Investigation of lipid metabolism dysregulation and the effects on immune microenvironments in pan-cancer using multiple omics data

Abstract

Background Lipid metabolism reprogramming is a hallmark for tumor which contributes to tumorigenesis and progression, but the commonality and difference of lipid metabolism among pan-cancer is not fully investigated. Increasing evidences suggest that the alterations in tumor metabolism, including metabolite abundance and accumulation of metabolic products, lead to local immunosuppression in the tumor microenvironment. An integrated analysis of lipid metabolism in cancers from different tissues using multiple omics data may provide novel insight into the understanding of tumorigenesis and progression. Results Through systematic analysis of the multiple omics data from TCGA, we found that the most-widely altered lipid metabolism pathways in pan-cancer are fatty acid metabolism, arachidonic acid metabolism, cholesterol metabolism and PPAR signaling. Gene expression profiles of fatty acid metabolism show commonalities across pan-cancer, while the alteration in cholesterol metabolism and arachidonic acid metabolism differ with tissue origin, suggesting tissue specific lipid metabolism features in different tumor types. An integrated analysis of gene expression, DNA methylation and mutations revealed factors that regulate gene expression, including the differentially methylated sites and mutations of the lipid genes, as well as mutation and differential expression of the up-stream transcription factors for the lipid metabolism pathways. Correlation analysis of the proportion of immune cells in the tumor microenvironment and the expression of lipid metabolism genes revealed immune-related differentially expressed lipid metabolic genes, indicating the potential crosstalk between lipid metabolism and immune response. Genes related to lipid metabolism and immune response that are associated with poor prognosis were discovered including HMGCS2, GPX2 and CD36, which may provide clues for tumor biomarkers or therapeutic targets. Conclusions Our study provides an integrated analysis of lipid metabolism in pan-cancer, highlights the perturbation of key metabolism processes in tumorigenesis and clarificates the regulation mechanism of abnormal lipid metabolism and effects of lipid metabolism on tumor immune microenvironment. This study also provides new clues for biomarkers or therapeutic targets of lipid metabolism in tumors. Electronic supplementary material The online version of this article (10.1186/s12859-019-2734-4) contains supplementary material, which is available to authorized users.

Construction of a lipid metabolism‐related and immune‐associated prognostic signature for hepatocellular carcinoma

“…Accumulative evidence has suggested that alterations in tumor lipid metabolism could lead to tumor progression and local immunosuppression in the TME. 21 Due to the limited efficacy of diverse therapeutic methods of HCC, like chemotherapy, radiofrequency ablation, liver transplantation, and surgical resection exploring novel biomarkers is urgently needed, which could not only predict the OS of HCC patients, but also be utilized to guide anticancer therapy. Consequently, recent studies have shed more light on the aberrant lipid metabolism and its effect on the immune microenvironment in the context of HCC.…”

ITRAQ-based Bioinformatics Analysis Reveals the Potential Anticancer Effects of ATP4B in Gastric Cancer

“…Besides altered glucose metabolic phenotype, biosynthesis and utilization of lipids abnormality as well as amino acid metabolism changes are also recognized as the one of the most common metabolic features of cancer cells. In the last few decades, increasing studies suggested that dysregulation of lipid metabolism, especially for the reactivation of de novo fatty acid products, were essential for tumor progression [26,27]. High rate of glucose uptake and deregulated lipid metabolism have been recognized as a pivotal hallmark of cancer [28].…”

Aberrant lipid metabolism in hepatocellular carcinoma cells as well as immune microenvironment: A review

“…Increasing evidence suggests that alterations in tumour lipid metabolism, including metabolite abundance and accumulation of lipid metabolic products, lead to tumour development as well as local immunosuppression in the TME . For instance, a previous study illustrated that the deletion of 5‐lipoxygenase in the TME promoted lung cancer progression and metastasis through regulating T‐cell recruitment .…”

“…Among them, sterol regulatory element‐binding protein 1 (SREBP‐1), a crucial TF, greatly affects the downstream targeted lipid genes, especially for the downstream target genes in the cholesterol metabolism pathway, which is also a master regulator of SCD, ACC and FASN. [ Such result indicates that SREBP‐1 up‐regulation promotes the synthesis of FAs related to the up‐regulation of ATP‐citrate lyase (ACLY), FASN and SCD; increases cholesterol uptake into hepatocytes correlated with proprotein convertase subtilisin kexin 9(PCKS9) up‐regulation; and modulates mitochondrial fatty acid oxidation(FAO) associated with acetyl‐CoA carboxylase beta(ACACB) down‐regulation . Moreover, the large‐scale gene expression profiling conducted by Yamashita et al revealed marked activation of the SREBP‐1‐mediated lipogenic pathway in HCC and suggested that the up‐regulated SREBP‐1 protein expression was associated with dismal prognosis.…”