Cancer letters最新文献

We intend to explore the capability of ChatGPT 4.0 in generating innovative research hypotheses to address key challenges in the early diagnosis of colorectal cancer (CRC). We asked ChatGPT to generate hypotheses focusing on three main challenges: improving screening accuracy, overcoming technological limitations, and identifying reliable biomarkers. The hypotheses were evaluated for novelty. The experimental plans provided by ChatGPT for selected hypotheses were assessed for completion and feasibility. As a result, ChatGPT generated a total of 65 hypotheses. ChatGPT rated all 65 hypotheses, with 25 hypotheses receiving the highest rating (5) and 40 hypotheses receiving a rating of 4 or lower. The research team evaluated a total of 65 hypotheses, assigning them the following grades: hypotheses were rated as excellent (Grade 5), 16 were deemed suitable (Grade 4), 31 were classified as satisfactory (Grade 3), 12 were identified as needing Improvement (Grade 2), and one was considered poor (Grade 1). Additionally, the study determined that 17 of the generated hypotheses had corresponding publications. Out of the three experimental plans assessed, one was rated excellent (5) for feasibility, while the others received good (4) and moderate (3) ratings. Predicted outcomes and alternative approaches were rated as good, with some areas requiring further improvement. Our data demonstrate that AI has the potential to revolutionize hypothesis generation in medical research, though further validation through experimental and clinical studies is needed. This study suggests that while AI can generate novel hypotheses, human expertise is essential for evaluating their practicality and relevance in scientific research.

Non-small cell lung cancer (NSCLC) is acknowledged as the primary subtype of lung cancer. The Warburg effect, marked by elevated glucose consumption and lactate fermentation, is a prevalent characteristic of NSCLC. The mechanisms by which circRNA mediates the regulation of the Warburg effect and immune evasion in NSCLC remain unclear.. This study found an elevated circRNA, circRUNX1, whiche promotes glycolysis and lactate generation, resulting in the infiltration of regulatory T cell (Treg) in NSCLC. circRUNX1 acts as a miR-145 sponge, inhibiting its negative regulation of the target gene HK2, therefore facilitating glycolysis and lactate generation. The accumulation of lactic acid in the tumor microenvironment promotes Treg cell proliferation and aids immune evasion. Functionally, the suppression of circRUNX1 significantly impedes tumor development both in vitro and in vivo. These findings collectively clarity a previously unexamined mechanism linking the circRUNX1/miR-145/HK2 axis in regulation of the Warburg effect and immune evasion in NSCLC.

The Hedgehog Signaling Pathway plays an important role in cancer development and chemotherapy resistance. However, whether the pathway functions depend on the metabolic reprogramming of cancer cells has not been well studied. In this study, we found that the expression level of Gli1, a key transcription factor downstream of the Hedgehog Signaling Pathway, is significantly increased in patients with pancreatic cancer resistant to gemcitabine neoadjuvant chemotherapy. Through metabolomics analysis, we confirmed that Gli1 can promote the transformation of cancer cells from a glycolytic-dominated metabolic pattern to a unique metabolic pattern called "Pentose Phosphate Recycling". Transcriptome sequencing and in vitro experiments suggest that Gli1 promotes pentose phosphate recycling through transcriptional activation of key enzymes Phosphogluconate dehydrogenase (PGD) and Transketolase (TKT). The identified metabolic rerouting in oxidative and non-oxidative pentose phosphate pathway has important physiological roles in maximizing NADPH reduction and nucleotide synthesis. Therefore, the pentose phosphate cycle driven by Gli1 can resist gemcitabine-induced DNA damage by promoting pyrimidine synthesis and resist gemcitabine-induced ferroptosis by scavenging lipid Reactive Oxygen Species (Lipid ROS). Combining the Gli1 inhibitor GANT21 with gemcitabine exerts a maximal tumour suppressor effect by simultaneously promoting DNA damage and ferroptosis. Collectively, these results reveal that Gli1 drives chemotherapy resistance in cancer cells by inducing metabolic reprogramming, providing a novel target and therapeutic strategy for reversing chemotherapy resistance.

Successful immune checkpoint inhibitor (ICI) therapy occurs in only a fraction of melanoma patients, and yet all patients are susceptible to potentially serious ICI-related side-effects. No current biomarkers robustly predict ICI treatment response in melanoma patients. In this study we sought to identify methylome and transcriptome markers which have the potential to predict immunotherapy response in melanoma patients ahead of treatment with anti-PD1 ICI monotherapy. Using Infinium MethylationEPIC microarrays, we analysed DNA methylation profiles of >850,000 CpG sites in pre-treatment melanoma tissues from patients administered anti-PD-1 monotherapy as first-line treatment. In addition, we analysed transcriptomes using RNA-seq. DNA methylation and gene expression data were then statistically compared to patient response to anti-PD1 therapy. We identified 2,579 DNA hypomethylation and hypermethylation alterations correlating with melanoma response to anti-PD1 therapy. An integrative analysis of DNA methylomes and transcriptomes identified a subset of 35 loci, 13 of which were significantly differentially methylated in both initial discovery and external validation datasets. Functional enrichment analysis of hypomethylated sites (p-value < 0.05) in non-responders was associated with "Formation of the cornified envelope", "Regulation of epithelial cell proliferation", and "Purine-containing compound metabolic process". We have identified novel integrated DNA methylation and gene expression markers, which correlate with anti-PD1 treatment response in melanoma patients. These findings suggest a relationship between tumour-associated genomic DNA methylation, gene expression patterns, and anti-PD1 ICI immunotherapy response in melanoma patients.

Both Mdm2 and Mdm4 inhibit p53 activity by masking of its transcriptional activation domain. In addition, Mdm2 functions as an E3 ubiquitin ligase, targeting p53 for degradation. The Mdm4 amino terminus binds wild type and mutant p53 while its RING domain, which lacks E3 ligase activity, is required for heterodimerization with Mdm2. To determine how these domains of Mdm4 regulate p53, we generated mouse models with either a deletion of the Mdm4 RING domain (Mdm4^ΔR) or all of Mdm4 (Mdm4^─) on a hypomorphic (p53^neo) background. Mdm4^ΔR mice exhibited elevated p53 levels and activity, albeit to a lesser extent than mice with complete Mdm4 loss, indicating that the amino terminus of Mdm4 contributes to p53 inhibition. Moreover, in the absence of Mdm2, neither the deletion of the Mdm4 RING domain nor the complete loss of Mdm4 further increased p53 protein levels on a mutant p53 background, indicating that Mdm4 modulates Mdm2 in its regulation of p53 stability. Collectively, our findings suggest that Mdm4 contributes to p53 inhibition by modulating Mdm2 activity via both its amino terminus and RING domains.