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Published on: October 21, 2022
Identification and validation of the mitochondrial function related hub genes by unsupervised machine learning and
Xing Jin1, Huan Zhang1, Qihai Sui1
1Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, No. 180, Fenglin Road, Shanghai, 200032, China.
Background:
The mitochondrion and its associated genes were heavily implicated in developing and therapy tumors as the primary cellular organelle in charge of metabolic reprogramming and ferroptosis. Our work focuses on discovering new potential targets while analyzing the multi-omics data of mitochondria-related genes in lung adenocarcinoma (LUAD).
Methods:
The Cancer Genome Atlas (TCGA) database provided multi-omics data for LUAD patients. Based on the expression profile of the genes associated with mitochondria, the patients were grouped by the unsupervised clustering method. R was used to explore the differential expressed protein-code gene, miRNA, and lncRNA, as well as their enriched functions and ceRNA networks. Additionally, the discrepancy between immune infiltration and genetic variation was comprehensively characterized. Our clinical samples and in vitro experiments investigated the hub gene determined by LASSO and batch analysis.
Results:
Two clusters are distinguished using unsupervised consensus clustering based on mitochondrial heterogeneity. The integrated analysis emphasized that patients in cluster B had a worse prognosis, higher mutation frequencies, and less immune cell infiltration. The hub genes DARS2 and COX5B are identified by further analysis using LASSO penalization. In vitro experiments indicated that DARS2 and COX5B knockdown inhibited tumor cell proliferation. The specimen of our hospital cohort conducted the immunohistochemistry analysis and validated that DARS2 and COX5B's expression was significantly higher in the tumor than in adjacent normal tissue and correlated to LUAD patients' prognosis.
Conclusion:
Our observations implied that LUAD patients' tumors had distinct mitochondrial function heterogeneity with different clinical and molecular characteristics. DARS2 and COX5B might be critical genes involved in mitochondrial alterations and potential therapeutic targets.
Insights
Mitochondrial gene analysis in lung adenocarcinoma (LUAD) revealed two patient clusters with distinct prognoses. Key genes DARS2 and COX5B were identified as potential therapeutic targets due to their role in tumor growth.
Area of Science:
- Genomics and Molecular Biology
- Cancer Research
- Mitochondrial Biology
Background:
- Mitochondria and their genes are crucial in cancer metabolic reprogramming and ferroptosis.
- Understanding mitochondrial heterogeneity is key for developing new therapeutic strategies in lung adenocarcinoma (LUAD).
Purpose of the Study:
- To analyze multi-omics data of mitochondria-related genes in LUAD.
- To identify novel therapeutic targets by exploring mitochondrial heterogeneity and its clinical implications.
Main Methods:
- Utilized multi-omics data from The Cancer Genome Atlas (TCGA) for LUAD patients.
- Employed unsupervised clustering to group patients based on mitochondrial gene expression.
- Performed differential expression analysis, functional enrichment, ceRNA network construction, and immune infiltration analysis using R; validated hub genes (DARS2, COX5B) via LASSO, in vitro experiments, and immunohistochemistry.
Main Results:
- Identified two distinct patient clusters based on mitochondrial heterogeneity, with cluster B showing poorer prognosis, higher mutation rates, and reduced immune infiltration.
- Discovered DARS2 and COX5B as key hub genes; their knockdown inhibited LUAD cell proliferation.
- Validated elevated DARS2 and COX5B expression in tumor tissues compared to normal tissues, correlating with patient prognosis.
Conclusions:
- LUAD tumors exhibit significant mitochondrial function heterogeneity, linked to distinct clinical and molecular features.
- DARS2 and COX5B are identified as critical genes in mitochondrial alterations and represent promising therapeutic targets for LUAD.
