Identification of glycolysis related pathways in pancreatic adenocarcinoma and liver hepatocellular carcinoma based on TCGA and GEO datasets

Ji Li,Xin Meng,Yao Zhang,Peipei Yue,Yan Li,Chen Zhu,Biao Wang,Tianyu Zheng

doi:10.1186/s12935-021-01809-y

Abstract

BackgroundAbnormal energy metabolism is one of the characteristics of tumor cells, and it is also a research hotspot in recent years. Due to the complexity of digestive system structure, the frequency of tumor is relatively high. We aim to clarify the prognostic significance of energy metabolism in digestive system tumors and the underlying mechanisms.MethodsGene set variance analysis (GSVA) R package was used to establish the metabolic score, and the score was used to represent the metabolic level. The relationship between the metabolism and prognosis of digestive system tumors was explored using the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Volcano plots and gene ontology (GO) analyze were used to show different genes and different functions enriched between different glycolysis levels, and GSEA was used to analyze the pathway enrichment. Nomogram was constructed by R package based on gene characteristics and clinical parameters. qPCR and Western Blot were applied to analyze gene expression. All statistical analyses were conducted using SPSS, GraphPad Prism 7, and R software. All validated experiments were performed three times independently.ResultsHigh glycolysis metabolism score was significantly associated with poor prognosis in pancreatic adenocarcinoma (PAAD) and liver hepatocellular carcinoma (LIHC). The STAT3 (signal transducer and activator of transcription 3) and YAP1 (Yes1-associated transcriptional regulator) pathways were the most critical signaling pathways in glycolysis modulation in PAAD and LIHC, respectively. Interestingly, elevated glycolysis levels could also enhance STAT3 and YAP1 activity in PAAD and LIHC cells, respectively, forming a positive feedback loop.ConclusionsOur results may provide new insights into the indispensable role of glycolysis metabolism in digestive system tumors and guide the direction of future metabolism–signaling target combined therapy.

Highlights

Digestive system tumors are the most common type of tumor, and have become a major human health hazard owing to their high morbidity and mortality [1,2,3,4]
We have found that, in hepatocellular carcinoma cells under hypoxic conditions, Yes1-associated protein (YAP1) and hypoxia-inducible factor 1α (HIF-1α) bind to activate pyruvate kinase M1/2 (PKM2) to promote glycolysis [11]
We downloaded the datasets of digestive system tumors from the Cancer Genome Atlas (TCGA) database, and the most appropriate gene sets of glycolysis, fatty acid and glutamine metabolism downloaded from MSigDB

Summary

Introduction

Digestive system tumors are the most common type of tumor, and have become a major human health hazard owing to their high morbidity and mortality [1,2,3,4]. PAAD and LIHC are highly malignant tumors, which are the leading causes of cancer death all over the world, and patients are usually diagnosed at advanced stages. Energy metabolism reprogramming can promote cell growth and proliferation, and has been recognized as a new cancer marker [5]. Tumor is a metabolic disease, tumor cells must constantly increase the synthesis of new substances and maintain the energy supply to sustain proliferation and distant metastasis. [18F]-fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET/CT) scans can identify malignant lesions by targeting the high glycolysis rate of cancer cells [8]. Liver is the metabolic factory of the body, which may lead to PAAD and LIHC being more sensitive to glycolysis. We aim to clarify the prognostic significance of energy metabolism in digestive system tumors and the underlying mechanisms

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