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      Identification of A Risk Signature Based on Lactic Acid Metabolism-Related LncRNAs in Patients With Esophageal Squamous Cell Carcinoma

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          Abstract

          Lactic acid, formerly thought of as a byproduct of glycolysis or a metabolic waste produced, has now been identified as a key regulator of cancer growth, maintenance, and progression. However, the results of investigations on lactic acid metabolism-related long non-coding RNAs (LRLs) in esophageal squamous cell carcinoma (ESCC) remain inconclusive. In this study, univariate Cox regression analysis was carried out in the TCGA cohort, and 9 lncRNAs were shown to be significantly associated with prognosis. Least absolute shrinkage and selection operator (LASSO) regression analysis and multivariate Cox regression analysis were then used in the GEO cohort. 6 LRLs were identified as independent prognostic factors for ESCC patients used to construct a prognostic risk-related signature subsequently. Two groups were formed based on the middle value of risk scores: a low-risk group and a high-risk group. Following that, we conducted Kaplan-Meier survival analysis, which revealed that the high-risk group had a lower survival probability than the low-risk group in both GEO and TCGA cohorts. On multivariate Cox regression analysis, the prognostic signature was shown to be independent prognostic factor, and it was found to be a better predictor of the prognosis of ESCC patients than the currently widely used grading and staging approaches. The established nomogram can be conveniently applied in the clinic to predict the 1-, 3-, and 5- year survival rates of patients. There was a significant link found between the 6 LRLs-based prognostic signature and immune-cell infiltration, tumor microenvironment (TME), tumor somatic mutational status, and chemotherapeutic treatment sensitivity in the study population. Finally, we used GTEx RNA-seq data and qRT-PCR experiments to verify the expression levels of 6 LRLs. In conclusion, we constructed a prognostic signature which could predict the prognosis and immunotherapy response of ESCC patients.

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          Most cited references23

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          Lactate Metabolism in Human Lung Tumors

          Cancer cells consume glucose and secrete lactate in culture. It is unknown whether lactate contributes to energy metabolism in living tumors. We previously reported that human non-small cell lung cancers (NSCLC) oxidize glucose in the tricarboxylic acid (TCA) cycle. Here we show that lactate is also a TCA cycle carbon source for NSCLC. In human NSCLC, evidence of lactate utilization was most apparent in tumors with high 18 fluorodeoxyglucose uptake and aggressive oncological behavior. Infusing human NSCLC patients with 13 C-lactate revealed extensive labeling of TCA cycle metabolites. In mice, deleting monocarboxylate transporter-1 (MCT1) from tumor cells eliminated lactate-dependent metabolite labeling, confirming tumor-cell autonomous lactate uptake. Strikingly, directly comparing lactate and glucose metabolism in vivo indicated that lactate's contribution to the TCA cycle predominates. The data indicate that tumors, including bona fide human NSCLC, can use lactate as a fuel in vivo. Human non-small cell lung cancer preferentially utilizes lactate over glucose to fuel TCA cycle and sustain tumor metabolism in vivo.
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            Epidemiology of Esophageal Squamous Cell Carcinoma.

            Esophageal squamous cell carcinoma (ESCC) accounts for about 90% of the 456,000 incident esophageal cancers each year. Regions of high incidence include Eastern to Central Asia, along the Rift Valley in East Africa, and into South Africa. There are many causes of ESCC, which vary among regions. Early studies in France associated smoking cigarettes and heavy alcohol consumption with high rates of ESCC, but these factors cannot explain the high incidence in other regions. We discuss other risk factors for ESCC, including polycyclic aromatic hydrocarbons from a variety of sources, high-temperature foods, diet, and oral health and the microbiome-all require further research. A growing list of defined genomic regions affects susceptibility, but large genome-wide association studies have been conducted with ethnic Chinese subjects only; more studies are called for in the rest of Asia and Africa. ESCC has been understudied, but growing infrastructure in more high-incidence countries will allow rapid progress in our understanding.
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              Lactate: a metabolic key player in cancer.

              Increased glucose uptake and accumulation of lactate, even under normoxic conditions (i.e., aerobic glycolysis or the Warburg Effect), is a common feature of cancer cells. This phenomenon clearly indicates that lactate is not a surrogate of tumor hypoxia. Tumor lactate can predict for metastases and overall survival of patients, as shown by several studies of different entities. Metastasis of tumors is promoted by lactate-induced secretion of hyaluronan by tumor-associated fibroblasts that create a milieu favorable for migration. Lactate itself has been found to induce the migration of cells and cell clusters. Furthermore, radioresistance has been positively correlated with lactate concentrations, suggesting an antioxidative capacity of lactate. Findings on interactions of tumor metabolites with immune cells indicate a contribution of lactate to the immune escape. Furthermore, lactate bridges the gap between high lactate levels in wound healing, chronic inflammation, and cancer development. Tumor cells ensure sufficient oxygen and nutrient supply for proliferation through lactate-induced secretion of VEGF, resulting in the formation of new vessels. In summary, accumulation of lactate in solid tumors is a pivotal and early event in the development of malignancies. The determination of lactate should enter further clinical trials to confirm its relevance in cancer biology. ©2011 AACR
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                Author and article information

                Contributors
                Journal
                Front Cell Dev Biol
                Front Cell Dev Biol
                Front. Cell Dev. Biol.
                Frontiers in Cell and Developmental Biology
                Frontiers Media S.A.
                2296-634X
                12 May 2022
                2022
                : 10
                : 845293
                Affiliations
                [1] 1 Department of Thoracic Surgery , The Second Hospital of Hebei Medical University , Shijiazhuang, China
                [2] 2 Department of Thoracic Surgery , Hebei Chest Hospital , Shijiazhuang, China
                [3] 3 Clinical Laboratory Center , The Second Hospital of Hebei Medical University , Shijiazhuang, China
                Author notes

                Edited by: Yubing Zhou, First Affiliated Hospital of Zhengzhou University, China

                Reviewed by: Jinhui Liu, Nanjing Medical University, China

                Hao Long, Sun Yat-sen University Cancer Center (SYSUCC), China

                Jianyong Zhang, Zunyi Medical University, China

                Jiaxi Lu, Chongqing University, China

                Jian Wang, Kunming Medical University, China

                *Correspondence: Shujun Li, lishujun2333@ 123456163.com

                This article was submitted to Cancer Cell Biology, a section of the journal Frontiers in Cell and Developmental Biology

                Article
                845293
                10.3389/fcell.2022.845293
                9134121
                35646892
                24d1fb04-c1d7-4420-a411-8fd84e9d6c5a
                Copyright © 2022 Zhao, Li, Dong, Zhang, Guo, Li and Li.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 29 December 2021
                : 11 March 2022
                Categories
                Cell and Developmental Biology
                Original Research

                esophageal squamous cell carcinoma,lactate metabolism,prognostic long noncoding rna,prognostic model,immune microenvironment,chemotherapy response

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