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Identifying and validating the roles of the cuproptosis-related gene DKC1 in cancer with a focus on esophageal carcinoma.
BACKGROUND: Esophageal cancer is a common malignancy of the digestive tract. Despite remarkable advancements in its treatment, the overall prognosis for patients remains poor. Cuproptosis is a form of programmed cell death that affects the malignant progression of tumors. This study aimed to examine the impact of the cuproptosis-associated gene DKC1 on the malignant progression of esophageal cancer. METHODS: Clinical and RNA sequencing data of patients with esophageal cancer were extracted from The Cancer Genome Atlas (TCGA). Univariate Cox regression analysis was used to identify the differentially expressed genes related to cuproptosis that are associated with prognosis. We then validated the difference in the expression of DKC1 between tumor and normal tissues via three-dimensional multiomics difference analysis. Subsequently, we investigated the association between DKC1 expression and the tumor microenvironment by employing the TIMER2.0 algorithm, which was further validated in 96 single-cell datasets obtained from the TISCH database. Additionally, the functional role of DKC1 in pancarcinoma was assessed through GSEA. Furthermore, a comprehensive pancancer survival map was constructed, and the expression of DKC1 was verified in various molecular subtypes. By utilizing the CellMiner, GDSC, and CTRP databases, we successfully established a connection between DKC1 and drug sensitivity. Finally, the involvement of DKC1 in the progression of esophageal cancer was investigated through in vivo and in vitro experiments. RESULTS: In this study, we identified a copper death-related gene, DKC1, in esophageal cancer. Furthermore, we observed varying levels of DKC1 expression across different tumor types. Additionally, we conducted an analysis to determine the correlation between DKC1 expression and clinical features, revealing its association with common cell cycle pathways and multiple metabolic pathways. Notably, high DKC1 expression was found to indicate poor prognosis in patients with various tumors and to influence drug sensitivity. Moreover, our investigation revealed significant associations between DKC1 expression and the expression of molecules involved in immune regulation and infiltration of lymphocyte subtypes. Ultimately, the increased expression of DKC1 in esophageal cancer tissues was verified using clinical tissue samples. Furthermore, DKC1-mediated promotion of esophageal cancer cell proliferation and migration was confirmed through both in vitro and in vivo experiments. Additionally, it is plausible that DKC1 may play a role in the regulation of cuproptosis. CONCLUSION: In this study, we conducted a systematic analysis of DKC1 and its regulatory factors and experimentally validated its excellent diagnostic and prognostic abilities in various cancers. Further research indicated that DKC1 may reshape the tumor microenvironment (TME), highlighting the potential of DKC1-based cancer treatment and its usefulness in predicting the response to chemotherapy.
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Single-cell RNA sequencing reveals the mechanism of PI3K/AKT/mTOR signaling pathway activation in lung adenocarcinoma by KRAS mutation.
BACKGROUND: Aberrant activation of the phosphatidlinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway has been shown to play an important role in lung adenocarcinoma (LUAD). The effect of KRAS mutations, one of the important signatures of LUAD, on the PI3K/AKT/mTOR pathway in LUAD remains unclear. METHODS: The Seurat package and principal component analysis were used for cell categorization of single-cell RNA sequencing data of LUAD. The AUCell score was used to assess the activity of the PI3K/AKT/mTOR pathway. Meanwhile, using the gene expression profiles and mutation profiles in the The Cancer Genome Atlas dataset, LUAD patients were categorized into KRAS-mutant (KRAS-MT) and KRAS-wild-types (KRAS-WT), and the corresponding enrichment scores were calculated using gene set enrichment analysis analysis. Finally, the subpopulation of cells with the highest pathway activity was identified, the copy number variation profile of this subpopulation was inscribed using the inferCNV package and the CMap database was utilized to make predictions for drugs targeting this subpopulation. RESULTS: There is higher PI3K/AKT/mTOR pathway activity in LUAD epithelial cells with KRAS mutations, and high expression of KRAS, PIK3CA, AKT1 and PDPK1. In particular, we found significantly higher levels of pathway activity and associated gene expression in KRAS-MT than in KRAS-WT. We identified the highest pathway activity on a subpopulation of GRB2+ epithelial cells and the presence of amplified genes within its pathway. Finally, drugs were able to target GRB2+ epithelial cell subpopulations, such as wortmannin, palbociclib and angiogenesis inhibitor. CONCLUSIONS: The present study provides a basic theory for the activation of the PI3K/AKT/mTOR signaling pathway as a result of KRAS mutations.
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Comprehensively analysis of IL33 in hepatocellular carcinoma prognosis, immune microenvironment and biological role.
