Background: Globally, pancreatic adenocarcinoma (PAAD) is a common and highly devastating gastrointestinal malignancy that seriously threatens human health. Pyroptosis refers to an emerging form of programmed cell death that has been discovered in recent years, and studies have demonstrated that long non-coding RNA (lncRNA) may act as a moderator in the pyroptosis process of cancer cells. However, relevant explorations about lncRNAs and pyroptosis are still insufficient in PAAD. Therefore, our research is designed to make a comprehensive analysis of the potential values of pyroptosis-related lncRNAs in PAAD.Methods: By integrating the RNA-sequencing, somatic mutation, and copy number variation (CNV) datasets, as well as the clinicopathological features, we established and validated a risk signature based on pyroptosis-related lncRNAs, and comprehensively analyzed its clinical significance and the potential connection with the tumor immune microenvironment (TIME).Consequences: The genetic variation landscape displayed that the somatic mutations were rare while CNV changes were general and mainly concentrated on copy number amplification of these 52 pyroptosis-related genes. Subsequently, a risk signature consisting of 10 lncRNAs (TRAF3IP2-AS1, LINC00519, LINC01133, LINC02251, AC005332.6, AL590787.1, AC090114.2, TRPC7-AS1, MIR223HG, and MIR3142HG) was constructed and patients were divided into different subgroups according to the median risk score; patients with high-risk scores presented worse outcomes compared to those with low-risk scores in the training, testing, and entire cohorts. Furthermore, patients at low-risk scores possessed a higher infiltration abundance of immune cells compared with high-risk patients, which was consistent with the expression levels of lncRNAs between the high/low-risk groups. Drug sensitivity analysis showed that low-risk scores were related to anti-cancer agents like AICAR and Axitinib, whereas high-risk scores were connected with certain drugs such as AUY922. These results demonstrated that our risk signature could be used for prognosis prediction; additionally, it was also related to the TIME that might act as a potential indicator to instruct immunotherapeutic strategies.Conclusion: This work explored the significance of the risk model constructed by pyroptosis-related lncRNAs in prognosis prediction and its internal link with the immune microenvironment of PAAD. The results are expected to assist in the diagnosis, prognostic assessment, and management of patients with PAAD.
As a new type of post-translational modification (PTM), lysine 2-hydroxyisobutyrylation (Khib) was firstly identified in histones and functioned as a regulator of transactivation in mammals. However, the role of Khib proteins remains to be investigated. Here, we firstly identified 10,367 Khib sites on 2,325 modified proteins in seven patients with pancreatic cancer by applying liquid chromatography with tandem mass spectrometry (LC-MS/MS) qualitative proteomics techniques. Among them, 27 Khib-modified sites were identified in histones. Bioinformatics analysis revealed that the Khib-modified proteins were mainly distributed in the cytoplasm and enhanced in metabolic pathways, including glycolysis/gluconeogenesis, the tricarboxylic acid cycle (TCA cycle), and fatty acid degradation. In an overlapping comparison of lysine 2-hydroxyisobutyrylation, succinylation, and acetylation in humans, 105 proteins with 80 sites were modified by all three PTMs, suggesting there may be a complex network among the different modified proteins and sites. Furthermore, MG149, which was identified as a Tip60 inhibitor, significantly decreased the total Khib modification level in pancreatic cancer (PC) and strongly suppressed PC’s proliferation, migration, and invasion ability. Overall, our study is the first profiling of lysine 2-hydroxyisobutyrylome and provides a new database for better investigating Khib in PC.
The five-year survival rate of hepatocellular carcinoma (HCC) remains unsatisfactory. This reflects, in part, the paucity of effective methods that allow the target-specific diagnosis and therapy of HCC. Here, we report a strategy based on engineered human serum albumin (HSA) that permits the HCC-targeted delivery of diagnostic and therapeutic agents. Covalent cysteine conjugation combined with the exploitation of host−guest chemistry was used to effect the orthogonal functionalization of HSA with two functionally independent peptides. One of these peptides targets glypican-3 (GPC-3), an HCC-specific biomarker, while the second reduces macrophage phagocytosis through immune-checkpoint stimulation. This orthogonally engineered HSA proved effective for the GPC-3-targeted delivery of near-infrared fluorescent and phototherapeutic agents, thus permitting target-specific optical visualization and photodynamic ablation of HCC in vivo. This study thus offers new insights into specificity-enhanced fluorescence-guided surgery and phototherapy of HCC through the orthogonal engineering of biocompatible proteins.
