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Gut Microbes Dec 2023Colorectal cancer (CRC) is one of the most commonly diagnosed cancers worldwide. While a close correlation between chronic infection and CRC has been reported, the role...
Colorectal cancer (CRC) is one of the most commonly diagnosed cancers worldwide. While a close correlation between chronic infection and CRC has been reported, the role of the virome has been overlooked. Here, we infected -mutant mouse models and C57BL/6 mice with and conducted a comprehensive metagenomics analysis of -induced changes in lower gastrointestinal tract bacterial and viral communities. We observed an expansion of temperate phages in infected mice at the early stage of carcinogenesis. Some of the temperate phages were predicted to infect bacteria associated with CRC, including . We also observed a high prevalence of virulent genes, such as , , and , encoded by temperate phages. In addition, we identified phages associated with pre-onset and onset of -promoted carcinogenesis. Through co-occurrence network analysis, we found strong associations between the viral and bacterial communities in infected mice before the onset of carcinogenesis. These findings suggest that the expansion of temperate phages, possibly caused by prophage induction triggered by infection, may have contributed to the development of CRC in mice by interacting with the bacterial community.
Topics: Animals; Mice; Bacteriophages; Helicobacter pylori; Virome; Helicobacter Infections; Gastrointestinal Microbiome; Mice, Inbred C57BL; Colorectal Neoplasms; Carcinogenesis
PubMed: 37747149
DOI: 10.1080/19490976.2023.2257291 -
Cells Sep 2023The Wnt signaling pathway is a highly conserved regulator of metazoan development and stem cell maintenance. Activation of Wnt signaling is an early step in diverse... (Review)
Review
The Wnt signaling pathway is a highly conserved regulator of metazoan development and stem cell maintenance. Activation of Wnt signaling is an early step in diverse malignancies. Work over the past four decades has defined a "canonical" Wnt pathway that is initiated by Wnt proteins, secreted glycoproteins that bind to a surface receptor complex and activate intracellular signal transduction by inhibiting a catalytic complex composed of the classical tumor suppressor Adenomatous Polyposis Coli (APC), Axin, and Glycogen Synthase Kinase-3 (GSK-3). The best characterized effector of this complex is β-catenin, which is stabilized by inhibition of GSK-3, allowing β-catenin entrance to the nucleus and activation of Wnt target gene transcription, leading to multiple cancers when inappropriately activated. However, canonical Wnt signaling through the APC/Axin/GSK-3 complex impinges on other effectors, independently of β-catenin, including the mechanistic Target of Rapamycin (mTOR), regulators of protein stability, mitotic spindle orientation, and Hippo signaling. This review focuses on these alternative effectors of the canonical Wnt pathway and how they may contribute to cancers.
Topics: Animals; Wnt Signaling Pathway; Glycogen Synthase Kinase 3; Axin Protein; beta Catenin; Adenomatous Polyposis Coli
PubMed: 37759479
DOI: 10.3390/cells12182256 -
Clinical Cancer Research : An Official... Jul 2023More than 10% of assessed patients with appendiceal adenocarcinoma have a pathogenic (P) or likely pathogenic (LP) germline variant, including genes implicated in...
PURPOSE
More than 10% of assessed patients with appendiceal adenocarcinoma have a pathogenic (P) or likely pathogenic (LP) germline variant, including genes implicated in heritable gastrointestinal cancer syndromes, such as Lynch syndrome. We defined the clinical and molecular impact of heritable alterations in appendiceal adenocarcinoma to evaluate the need for dedicated appendiceal screening and prevention strategies in patients with LP/P germline variants.
EXPERIMENTAL DESIGN
We performed an integrated germline and somatic molecular analysis for patients with confirmed appendiceal adenocarcinoma. Patients underwent paired tumor-normal sequencing for up to 90 hereditary cancer risk genes and 505 genes for somatic mutation profiling. We defined the cooccurrence of LP/P germline variants and second-hit pathogenic somatic alterations. The associations between germline variants and patient clinicopathologic features were also evaluated.
RESULTS
Twenty-five of 237 patients (10.5%) carried pathogenic or likely pathogenic germline variants in cancer susceptibility genes. Clinicopathologic characteristics and appendiceal adenocarcinoma-specific survival were similar in patients with or without germline variants. Most (92%, N = 23/25) patients with germline variants demonstrated no second-hit somatic alterations, including loss of heterozygosity. Two patients with a germline APC I1307K low-penetrance founder variant exhibited secondary somatic pathogenic alterations in APC. However, only one patient tumor exhibited APC-mediated WNT signaling dysregulation: a plausible consequence of multiple somatic APC mutations with no germline variant contribution. Four patients had germline variants in PMS2 or MSH2 associated with Lynch syndrome, yet their cancers were microsatellite-stable.
