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

Abstract

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. The objective of this study is to investigate the association between genes associated with sphingolipid metabolism, genetic variations in colorectal cancer (CRC), and clinicopathological factors in CRC patients. We enrolled 82 consecutive patients with stage I–IV CRC who underwent tumor resection at a single institution in 2019–2021. We measured the expression levels of genes related to sphingolipid metabolism and examined the relationships between CRC gene mutations and the clinicopathological data of each individual patient. The relationship between CRC gene mutations and expression levels of ceramide synthase (CERS), N-acylsphingosine amidohydrolase (ASAH), and alkaline ceramidase (ACER) genes involved in sphingolipid metabolism was examined CRES4 expression was significantly lower in the CRC KRAS gene mutation group (p = 0.004); vascular invasion was more common in colorectal cancer patients with high CERS4 expression (p = 0.0057). 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.

The Regulatory Effect of Huangshui Polysaccharides on Intestinal Microbiota and Metabolites during In Vitro Fermentation

“…The reason for this result might be related to the molecular weight, which required further exploration. Meanwhile, the metabolic pathways enriched by HSP40-0 and HSP60-0 were mainly related to oxidative stress and energy metabolism, whereas HSP80-0 only enriched sphingolipid metabolism, which might be related to cancer . Based on the analysis of metabolic pathways enriched by different HSPs, the following three points deserved attention.…”

Sphingolipids: Less Enigmatic but Still Many Questions about the Role(s) of Ceramide in the Synthesis/Function of the Ganglioside Class of Glycosphingolipids

“…Long-chain hydroxylated fatty acids tend to be present in the ceramide components of these compounds [21,22]. Brain (primarily neurons [33], skeletal muscle, testis [32] ER Head and neck squamous cell carcinoma [34] CerS2 C20-26-CoA + sphinganine/sphingosine [32] Kidneys, liver, spleen, intestine, bone marrow, lymph nodes, and thymus [32] ER Defective myelination, followed by neurological decline [35] CerS3 C22-C26-CoA + sphinganine/sphingosine [32] Primarily testis, skin, and prostate [32] ER Congenital ichthyosis [36] Used commercially to treat psoriasis [37] CerS4 C18-C20-CoA + sphinganine/sphingosine [32] Broad, with more in heart, leukocytes, skin, and spleen ER KRAS-mutant colorectal cancer [38] CerS5 C16-CoA + sphinganine/sphingosine [39] Low but more in prostate and skeletal muscle ER Mice more susceptible to inducible colitis and associated colon cancer [40] CerS6 C14-C16-CoA + sphinganine/sphingosine [32] Low but it is in intestine, spleen, thymus, and lymph nodes ER Overexpression in acute lymphoblastic leukemia enhances resistance to chemotherapy [41] as well as triple-negative breast cancer [42] DEGS1 Dihyroceramide NADPH/H + Ubiquitous but greater in liver, Harderian gland, kineys, and lungs [43] ER/mitochondria [44] Decreased activity associated with severe neurological defects [45] CERT Ceramide with C14-C20 fatty acids [46] ATP-dependent [47] Ubiquitous [48] ER + Golgi Cytosol [47] Affects diabetes [49], Alzheimer's senescence [50] Developmental disorders [51] ASAH1 Ceramide, preferably with C16:0-C18:0 [52] Saposin D [53] Ubiquitous, especially in heart and kidneys [54] Lysosomes [54] LSD, Farber's disease, spinal muscular atrophy…”