Abstract
Background: The potential biological processes and laws of the biological components in malignant tumors can be understood more systematically and comprehensively through multi-omics analysis. This study elaborately explored the role of lipid metabolism in the prognosis of colorectal cancer (CRC) from the metabonomics and transcriptomics. Methods: We performed K-means unsupervised clustering algorithm and t test to identify the differential lipid metabolites determined by liquid chromatography tandem mass spectrometry (LC-MS/MS) in the serum of 236 CRC patients of the First Hospital of Jilin University (JLUFH). Cox regression analysis was used to identify prognosis-associated lipid metabolites and to construct multi-lipid-metabolite prognostic signature. The composite nomogram composed of independent prognostic factors was utilized to individually predict the outcome of CRC patients. Glycerophospholipid metabolism was the most significant enrichment pathway for lipid metabolites in CRC, whose related hub genes (GMRHGs) were distinguished by gene set variation analysis (GSVA) and weighted gene co-expression network analysis (WGCNA). Cox regression and least absolute shrinkage and selection operator (LASSO) regression analysis were utilized to develop the prognostic signature. Results: Six-lipid-metabolite and five-GMRHG prognostic signatures were developed, indicating favorable survival stratification effects on CRC patients. Using the independent prognostic factors as variables, we established a composite nomogram to individually evaluate the prognosis of CRC patients. The AUCs of one-, three-, and five-year ROC curves were 0.815, 0.815, and 0.805, respectively, showing auspicious prognostic accuracy. Furthermore, we explored the potential relationship between tumor microenvironment (TME) and immune infiltration. Moreover, the mutational frequency of TP53 in the high-risk group was significantly higher than that in the low-risk group (p < 0.001), while in the coordinate mutational status of TP53, the overall survival of CRC patients in the high-risk group was significantly lower than that in low-risk group with statistical differences. Conclusion: We identified the significance of lipid metabolism for the prognosis of CRC from the aspects of metabonomics and transcriptomics, which can provide a novel perspective for promoting individualized treatment and revealing the potential molecular biological characteristics of CRC. The composite nomogram including a six-lipid-metabolite prognostic signature is a promising predictor of the prognosis of CRC patients.
Highlights
The morbidity and mortality of colorectal cancer (CRC) remained stubbornly high in the world, respectively ranking the third and fourth (Gao et al, 2016; Zhang et al, 2017)
For the JLUFH CRC patients, we found that CRC patients with advanced pathological stage and mucinous adenocarcinomas were mainly distributed in the high-risk group with significant statistical difference (p 0.031 and p 0.001) (Figures 7A,B)
Cer could be synthesized from serine and palmitate with de novo synthesis, and it could induce the apoptosis of cancer cells (Kramer et al, 2015) and protect cancer cells from apoptosis (Mesicek et al, 2010)
Summary
The morbidity and mortality of CRC remained stubbornly high in the world, respectively ranking the third and fourth (Gao et al, 2016; Zhang et al, 2017). The mechanism of occurrence, development, and invasion of CRC was still well unclear. To find the molecular mechanism and favorable prognostic monitoring index for the occurrence, development and invasion of CRC was the hotspot of the current research. A large number of studies have shown that abnormal lipid metabolism was closely correlated with the occurrence and development of tumor. The level of TC was positively correlated with the occurrence of breast cancer, prostate cancer, and colon cancers. Since the survival of tumor cells mainly depended on FASN-mediated de novo synthesis of fatty acids, FASN was considered as the one of the important targets for human cancer therapy (Lupu and Menendez, 2006). This study elaborately explored the role of lipid metabolism in the prognosis of colorectal cancer (CRC) from the metabonomics and transcriptomics
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