IL33 plays an important role in cancer. However, the role of liver cancer remains unclear. Open-accessed data was obtained from the Cancer Genome Atlas, Xena, and TISCH databases. Different algorithms and R packages are used to perform various analyses. Here, in our comprehensive study on IL33 in HCC, we observed its differential expression across cancers, implicating its role in cancer development. The single-cell analysis highlighted its primary expression in endothelial cells, unveiling correlations within the HCC microenvironment. Also, the expression level of IL33 was correlated with patients survival, emphasizing its potential prognostic value. Biological enrichment analyses revealed associations with stem cell division, angiogenesis, and inflammatory response. IL33's impact on the immune microenvironment showcased correlations with diverse immune cells. Genomic features and drug sensitivity analyses provided insights into IL33's broader implications. In a pan-cancer context, IL33 emerged as a potential tumour-inhibitor, influencing immune-related molecules. This study significantly advances our understanding of IL33 in cancer biology. IL33 exhibited differential expression across cancers, particularly in endothelial cells within the HCC microenvironment. IL33 is correlated with the survival of HCC patients, indicating potential prognostic value and highlighting its broader implications in cancer biology.
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Four Decades of Inquiry Into the Genetic Bases of Specific Reading Disability.
PURPOSE: This study investigated the genetic bases of specific reading disability (SRD) by systematically cataloging candidate genes reported as associated with SRD and reading-related processes over the last 4 decades and analyzing their evolutionary conservation, developmental expression patterns, and functional networks to address significant knowledge gaps in understanding the genetic architecture of reading (dis)ability. METHOD: Through a comprehensive literature review, we identified 175 putative SRD (and reading-related processes) candidate genes (hereafter, SRD genes). Using bioinformatic approaches, we analyzed their evolutionary conservation across species, examined their expression patterns in developmental and single-cell transcriptome data sets from the Allen Brain Atlas, and performed functional pathway analyses to identify biological processes associated with these genes. RESULTS: SRD genes showed remarkable evolutionary conservation, with enrichment in ancient taxonomic groups. Developmental transcriptome analysis revealed two distinct gene clusters with expression differentiation around 24 postconception weeks: early genes associated with brain morphology development and later genes involved in synaptic signaling. Single-cell analysis identified cell-type-specific expression patterns and protein-protein interaction networks with hub genes potentially coordinating reading-related neural pathways. CONCLUSIONS: Our findings challenge the notion of the existence of reading-specific genes, suggesting instead that SRD reflects the disruption of ancient evolutionary neural mechanisms operating within human-specific brain architecture. The identification of developmental expression transitions and functional networks provides insight into how genetic variation might impact reading development and offers potential targets for future clinical approaches to the identification and remediation of reading difficulties. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.30290446.
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Comprehensive Analysis and Experimental Validation of TLL2 as a Potential New Prognostic Biomarker Associated with Immune Infiltration in Lung Adenocarcinoma.
BACKGROUND: The precise function of Tolloid Like 2 (TLL2) remains uncertain within the context of Lung Adenocarcinoma (LUAD). OBJECTIVES: The primary objective of this investigation was to conduct a thorough analysis. METHODS: To assess its diagnostic utility, data from The Cancer Genome Atlas (TCGA) database were used to assess TLL2 expression in pan-cancer and LUAD. The study has also investigated the correlation between TLL2 expression levels and LUAD symptoms and prognosis. Furthermore, the study has explored possible regulatory networks involving TLL2, including its association with immune infiltration, tumor stemness index (mRNAsi), and drug sensitivity in LUAD. We have explored TLL2 expression in single-cell sequencing of LUAD and the genomic variation and clinical significance of TLL2 in LUAD. The expression of TLL2 has been validated in GSE87340 and cell lines by quantitative Real-time PCR (qRT-PCR). RESULTS: An abnormal expression of TLL2 has been found in pan-cancer and LUAD. In LUAD patients, elevated levels of TLL2 were significantly related to the T stage (p = 0.046) and the pathological stage (p = 0.016). The expression of TLL2 in patients with LUAD was significantly associated with poorer Overall Survival (OS) (p < 0.001). The expression of TLL2 was determined to be an independent predictor of poorer OS (p = 0.042). TLL2 was associated with ribosome, neuroactive ligand-receptor interaction, allograft rejection, ECM receptor interaction, asthma, porphyrin and chlorophyll metabolism, focal adhesion, pentose and glucuronate inter-conversions, and ascorbate and aldarate metabolism. The expression of TLL2 in LUAD was correlated with immune infiltration and mRNAsi. The expression of TLL2 was significantly and negatively correlated with TAK-715, XMD13-2, STF-62247, OSI-930, and EHT-1864 in LUAD. The TLL2 gene was up- -regulated in multiple individual LUAD cells. LUAD patients with altered TLL2 had a shorter PFS as opposed to those with unaltered TLL2. The expression of TLL2 was significantly increased in LUAD cells. CONCLUSION: For patients with LUAD, TLL2 may serve as an immunotherapeutic target and a useful prognosis biomarker.
