma cells from nutrient deprivation-induced cell death.

NSMase2-mediated generation of ceramide may be further influenced by the expression of other ceramide-metabolizing enzymes, such as ceramidases, ceramide kinase and glucosyltransferase, and enzymes involved in de novo ceramide synthesis.

Thus, the role of nSMase2 is context-dependent and has not been examined in OSCC cells.

The Garnis research team concluded in their Oncotarget paper, "we have identified the promoter region of SMPD3 as a common site of hypermethylation and downregulation in oral tumors and in oral dysplasia and cancer cell lines."

Our experiments suggest that SMPD3 regulates the migratory capacity of tumors cells and can alter their response to EGFR-targeted therapy.

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Full text - https://doi.org/10.18632/oncotarget.27458

Correspondence to - Cathie Garnis - [email protected]

Keywords - oral squamous cell carcinoma, DNA methylation, SMPD3, erlotinib, cancer progression

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