Hyper-Elongation in Colorectal Cancer Tissue – Cerotic Acid is a Potential Novel Serum Metabolic Marker of Colorectal Malignancies

Abstract

Backgrounds/Aims: Colorectal cancer (CRC) cells show some alterations of lipid metabolism. Elongation of fatty acids (FA) has not been studied in CRC tissues thus far. The aim of this study was to verify if CRC specimens and normal colon mucosa differ in terms of their levels of very long-chain FAs, a product of FA elongation. Moreover, the expression of elongase genes has been studied in normal tissue and CRC. Finally, we searched for some specific products of FA elongation in serum of CRC patients. Methods: The specimens of normal colon mucosa and CRC were obtained from nineteen CRC patients differ in terms of FA elongation. We also searched for some specific products of FA elongation in serum of CRC patients and from healthy volunteers. Tissue and serum FA profiles were determined by means of gas chromatography-mass spectrometry (GC/MS), and the tissue expression of elongases (ELOVLs) was analyzed with real-time PCR. Results: Compared to normal colon tissue, CRC specimens showed significantly higher levels of 22-, 24- and 26-carbon FAs, stronger expressions of ELOVL1 and ELOVL6 (4- and 9-fold elevated respectively), and higher values of 18: 0/16: 0 elongation index. We also demonstrated presence of cerotic acid (26: 0) in serum of all CRC patients but in none of the healthy controls. Conclusions: CRC tissue seems to be characterized by enhanced FA elongation (hyper-elongation). Presence of cerotic acid in CRC patients sera and absence of this FA in healthy subjects points to this compound as a strong candidate for specific metabolic marker of colorectal malignancies.

Decreased Triacylglycerol Content and Elevated Contents of Cell Membrane Lipids in Colorectal Cancer Tissue: A Lipidomic Study

“…In line with these findings, CRC tissue contained also elevated levels of PUFAs and SFAs, the main components of polar membrane lipids, and lower levels of MUFAs, the primary component of TGs. The observation on elevated levels of PUFAs and SFAs and reduced levels of MUFAs (especially 18:1) in CRC tissue is consistent with the results of our previous research [28] and studies conducted by some other authors [18]. However, the results of the studies analyzing FA profile of colorectal cancer are inconclusive, as some researchers observed elevated levels of n-6 PUFAs and reduced levels of n-3 PUFAs in phospholipids from CRC tissues [29], whereas others reported opposite results, i.e., increased levels of n-3 PUFAs and decreased levels of n-6 PUFAs in the tumor tissue [30].…”

“…In our opinion, a better insight into the systemic alterations of lipid metabolism in CRC patients, and especially into the alterations within the tumor tissue, would facilitate the development of novel therapeutic strategies. Furthermore, some serum lipids might theoretically serve as CRC markers [28]. Despite progress in the diagnostics and treatment of cancer, earlier detection of the disease and development of novel targeted therapies, many malignancies still do not respond adequately to currently available regimens.…”

Butyrate and docosahexaenoic acid interact in alterations of specific lipid classes in differentiating colon cancer cells

“…Inhibition of ELOVL6 was shown to significantly reduce the proliferation of squamous cell carcinoma cell lines in vitro and to attenuate their growth as a xenograft in an in vivo mouse model. Just recently, elevated expression and activity of ELOVLs have been demonstrated also in colon cancer tissue . Our present data indicate that the mechanisms regulating expression/activities of elongases in colon cancer cells that are induced by various types of fatty acids, including PUFAs or short‐chain fatty acids, such as butyrate, deserve further attention.…”

A humanized yeast phenomic model of deoxycytidine kinase to predict genetic buffering of nucleoside analog cytotoxicity

“…5D; Table 3) included: (1) YTA7/ATAD2/ATAD2B , which localizes to chromatin and regulates histone gene expression. ATAD2 overexpression portends poor prognosis in gastric, colorectal, cervical, hepatocellular carcinoma, lung, and breast cancer, and thus overexpression sensitivity could represent the potential to target a driver gene [119-125]; (2) PIF1 / PIF1 , a DNA helicase, which is involved in telomere regulation and is required during oncogenic stress [113]; (3) RPS1B/RPS3A , which is a small subunit ribosomal protein that is overexpressed in hepatitis B associated hepatocellular carcinoma and non-small cell lung cancer [114,115]; (4) LEO1/LEO1 , which associates with the RNA polymerase II and acts as an oncogene in acute myelogenous leukemia [156]; (5) ELO3/ELOVL1/ELOVL2/ ELOVL4/ELOVL6 , which constitutes a family of fatty acid elongases that function in sphingolipid biosynthesis, among which ELOVL1 is overexpressed in breast and colorectal cancer tissue [107,108], ELOVL2 is upregulated in hepatocellular carcinoma [109], and ELOVL6 is overexpressed and associated with poor prognosis in liver and breast cancer [110,111] ; (6) MDL2/ABCB10 , which is a mitochondrial inner membrane ATP-binding cassette protein and is upregulated in breast cancer [112]; (7) CPR3/PPIA , which is a mitochondrial cyclophilin that is upregulated in lung cancer, esophageal, and pancreatic cancer [104-106]; and (8) SAC3/MCM3AP/SAC3D1 , which is a nuclear pore-associated protein functioning in transcription and mRNA export, with MCM3AP being upregulated in glioma cells [116], while SAC3D1 is upregulated in cervical cancer and hepatocellular carcinoma [117,118]. Yeast gene deletion suppression together with overexpression sensitivity of human homologs in cancer reveals potential therapeutic vulnerabilities that can be further explored in both systems.…”