Background: Cuproptosis and necroptosis represent two distinct programmed cell death modalities implicated in neoplastic progression; however, the role of combining cuproptosis and necroptosis in hepatocellular carcinoma (HCC) remains to be elucidated.Methods: A total of 29 cuproptosis-related necroptosis genes (CRNGs) were identified, followed by an extensive analysis of their mutational characteristics, expression patterns, prognostic implications, and associations with the tumor microenvironment (TME). Subsequently, a CRNG subtype-related signature was developed, and its value of prognostic prediction, TME, and therapeutic responses in HCC were thoroughly investigated. Last, quantitative real-time PCR and Western blotting were employed for investigating the signature gene expression in 15 paired clinical tissue samples.Results: Two distinct CRNG subtypes were discerned, demonstrating associations between CRNG expression patterns, clinicopathological attributes, prognosis, and the TME. A CRNG subtype-related prognostic signature, subjected to external validation, was constructed, serving as an independent prognostic factor for HCC patients, indicating poor prognosis for high-risk individuals. Concurrently, the signature’s correlations with an immune-suppressive TME, mutational features, stemness properties, immune checkpoint genes, chemoresistance-associated genes, and drug sensitivity were observed, signifying its utility in predicting treatment responses. Subsequently, highly accurate and clinically convenient nomograms were developed, and the signature genes were validated via quantitative real-time PCR and Western blotting, further substantiating the stability and dependability of the CRNG subtype-related prognostic signature.Conclusion: Overall, this investigation presented an extensive panorama of CRNGs and developed the CRNG subtype-related prognostic signature, which holds potential for implementation in personalized treatment strategies and prognostic forecasting for HCC patients.
Objective Hepatocellular carcinoma (HCC) is an extremely deadly cancer with few effective therapeutic options available. Ceramide synthases (CERS), a family of enzymes that regulate sphingolipid metabolism, have been suggested to play a role in cancer initiation and progression. Whereas the specific functions of CERS in HCC pathogenesis have not yet been fully elucidated. Methods The TCGA and ICGC databases were employed to analyze the expression levels and clinical relevance of CERS genes in HCC. Functional enrichment analyses were performed to identify pathways and functions associated with CERS5. The correlation between CERS5 and the tumor immune microenvironment was investigated. The mutation landscape and immunotherapy efficacy were evaluated. Functional experiments in vitro were conducted to assess CERS5’s impact on HCC cell proliferation and invasion. Results Aberrant expression of the CERS family was detected not only in HCC but also in other cancers, and has been linked to both overall survival and disease-free survival. Among the CERS family members, CERS5 was identified as the only prognosis-related gene, with up-regulated in HCC validated in the ICGC database and clinical tissue samples. Higher expression levels of CERS5 were associated with a poorer prognosis as well as an advanced pathologic stage and grade, as confirmed by the TCGA and ICGC databases. Besides, a prognostic nomogram combining pathologic stage, tumor status, and the expression of CERS5 was established and further validated, which suggested a favorable value for prognosis prediction. Functional enrichment analyses showed that the overexpression of CERS5 resulted in enriched pathways associated with carcinogenesis, drug metabolism, the PI3K/AKT/mTOR signaling pathway, and cancer immune-related pathways. In addition, the overexpression of CERS5 correlated positively with the expression of genes associated with immunogenic cell death modulators and immune checkpoints, levels of immune cell infiltration, and immunotherapy response, which was featured in an immunologically “hot” environment in the tumor microenvironment. Finally, the functional experiments showed that CERS5 knockdown has been shown to inhibit the growth and invasion of hepatocellular carcinoma, potentially through targeting the PI3K/AKT/mTOR signaling pathway. Conclusions Based on our findings, CERS5 appears to have great potential as both a precise prognostic biomarker and a novel therapeutic target in HCC.
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