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Hepatocellular carcinoma hosts cholinergic neural cells and tumoral hepatocytes harboring targetable muscarinic receptors.
BACKGROUND & AIMS: Owing to unexplained interpatient variation and treatment failure in hepatocellular carcinoma (HCC), novel therapeutic approaches remain an urgent clinical need. Hepatic neurons, belonging to the autonomic nervous system (ANS), mediate liver/whole body crosstalk. Pathological innervation of the ANS has been identified in cancer, nurturing tumor stroma and conferring stronger carcinogenic properties. METHODS: We characterized the innervation of liver tumors from the French Liver Biobank, then applied bioinformatics to TCGA (The Cancer Genome Atlas), several other datasets and a European validation cohort, to re-evaluate patient stratification. Cell biology and pharmacology studies were also performed. RESULTS: Densely packed nucleated DCX+, synaptophysin+, NeuN+, VAChT+, TH-, CD31-, CD45- clusters, to date undetected, were identified in human HCCs, and independently confirmed by single-cell RNA sequencing data. Using the new concept of a neuronal score, human and rat HCCs displayed tightly netrin-1-associated neural reconfiguration towards cholinergic polarity, which was associated with chronic liver disease progression, cancer onset and many features of aggressive (proliferative class) HCC, including shortened survival. This score was conditioned by tumoral hepatocytes, and predicted sorafenib efficacy in the STORM HCC phase III trial. Conversely, intratumoral adrenergic lymphocytes were enriched in TEMRA and cytotoxic phenotypes. Amongst all cholinergic transcripts, the medically targeted CHRM3 receptor was enriched and associated with pathogenic traits in HCC, as well as poor prognosis in HCC stages 1-2, while its level dropped upon experimental re-differentiation. Its pharmacological inhibition with low concentrations of anticholinergic drugs, but not cholinomimetics, decreased anchorage-independent growth and anoikis, synergized with sorafenib and lenvatinib in HCC class 1 to 3 lines, yet not in primary human hepatocytes, and preserved mature hepatocyte functions. CONCLUSION: These data identify cholinergic processes as instrumental in liver carcinogenesis and support the use of EMA/FDA-approved cholinergic drugs in HCC research. IMPACT AND IMPLICATIONS: Hepatocellular carcinoma (HCC) care has long been hampered by the enigmatic nature of disease evolution, as well as of response or resistance to treatment. Hepatic neurons are likely the least studied liver cell type and mediate patients singularities from the ANS to the organ in real-time. Cholinergic inputs identified in this study as pathogenic may be targeted with the well charted pharmacopoeia of neurotropic drugs already available, for basic or clinical research purposes, with an expected high level of safety.
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Development and validation of a novel fibroblast scoring model for lung adenocarcinoma.
The interaction between cancer-associated fibroblasts (CAFs) and the tumor microenvironment (TME) is a key factor for promoting tumor progression. In lung cancer, the crosstalk between CAFs and malignant and immune cells is expected to provide new directions for the development of immunotherapy. In this study, we have systematically analyzed a single-cell dataset and identified interacting genes between CAFs and other cells. Subsequently, a robust fibroblast-related score (FRS) was developed. Kaplan-Meier (KM) and ROC analyses showed its good predictive power for patient prognoses in the training set comprising of specimens from the cancer genome atlas (TCGA) and in three external validation sets from the Gene Expression Omnibus (GEO). Univariate and multivariate Cox regression analyses suggested that FRS was a significant prognostic factor independent of multiple clinical characteristics. Functional enrichment and ssGSEA analyses indicated that patients with a high FRS developed "cold" tumors with active tumor proliferation and immunosuppression capacities. In contrast, those with a low FRS developed "hot" tumors with active immune function and cell killing abilities. Genomic variation analysis showed that the patients with a high FRS possessed a higher somatic mutation burden and copy number alterations and were more sensitive to chemotherapy; patients with a low FRS were more sensitive to immunotherapy, particularly anti-PD1 therapy. Overall, these findings advance the understanding of CAFs in tumor progression and we generated a reliable FRS-based model to assess patient prognoses and guide clinical decision-making.
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Cervical cancer immune infiltration microenvironment identification, construction of immune scores, assisting patient prognosis and immunotherapy.
