Ceramide synthase CERS4 gene downregulation is associated with KRAS mutation in colorectal cancer

Abstract

Abstract Background Ceramide, the central molecule in sphingolipid synthesis, is a bioactive lipid that serves as a regulatory molecule in the anti-inflammatory responses, apoptosis, programmed necrosis, autophagy, and cell motility of cancer cells. In particular, the authors have reported differences in sphingolipid content in colorectal cancer tissues. The associations among genetic mutations, clinicopathological factors, and sphingolipid metabolism in colorectal cancer (CRC) have not been investigated. Purpose The aim of this study was to clarify the relationships among mutations of genes associated with sphingolipid metabolism and clinicopathological factors in CRC. Patients and Methods We performed a cohort study of the medical records of 82 consecutive patients with stage I-IV CRC who underwent tumor resection at a single institution in 2019–2021. We quantified the expression levels of genes involved in sphingolipid metabolism and analyzed the correlation between these gene expression profiles and the clinical data of each patient. Results: When relationships between patients’ KRAS mutation status and levels of ceramide synthase (CERS), N-acylsphingosine amidohydrolase (ASAH) and alkaline ceramidase (ACER) genes, all involved in sphingolipid metabolism, the CRES4 expression level was significantly lower in the KRAS mutant group (p = 0.004). In terms of clinicopathological measures, the rate of venous invasion was significantly higher in the low-CERS4-expression group (p = 0.0057). Conclusions By examining the correlation between sphingolipid gene expression and clinical factors, we were able to identify cancer types in which sphingolipid metabolism is particularly relevant. CERS4 expression was significantly reduced in KRAS mutant CRC. Moreover, CRC with decreased CERS4 showed significantly more frequent venous invasion.