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LDHA, BIK, and CNIH4 Are Diagnostic Markers of Endoplasmic Reticulum Stress in Lung Cancer Comorbid With Sepsis:
Yifeng Pan1,2, Xiaoru Liu1,2, Jiawen Wang1,2
1The Eighth Clinical Medical College of Guangzhou University of Chinese Medicine, Foshan, 528000, Guangdong, China.
Background:
Lung cancer is intricately associated with the onset of sepsis. Endoplasmic reticulum (ER) stress (ERS) is a cellular stress response to aberrant protein folding in the ER, closely associated with the cellular immune response. Currently, numerous research have elucidated the correlation between ERS and lung cancer, as well as sepsis. The mechanism of ERS in lung cancer comorbid with sepsis requires more investigation.
Objectives:
This study aimed to investigate the interacting mechanisms between ERS and the immune response, explore prospective ERS-related diagnostic biomarkers for lung cancer comorbid with sepsis, and elucidate their underlying pathological roles.
Methods:
Datasets for lung cancer and sepsis were sourced from the Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) and weighted gene coexpression network analysis (WGCNA) modules were intersected with ERS-related genes. Protein-protein interaction (PPI) and enrichment analyses were conducted. A genetic diagnostic model was developed using exhaustive machine learning algorithms, with accuracy assessed by receiver operating characteristic (ROC) curves and confusion matrices. Hub genes (area under the curve [AUC] ≥ 0.7) were analyzed for immune cell infiltration and cross-validated using single-cell RNA sequencing datasets. Crucially, the expression and functional roles of the hub genes were experimentally validated by western blot in clinical tissue cohorts (adjacent normal, lung cancer, and lung cancer with sepsis) and via wound healing and Transwell assays in PC9 lung cancer cells. Finally, prospective therapeutic agents were identified through molecular docking.
Results:
Machine learning identified lactate dehydrogenase A (LDHA), Bcl-2 interacting killer (BIK), and cornichon homolog 4 (CNIH4) as robust diagnostic biomarkers. Western blot analysis confirmed that the protein expression levels of LDHA, BIK, and CNIH4 were significantly upregulated in lung cancer and further elevated in the lung cancer comorbid with sepsis group. In vitro functional assays demonstrated that silencing these genes significantly inhibited the migration and invasion capabilities of PC9 cells. Single-cell analysis revealed that these markers exhibit cell-type-specific expression in malignant cells and regulate immune dysregulation, particularly correlating with the functions of plasma cells and monocytes. Molecular docking indicated that tetrahydro-NAD and amikacin are promising therapeutic candidates.
Conclusions:
We identified and experimentally validated LDHA, BIK, and CNIH4 as specific ERS-associated diagnostic biomarkers for lung cancer comorbid with sepsis. These markers drive tumor progression and modulate cellular immune responses, providing novel insights and therapeutic targets for this comorbidity.
