Lung adenocarcinoma (LUAD) remains the most common subtype of lung malignancy. Cuproptosis is a newly identified cell death which could regulate tumor cell proliferation and progression. Long non-coding RNAs (lncRNAs) are key molecules and potential biomarkers for diagnosing and treating various diseases. However, the effects of cuproptosis-related lncRNAs on LUAD are still unclear. In our study, 7 cuproptosis-related lncRNAs were selected to establish a prognostic model using univariate Cox regression analysis, LASSO algorithm, and multivariate analysis. Furthermore, we evaluated AC008764.2, AL022323.1, ELN-AS1, and LINC00578, which were identified as protective lncRNAs, while AL031667.3, AL606489.1, and MIR31HG were identified as risk lncRNAs. The risk score calculated by the prognostic model proved to be an effective independent factor compared with other clinical features by Cox regression analyses [univariate analysis: hazard ratio (HR) = 1.065, 95% confidence interval (CI) = 1.043–1.087, P < 0.001; multivariate analysis: HR = 1.067, 95% CI = 1.044–1.091, P < 0.001]. In addition, both analyses (ROC and nomogram) were used to corroborate the accuracy and reliability of this signature. The correlation between cuproptosis-related lncRNAs and immune microenvironment was elucidated, where 7 immune cells and 8 immune-correlated pathways were found to be differentially expressed between two risk groups. Furthermore, our results also identified and verified the ceRNA of cuproptosis-related lncRNA MIR31HG/miR-193a-3p/TNFRSF21 regulatory axis using bioinformatics tools. MIR31HG was highly expressed in LUAD specimens and some LUAD cell lines. Inhibition of MIR31HG clearly reduced the proliferation, migration, and invasion of the LUAD cells. MIR31HG showed oncogenic features via sponging miR-193a-3p and tended to positively regulate TNFRSF21 expression. In a word, lncRNA MIR31HG acts as an oncogene in LUAD by targeting miR-193a-3p to modulate TNFRSF21, which may be beneficial to the gene therapy of LUAD.

Bladder cancer (BC) is the most common malignancy of the urinary system. Pyroptosis is a host programmed cell death. However, the effects of pyroptosis-related lncRNAs (PRLs) on BC have not yet been completely elucidated. In this study, a prognostic PRLs model and two ceRNA networks were established using sufficient bioinformatics analysis and preliminary RT-qPCR validation in vitro. 6 PRLs were identified to construct a prognostic model. Then, the prognostic model risk score was verified to be an effective independent factor (Training cohort: Univariate analysis: HR = 1.786, 95% Cl = 1.416-2.252, p < 0.001; multivariate analysis: HR = 1.664, 95% Cl = 1.308-2.116, p < 0.001; testing cohort: Univariate analysis: HR = 1.268, 95% Cl = 1.144-1.405, p < 0.001; multivariate analysis: HR = 1.141, 95% Cl = 1.018-1.280, p = 0.024). Moreover, ROC and nomogram were performed to assess the accuracy of this signature (1-year-AUC = 0.764, 3-years-AUC = 0.769, 5-years-AUC = 0.738). Consequently, we evaluated the survival curves of these 6 lncRNAs using Kaplan–Meier survival analysis, demonstrating that MAFG-DT was risk lncRNA, while OCIAD1-AS1, SLC25A25-AS1, SNHG18, PSMB8-AS1 and TRM31-AS1 were protective lncRNAs. We found a strong correlation between PRLs and tumor immune microenvironment by Pearson’s correlation analysis. As for sensitivity of anti-tumor drugs, the high-risk group was more sensitive to Sorafenib, Bicalutamide and Cisplatin, while the low-risk group was more sensitive to AKT.inhibitor.VIII, Salubrinal and Lenalidomide, etc. Meanwhile, we identified lncRNA OCIAD1-AS1/miR-141-3p/GPM6B and lncRNA OCIAD1-AS1/miR-200a-3p/AKAP11 regulatory axes, which may play a potential role in the progression of BC.

