Developing hypoxia and lactate metabolism-related molecular subtypes and prognostic signature for clear cell renal cell carcinoma through integrating machine learning

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Abstract

Background

The microenvironment of clear cell renal cell carcinoma (ccRCC) is characterized by hypoxia and increased lactate production. However, the impact of hypoxia and lactate metabolism on ccRCC remains incompletely understood. In this study, a new molecular subtype is developed based on hypoxia-related genes (HRGs) and lactate metabolism-related genes (LMRGs), aiming to create a tool that can predict the survival rate, immune microenvironment status, and responsiveness to treatment of ccRCC patients.

Method

We obtained RNA-seq data and clinical information of patients with ccRCC from TCGA and GEO. HRGs and LMRGs are sourced from the Molecular Signatures Database. Integrating 10 machine learning algorithms and 101 frameworks, we constructed a prognostic model related to hypoxia and lactate metabolism. Its accuracy and reliability are evaluated through constructing prognostic nomograms, drawing ROC curves, and validating with clinical datasets. Additionally, risk subgroups are evaluated based on functional enrichment, tumor mutational burden (TMB), immune cell infiltration degree, and immune checkpoint expression level. Finally, we evaluate the responsiveness of risk subgroups to immunotherapy and determine personalized drugs for specific risk subgroups.

Results

85 valuable prognostic genes were screened out. Functional enrichment analysis shows that the group with high-risk hypoxia and lactate metabolism-related genes scores (HLMRGS) is mainly involved in the activation of immune-related activities, while the low risk HLMRGS group is more active in metabolic and tumor-related pathways. At the same time, differences in the cellular functional states in the tumor microenvironment between the high risk HLMRGS group and the low risk HLMRGS group were observed. Finally, potential drugs for specific risk subgroups were determined.

Conclusion

We have developed a novel prognostic signature that integrates hypoxia and lactate metabolism. It is expected to become an effective tool for prognosis prediction, immunotherapy and personalized medicine of ccRCC.

Supplementary Information

The online version contains supplementary material available at 10.1007/s12672-024-01543-7.

Related collections

Most cited references 60

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Metabolic regulation of gene expression by histone lactylation

Di Zhang, Zhanyun Tang, He Huang … (2019)

The Warburg effect, originally describing augmented lactogenesis in cancer, is associated with diverse cellular processes such as angiogenesis, hypoxia, macrophage polarization, and T-cell activation. This phenomenon is intimately linked with multiple diseases including neoplasia, sepsis, and autoimmune diseases 1,2 . Lactate, a compound generated during Warburg effect, is widely known as an energy source and metabolic byproduct. However, its non-metabolic functions in physiology and disease remain unknown. Here we report lactate-derived histone lysine lactylation as a new epigenetic modification and demonstrate that histone lactylation directly stimulates gene transcription from chromatin. In total, we identify 28 lactylation sites on core histones in human and mouse cells. Hypoxia and bacterial challenges induce production of lactate through glycolysis that in turn serves as precursor for stimulating histone lactylation. Using bacterially exposed M1 macrophages as a model system, we demonstrate that histone lactylation has different temporal dynamics from acetylation. In the late phase of M1 macrophage polarization, elevated histone lactylation induces homeostatic genes involved in wound healing including arginase 1. Collectively, our results suggest the presence of an endogenous “lactate clock” in bacterially challenged M1 macrophages that turns on gene expression to promote homeostasis. Histone lactylation thus represents a new avenue for understanding the functions of lactate and its role in diverse pathophysiological conditions, including infection and cancer.

