Comprehensive analysis identifies DNA damage repair-related gene HCLS1 associated with good prognosis in lung adenocarcinoma.

Background: Lung cancer is the leading cause of cancer-associated mortality. Lung adenocarcinoma (LUAD) amounts to more than 40% of all lung malignancies. Therefore, developing clinically useful biomarkers for this disease is critical. DNA damage repair (DDR) is a complicated signal transduction process that ensures genomic stability. DDR should be comprehensively analyzed to elucidate their clinical significance and tumor immune microenvironment interactions. Methods: In this study, DDR-related genes (DRGs) were selected to investigate their prognostic impact on LUAD. A regression-based prognostic model was established based on The Cancer Genome Atlas (TCGA)-LUAD cohort and three external Gene Expression Omnibus (GEO) validation cohorts (GSE31210, GSE68465, and GSE72094). The robust, established model could independently predict the clinical outcomes in patients. Then, the prognostic performance of risk profiles was assessed using a time-dependent receiver operating characteristic (ROC) curve, Cox regression, nomogram, and Kaplan-Meier analyses. Furthermore, the potential biological functions and infiltration status of DRGs in LUAD were investigated with ESTIMATE and CIBERSORT. Finally, the effects of HCLS1 on the clinical features, prognosis, biological function, immune infiltration, and treatment response in LUAD were systematically analyzed. Results: Eleven DRGs were constructed to categorize patients into high- and low-risk groups. The risk score was an independent predictor of overall survival (OS). HCLS1 expression was downregulated in LUAD samples and linked with clinicopathological features. Multivariate Cox regression analysis using the Kaplan-Meier plotter revealed that low HCLS1 expression was independently associated with poor OS. Moreover, the HCLS1 high-expression group had higher immune-related gene expression and ESTIMATE scores. It was positively correlated with the infiltration of M1 macrophages, activated memory CD4 T cells, CD8 T cells, memory B cells, resting dendritic cells, and memory CD4 T cells, Tregs, and neutrophils. Conclusions: A new classification system was developed for LUAD according to DDR characteristics. This stratification has important clinical values, reliable prognosis, and immunotherapy in patients with LUAD. Moreover, HCLS1 is a potential prognostic biomarker of LUAD that correlates with the extent of immune cell infiltration in the tumor microenvironment (TME).

Comprehensive characterization of MUC16 mutations in lung adenocarcinoma for immunotherapies and prognosis: An observational study.

Lung adenocarcinoma (LUAD) is a non-small-cell lung cancer and is the leading cause of cancer-related deaths worldwide. Immunotherapy is a promising candidate for LUAD, and tumor mutation burden (TMB) could be a new biomarker to monitor the response of cancer patients to immunotherapy. It is known that the mucin 16 (MUC16) mutation is the most common and affects the progression and prognosis of several cancers. However, whether MUC16 mutations are associated with TMB and tumor-infiltrating immune cells in LUAD is not fully elucidated. All the data were obtained from the cancer genome atlas database to assess the prognostic value and potential mechanism of MUC16 in LUAD. An immune prognostic model (IPM) was developed based on immune-related genes that could be differentially expressed between MUC16MUT and MUC16WT LUAD patients. Later, the IPM effect on the prognosis and immunotherapy of LUAD was comprehensively evaluated. MUC16 was frequently mutated in LUAD, with a mutational frequency of 43.4%, significantly associated with higher TMB and better clinical prognosis. Based on 436 patients with LUAD, an IPM was established and validated to differentiate patients with a low or high risk of poor survival. The univariate and multivariate Cox regression analyses demonstrated that the IPM was an independent prognostic indicator for LUAD patients. Elevated expressions of PD-L1, LAG3, PDCD1, and SIGLEC15, and most of the T-effector and interferon-γ gene signatures, were depicted in the high-risk group. Moreover, the nomogram using the IPM and clinical prognostic factors also predicted the overall survival and clinical utility. Our project developed a robust risk signature depending on the MUC16 status and provided novel insights for individualized treatment options for LUAD patients.

Discovery of rafoxanide as a novel agent for the treatment of non-small cell lung cancer.

Non-small cell lung cancer (NSCLC), which accounts for approximately 85% of all lung cancer cases, is associated with a poor outcome. Rafoxanide is an anthelmintic drug that inhibits tumor growth in certain malignancies. However, its impact on NSCLC remains unknown. In this study, we examined the effect of rafoxanide on NSCLC and dissected the underlying mechanism. The results showed that rafoxanide significantly inhibited the growth, invasion, and migration of NSCLC cells. Besides, rafoxanide can induce NSCLC cell apoptosis and cell cycle arrest in a dose-dependent manner. RNA-seq analysis revealed that genes associated with endoplasmic reticulum stress (ER) stress responses were activated. Mechanistically, we found Rafoxanide can induce ER stress and activate the unfolded protein response (UPR). Apoptosis was activated by excessive ER stress, and autophagy was activated to partially alleviate ER stress. In vivo, we found that rafoxanide inhibited the growth of A549 and H1299 xenograft mouse models without severe side effects. Collectively, the present study indicates that rafoxanide may be a candidate drug for the treatment of NSCLC.