Gemcitabine (GEM), an antimetabolite that terminates DNA synthesis, is commonly used in the treatment of cancers including lung adenocarcinoma (LUAD). However, downregulation of sensitivity limits the therapeutic effect. Ferroptosis as the new form of regulated cell death has been shown to have great potential for cancer treatment with chemoresistance. Here, three genes with both ferroptosis and GEM-response-associated features were screened from RNA sequencing and public data for constructing an independent risk model. LUAD patients with different risk scores had differences in mutational landscape, gene enrichment pathways, and drug sensitivity. By Cell Counting Kit-8 assay, flow cytometry, and colony forming assay, we demonstrate that GEM and ferroptosis inducer (FIN) imidazole Ketone Erastin had a synergistic combined anti-proliferative effect on LUAD cells and knockdown of KIF20A (the core gene of our model) further enhanced cell death in vitro by inducing ferroptosis. In conclusion, we identified a link between ferroptosis and GEM response in LUAD cells and developed a robust signature that can effectively classify LUAD patients into subgroups with different overall survival. For LUAD, the combined treatment modality of GEM and FIN is potentially effective and KIF20A may be a new therapeutic target.
GTPase-activating protein (GAP) is a negative regulator of GTPase protein that is thought to promote the conversion of the active GTPase-GTP form to the GTPase-GDP form. Based on its ability to regulate GTPase proteins and other domains, GAPs are directly or indirectly involved in various cell requirement processes. We reviewed the existing evidence of GAPs regulating regulated cell death (RCD), mainly apoptosis and autophagy, as well as some novel RCDs, with particular attention to their association in diseases, especially cancer. We also considered that GAPs could affect tumor immunity and attempted to link GAPs, RCD and tumor immunity. A deeper understanding of the GAPs for regulating these processes could lead to the discovery of new therapeutic targets to avoid pathologic cell loss or to mediate cancer cell death.
Colon adenocarcinoma (COAD) is one of the most common malignancies, and its metastatic lesions are the leading cause of death in COAD patients. PANoptosis is a recently identified pathway for programmed cell death implicated in developing COAD. Long non-coding RNAs (lncRNAs) are key regulators of cancer occurrence and progress. Although their function has captured much attention in COAD, the relationship between COAD metastasis-associated lncRNA expression and PANoptosis remains elusive. Therefore, this study aimed to explore the potential regulatory roles of metastasis- and PANoptosis-associated lncRNAs in COAD. Nine lncRNAs associated with metastasis and PANoptosis in COAD were identified from The Cancer Genome Atlas (TCGA) and GEO databases. Their functions were analyzed by multiple bioinformatics methods, and the lncRNA-miRNA-mRNA network was constructed. Multivariate Cox analysis identified one lncRNA (SNHG7) significantly related to COAD prognosis. Subsequent analyses showed its expression correlated with tumor stage and lymph node metastasis. Moreover, drug sensitivity analysis and in vitro experiments suggest that lncRNA SNHG7 contributes to drug resistance in COAD. In summary, lncRNA SNHG7 is a potential target for diagnosing and treating COAD and plays a crucial role in regulating apoptosis, metastasis, and drug resistance in COAD.
Background: Osimertinib-based therapy effectively improves the prognosis of lung adenocarcinoma (LUAD) patients with epidermal growth factor receptor mutations. However, patients will have cancer progression after approximately one year due to the occurrence of drug resistance. Extensive evidence has revealed that lipid metabolism and tumor-associated macrophage (TAM) are associated with drug resistance, which deserves further exploration. Methods: An osimertinib resistance index (ORi) was built to investigate the link between lipid metabolism and osimertinib resistance. The ORi was constructed and validated using TCGA and GEO data, and the relationship between ORi and immune infiltration was discussed. Weighted gene co-expression network analysis based on the M2/M1 macrophage ratio determined the hub gene TIAM2 and the biological function of TIAM2 in LUAD was verified in vitro. Results: ORi based on nine lipid metabolism-related genes was successfully constructed, which could accurately reflect the resistance of LUAD patients to osimertinib, predict the prognosis, and correlate with M2-like TAM. Additionally, TIAM2 was found to increase osimertinib tolerance, enhance cell motility, and promote M2-like TAM polarization in LUAD. Conclusions: The lipid metabolism gene is strongly connected with osimertinib resistance. TIAM2 contributes to osimertinib resistance, enhances cell motility, and induces M2-like TAM polarization in LUAD.
Erlotinib is a highly specific and reversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), but resistance inevitably develops as the disease progresses. Erlotinib resistance and cancer stem cells (CSCs) are poor factors hindering the prognosis of patients with lung adenocarcinoma (LUAD). Although studies have shown that erlotinib resistance and CSCs can jointly promote cancer development, the mechanism is currently unclear. Here, we investigated the potential biomarker and molecular mechanism of erlotinib resistance and cancer stemness in LUAD. An erlotinib resistance model based on four genes was constructed from The Cancer Genome Atlas (TCGA), the GEO database, the Cancer Cell Line Encyclopedia (CCLE), and the Genomics of Drug Sensitivity in Cancer (GDSC). Through multiple bioinformatic analyses, NCAPG2 was identified as a key gene for erlotinib resistance and stemness in LUAD. Further in vitro experiments demonstrated that NCAPG2 maintains stemness and contributes to erlotinib resistance in LUAD. In summary, NCAPG2 plays a vital role in stemness and erlotinib resistance in LUAD.
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