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Role of hypoxia in cancer therapy by regulating the tumor microenvironment

Xinming Jing, Fengming Yang, Chuchu Shao … (2019)

Aim Clinical resistance is a complex phenomenon in major human cancers involving multifactorial mechanisms, and hypoxia is one of the key components that affect the cellular expression program and lead to therapy resistance. The present study aimed to summarize the role of hypoxia in cancer therapy by regulating the tumor microenvironment (TME) and to highlight the potential of hypoxia-targeted therapy. Methods Relevant published studies were retrieved from PubMed, Web of Science, and Embase using keywords such as hypoxia, cancer therapy, resistance, TME, cancer, apoptosis, DNA damage, autophagy, p53, and other similar terms. Results Recent studies have shown that hypoxia is associated with poor prognosis in patients by regulating the TME. It confers resistance to conventional therapies through a number of signaling pathways in apoptosis, autophagy, DNA damage, mitochondrial activity, p53, and drug efflux. Conclusion Hypoxia targeting might be relevant to overcome hypoxia-associated resistance in cancer treatment.

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Hypoxic microenvironment in cancer: molecular mechanisms and therapeutic interventions

Zhou Chen, Fangfang Han, Yan Du … (2023)

Having a hypoxic microenvironment is a common and salient feature of most solid tumors. Hypoxia has a profound effect on the biological behavior and malignant phenotype of cancer cells, mediates the effects of cancer chemotherapy, radiotherapy, and immunotherapy through complex mechanisms, and is closely associated with poor prognosis in various cancer patients. Accumulating studies have demonstrated that through normalization of the tumor vasculature, nanoparticle carriers and biocarriers can effectively increase the oxygen concentration in the tumor microenvironment, improve drug delivery and the efficacy of radiotherapy. They also increase infiltration of innate and adaptive anti-tumor immune cells to enhance the efficacy of immunotherapy. Furthermore, drugs targeting key genes associated with hypoxia, including hypoxia tracers, hypoxia-activated prodrugs, and drugs targeting hypoxia-inducible factors and downstream targets, can be used for visualization and quantitative analysis of tumor hypoxia and antitumor activity. However, the relationship between hypoxia and cancer is an area of research that requires further exploration. Here, we investigated the potential factors in the development of hypoxia in cancer, changes in signaling pathways that occur in cancer cells to adapt to hypoxic environments, the mechanisms of hypoxia-induced cancer immune tolerance, chemotherapeutic tolerance, and enhanced radiation tolerance, as well as the insights and applications of hypoxia in cancer therapy.

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Author and article information

Contributors

Sheng Luo: luosheng1027@163.com

Benzheng Zhou: zbz19830125@126.com

Journal

Journal ID (nlm-ta): Discov Oncol

Journal ID (iso-abbrev): Discov Oncol

Title: Discover Oncology

Publisher: Springer US (New York )

ISSN (Electronic): 2730-6011

Publication date (Electronic): 13 November 2024

Publication date PMC-release: 13 November 2024

Publication date Collection: December 2024

Volume: 15

Electronic Location Identifier: 653

Affiliations

[1 ]Department of Urology, People’s Hospital, Hubei University of Medicine, ( https://ror.org/01dr2b756) Xiangyang No. 1, Xiangyang, 441000 China

[2 ]Medical Record Statistics Department, People’s Hospital, Hubei University of Medicine, ( https://ror.org/01dr2b756) Xiangyang No. 1, Xiangyang, 441000 China

Article

Publisher ID: 1543

DOI: 10.1007/s12672-024-01543-7

PMC ID: 11561225

PubMed ID: 39538070

SO-VID: e5168617-cedb-405f-a4b5-6906523e4af4

License:

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

History

Date received : 16 September 2024

Date accepted : 6 November 2024

Funding

Funded by: Innovative Research Program of Xiangyang No.1 People's Hospital

Award ID: XYY2023SD15

Award Recipient : Jinhui Liu

Funded by: Nature Science Foundation of Hubei Province

Award ID: 2024AFB810

Award Recipient : Benzheng Zhou

Custom metadata

Keywords: ccrcc,hlmrgs,prognosis,immunotherapy

Data availability:

Keywords: ccrcc, hlmrgs, prognosis, immunotherapy