Oncotarget

Research Papers:

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

James Jabalee, Rebecca Towle, James Lawson, Christopher Dickman and Cathie Garnis _

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Abstract

James Jabalee1, Rebecca Towle1, James Lawson1, Christopher Dickman1 and Cathie Garnis1,2

1 Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada

2 Division of Otolaryngology, Department of Surgery, University of British Columbia, Vancouver, BC, Canada

Correspondence to:

Cathie Garnis,email: cgarnis@bccrc.ca

Keywords: oral squamous cell carcinoma; DNA methylation; SMPD3; erlotinib; cancer progression

Received: November 11, 2019     Accepted: January 13, 2020     Published: February 04, 2020

ABSTRACT

Neutral sphingomyelinase 2 (nSMase2), the product of the sphingomyelin phosphodiesterase 3 (SMPD3) gene, catalyzes the hydrolysis of sphingomyelin to ceramide. Ceramide acts on various signaling pathways to influence cell proliferation, survival, and stress response. Altered levels of sphingolipids and ceramides have been reported in various cancer types, including oral squamous cell carcinoma (OSCC). OSCC patients exhibit a poor 5-year survival rate of 50%, a figure that has remained stagnant for decades. To overcome this requires a better understanding of the molecular events driving this disease. The molecular analysis of the oral cavity reported here has identified the SMPD3 promoter region as a site of frequent hypermethylation and downregulation in pre-malignant and malignant tissues as compared with healthy control tissues. 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 (EGFR) inhibitor erlotinib. These results suggest that SMPD3 downregulation is a common event in OSCC progression and may promote the spread of tumor cells.


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