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Published on: November 19, 2019
A palmitoylation-related prognostic risk scoring model and tumor microenvironment characterization in lung
Haixiao Liu1, Yue Hu1, Lingyun Wang2
1Second Clinic, Guang' an men Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China.
Background:
Lung adenocarcinoma (LUAD) is the predominant pathological subtype of non-small cell lung cancer. Its considerable tumor heterogeneity and drug resistance present major clinical obstacles, resulting in unfavorable patient outcomes. Protein palmitoylation is known to be a key factor in tumorigenesis; however, its cell-specific expression patterns and prognostic value in LUAD remain incompletely characterized.
Methods:
Using two independent datasets, TCGA-LUAD and GSE68465, and scRNA-seq data from 10 LUAD samples, we analyzed the expression of palmitoylation-related genes. Through single-cell clustering, CNV analysis, and palmitoylation activity scoring, malignant epithelial cells were identified. 10 machine learning algorithms were applied to construct prognostic models based on differentially expressed genes. RT-qPCR was used to detect mRNA expression of prognostic marker genes in clinical samples. In vitro experiments validated SEC61G's role in regulating drug sensitivity.
Results:
A subset of malignant epithelial cells with high palmitoylation activity was identified. A 5-gene signature (UBE2S, SEC61G, CCT6A, GAPDH, HLA-DRA) was established by the integrated CoxBoost+SuperPC method, showing robust predictive efficacy in both GSE68465 and TCGA-LUAD. High-risk samples carried higher mutation burden, greater genomic heterogeneity, and a stronger tumor immunosuppressive microenvironment than the low-risk group. Clinical sample testing revealed upregulation of UBE2S, SEC61G, CCT6A, and GAPDH in LUAD patients and downregulation of HLA-DRA. SEC61G expression inversely correlated with AZD3759 sensitivity. In vitro, SEC61G knockdown or AZD3759 alone suppressed LUAD proliferation and induced apoptosis; no synergy was observed with combination therapy, indicating that SEC61G modulates AZD3759 sensitivity in LUAD cells.
Conclusion:
Our study comprehensively reveals the cellular heterogeneity of palmitoylation, establishes a robust palmitoylation-related prognostic model, and identifies SEC61G as a promising therapeutic target in LUAD, offering a novel perspective for LUAD precision stratification and treatment studies.