BACKGROUND: The immune microenvironment is of great significance in cervical cancer. However, there is still a lack of systematic research on the immune infiltration environment of cervical cancer. METHODS: We obtained cervical cancer transcriptome data and clinical information from the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases, evaluated the immune microenvironment of cervical cancer, determined immune subsets, constructed an immune cell infiltration scoring system, screened key immune-related genes, and performed single-cell data analysis and cell function analysis of key genes. RESULTS: We combined the TCGA and GEO data sets and obtained three different immune cell populations. We obtained two gene clusters, extracted 119 differential genes, and established an immune cell infiltration (ICI) scoring system. Finally, three key genes, IL1B, CST7, and ITGA5, were identified, and single-cell sequencing data were mined to distribute these key genes in different cell types. By up-regulating CST7 and down-regulating IL1B and ITGA5, cervical cancer cells' proliferation ability and invasion ability were successfully reduced. CONCLUSION: We conducted a comprehensive assessment of the state of the tumor immune microenvironment in cervical cancer, constructed the ICI scoring system, and identified the ICI scoring system as a potential indicator of susceptibility to immunotherapy for cervical cancer, identifying key genes suggesting that IL1B, CST7, and ITGA5 play an essential role in cervical cancer.
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Construction of immune-related signature and identification of S100A14 determining immune-suppressive microenvironment in pancreatic cancer.
Pancreatic cancer (PC) is a highly lethal and aggressive disease with its incidence and mortality quite discouraging. A robust prognostic signature and novel biomarkers are urgently needed for accurate stratification of the patients and optimization of clinical decision-making. Since the critical role of immune microenvironment in the progression of PC, a prognostic signature based on seven immune-related genes was established, which was validated in The Cancer Genome Atlas (TCGA) training set, TCGA testing set, TCGA entire set and GSE71729 set. Furthermore, S100A14 (S100 Calcium Binding Protein A14) was identified as the gene occupying the most paramount position in risk signature. According to the GSEA, CIBERSORT and ESTIMATE algorithm, S100A14 was mainly associated with lower proportion of CD8 + T cells and higher proportion of M0 macrophages in PC tissue. Meanwhile, analysis of single-cell dataset CRA001160 revealed a significant negative correlation between S100A14 expression in PC cells and CD8 + T cell infiltration, which was further confirmed by tissue microenvironment landscape imaging and machine learning-based analysis in our own PUMCH cohort. Additionally, analysis of a pan-pancreatic cancer cell line illustrated that S100A14 might inhibit CD8 + T cell activation via the upregulation of PD-L1 expression in PC cells, which was also verified by the immunohistochemical results of PUMCH cohort. Finally, tumor mutation burden analysis and immunophenoscore algorithm revealed that patients with high S100A14 expression had a higher probability of responding to immunotherapy. In conclusion, our study established an efficient immune-related prediction model and identified the potential role of S100A14 in regulating the immune microenvironment and serving as a biomarker for immunotherapy efficacy prediction.
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An integrative analysis reveals the prognostic value and potential functions of PSMD11 in hepatocellular carcinoma.
The global burden of hepatocellular carcinoma (HCC) as a preeminent etiology of cancer-related mortalities sheds light on the imperative necessity for a more profound comprehension of its fundamental biological mechanisms. In this context, the precise function of the 26S proteasome non-ATPase regulatory subunit 11 (PSMD11) in HCC remains equivocal. To address this vital knowledge gap, we interrogated the cancer genome atlas, genotype-tissue expression, International cancer genome consortium, gene expression omnibus, the cancer cell line encyclopedia, and tumor immune single-cell hub databases to evaluate the expression pattern of PSMD11, further confirmed by reverse-transcription quantitative polymerase chain reaction (RT-qPCR) in LO2, MHCC-97H, HepG2, and SMMC7721 cell lines. Additionally, we meticulously assessed the clinical significance and prognostic value of PSMD11, while also exploring its potential molecular mechanisms in HCC. Our findings demonstrated that PSMD11 was highly expressed in HCC tissues, correlating with pathologic stage and histologic grade, thereby conferring a poor prognosis. Mechanistically, PSMD11 appears to exert its tumorigenic effects through the modulation of tumor metabolism-related pathways. Impressively, low PSMD11 expression was associated with increased immune effector cell infiltration, heightened responsiveness to molecular targeted drugs such as dasatinib, erlotinib, gefitinib, and imatinib, as well as reduced somatic mutation rate. Additionally, we demonstrated that PSMD11 might modulate HCC development through intricate interactions with cuproptosis-related genes ATP7A, DLAT, and PDHA1. Our comprehensive analyses collectively suggest that PSMD11 represents a promising therapeutic target in HCC.