Ferroptosis is a mode of programmed cell death that plays a crucial role in tumor biology processes. Although tetrandrine citrate (TetC) has been demonstrated to exert anti-tumor effects, it is still unclear whether TetC inhibits lung adenocarcinoma (LUAD) progression by inducing ferroptosis. The study showcased the inhibitory effect of TetC on the viability and progression of tumor cells, including intracellular iron overload, accumulation of reactive oxygen species (ROS), over-expression of malondial-dehyde (MDA), and depletion of glutathione (GSH). Notably, TetC-induced cell death was clearly reversed by three different ferroptosis-related inhibitors. TetC also induced changes in the mitochondrial morphology of LUAD cells, similar to those observed in typical ferroptosis. Further analysis through Western blot (WB) and Immunofluorescence (IF) assays identified that TetC inhibited the expression and fluorescence intensity of both solute carrier family 7 (SLC7A11) and glutathione peroxidase-4 (GPX4). More importantly, over-expression of SLC7A11 could rescue the TetC-induced ferroptosis. Finally, in our vivo experiment, we discovered that TetC significantly slowed the growth rate of subcutaneous transplanted A549 cells, ultimately proving to be biosafe. In conclusion, our study first identified the mechanism by which TetC-induced ferroptosis in LUAD via SLC7A11/GPX4 signaling.

Background: Although there are numerous treatment methods for NSCLC, long-term survival remains a challenge for patients. The objective of this study is to investigate the role and causal relationship between the target of tetrandrine and non-small cell lung cancer (NSCLC) through transcriptome and single-cell sequencing data, summary-data-based Mendelian Randomization (SMR) and basic experiments. The aim is to provide a new perspective for the treatment of NSCLC. Methods: We obtained the drug target gene of tetrandrine through the drug database, and then used the GSE19188 data set to obtain the NSCLC pathogenic gene, established a drug-disease gene interaction network, screened out the hub drug-disease gene, and performed bioinformatics and tumor cell immune infiltration analysis. Single-cell sequencing data (GSE148071) to determine gene location, SMR to clarify causality and drug experiment verification. Results: 10 drug-disease genes were obtained from 213 drug targets and 529 disease genes. DO/GO/KEGG analysis showed that the above genes were all related to the progression and invasion of NSCLC. Four drug-disease genes were identified from a drug-disease PPI network. These four genes were highly expressed in tumors and positively correlated with plasma cells, T cells, and macrophages. Subsequent single-cell sequencing data confirmed that these four genes were distributed in epithelial cells, and SMR analysis revealed the causal relationship between CCNA2 and CCNB1 and the development of NSCLC. The final molecular docking and drug experiments showed that CCNA2 and CCNB1 are key targets for tetrandrine in the treatment of NSCLC.

Purpose A Mendelian randomization model analysis was employed to investigate the causal direction between CRP (C-reactive protein), Alb(albumin), and BMI(body mass index), as well as their impact on colorectal cancer (CRC) risk and postoperative prognosis. Methods Two-sample Mendelian randomization (MR) was conducted, with BMI set as the exposure variable and CRP, Alb, and CRC as the outcome variables, to determine if CRP and Alb mediate the causal relationship between BMI and CRC. Additionally, this relationship was examined using individual-level data from a retrospective cohort analysis of local cases, which included 374 incident cases of CRC. Results The analysis of the mediating effect of Alb on BMI and CRC risk demonstrated that in European and East Asian populations, BMI had a promoting effect on CRC risk (OR: 1.1903 and 1.3243, p < 0.05). A positive causal relationship was observed between BMI and Alb, but the effect was opposite (OR: 0.8671 and 0.9283, p < 0.05). Alb exhibited a protective effect against CRC (OR: 0.8707 and 0.7157, p < 0.05). The mediating effect of CRP indicated that BMI in European and East Asian populations was associated with an increased risk of CRC (OR: 1.0013 and 1.3243, p < 0.05). BMI and CRP had a positive causal relationship, with consistent effects (OR: 1.4306 and 1.1008, p < 0.05). CRP had a weak, albeit unclear, protective effect on CRC risk (OR: European, 0.9985; p < 0.05, and East Asian, 0.9992; p > 0.05). Relative to the MR results, a high BMI and Alb, along with a low CRP, were observed to be associated with more prolonged overall survival (OS) in the retrospective cohort univariate analysis (HR: 0.89, 0.92, and 1.02, P < 0.05). After adjusting for Alb, the association between BMI and CRC overall survival remained significant (HR: 0.91, P < 0.05). However, upon adjustment for CRP, BMI was not found to be independently associated with overall survival in patients with CRC. Conclusions The findings of this study support that BMI and related factors have a causal association with the risk of colorectal cancer.