CONCLUSIONS
Germline variants are likely incidental without a contributory driver role in appendiceal adenocarcinoma. Appendiceal adenocarcinoma screening in patients with germline variants is not clearly merited.
Topics: Humans; Colorectal Neoplasms, Hereditary Nonpolyposis; Germ-Line Mutation; Appendiceal Neoplasms; Neoplastic Syndromes, Hereditary; Adenocarcinoma; Genetic Predisposition to Disease
PubMed: 37289003
DOI: 10.1158/1078-0432.CCR-22-3956 -
BioRxiv : the Preprint Server For... Nov 2023Regulated cell cycle progression ensures homeostasis and prevents cancer. In proliferating cells, premature S phase entry is avoided by the E3 ubiquitin ligase APC/C...
Regulated cell cycle progression ensures homeostasis and prevents cancer. In proliferating cells, premature S phase entry is avoided by the E3 ubiquitin ligase APC/C (anaphase promoting complex/cyclosome), although the APC/C substrates whose degradation restrains G1-S progression are not fully known. The APC/C is also active in arrested cells that exited the cell cycle, but it is not clear if APC/C maintains all types of arrest. Here by expressing the APC/C inhibitor, EMI1, we show that APC/C activity is essential to prevent S phase entry in cells arrested by pharmacological CDK4/6 inhibition (Palbociclib). Thus, active protein degradation is required for arrest alongside repressed cell cycle gene expression. The mechanism of rapid and robust arrest bypass from inhibiting APC/C involves cyclin-dependent kinases acting in an atypical order to inactivate RB-mediated E2F repression. Inactivating APC/C first causes mitotic cyclin B accumulation which then promotes cyclin A expression. We propose that cyclin A is the key substrate for maintaining arrest because APC/C-resistant cyclin A, but not cyclin B, is sufficient to induce S phase entry. Cells bypassing arrest from CDK4/6 inhibition initiate DNA replication with severely reduced origin licensing. The simultaneous accumulation of S phase licensing inhibitors, such as cyclin A and geminin, with G1 licensing activators disrupts the normal order of G1-S progression. As a result, DNA synthesis and cell proliferation are profoundly impaired. Our findings predict that cancers with elevated EMI1 expression will tend to escape CDK4/6 inhibition into a premature, underlicensed S phase and suffer enhanced genome instability.
PubMed: 37986787
DOI: 10.1101/2023.11.09.566394 -
Molecular Therapy : the Journal of the... Mar 2024mRNA vaccines are promising for cancer treatment. Efficient delivery of mRNAs encoding tumor antigens to antigen-presenting cells (APCs) is critical to elicit anti-tumor...
mRNA vaccines are promising for cancer treatment. Efficient delivery of mRNAs encoding tumor antigens to antigen-presenting cells (APCs) is critical to elicit anti-tumor immunity. Herein, we identified a novel lipid nanoparticle (LNP) formulation, L17-F05, for mRNA vaccines by screening 34 ionizable lipids and 28 LNP formulations using human primary APCs. Subcutaneous delivery of L17-F05 mRNA vaccine encoding Gp100 and Trp2 inhibited tumor growth and prolonged the survival of mice bearing B16F10 melanoma. L17-F05 efficiently delivered mRNAs to conventional dendritic cells (cDCs) and macrophages in draining lymph nodes (dLNs). cDCs functioned as the main APCs by presenting antigens along with enhanced expression of co-stimulatory molecules. Macrophages triggered innate immune responses centered on type-I interferon (IFN-I) in dLNs. Lymph node (LN) macrophage depletion attenuated APC maturation and anti-tumor activity of L17-F05 mRNA vaccines. Loss-of-function studies revealed that L17-F05 works as a self-adjuvant by activating the stimulator of interferon genes (STING) pathway in macrophages. Collectively, the self-adjuvanticity of L17-F05 triggered innate immune responses in LN macrophages via the STING-IFN-I pathway, contributing to APC maturation and potent anti-tumor activity of L17-F05 mRNA vaccines. Our findings provide strategies for further optimization of mRNA vaccines based on the innate immune response driven by LN macrophages.
Topics: Animals; Mice; Humans; mRNA Vaccines; Cancer Vaccines; Immunity, Innate; Dendritic Cells; Macrophages; Interferons; Lymph Nodes
PubMed: 38243602
DOI: 10.1016/j.ymthe.2024.01.020 -
Genes, Chromosomes & Cancer Sep 2023The advancement of CRISPR mediated gene engineering provides an opportunity to improve upon preclinical human cell line models of cancer predisposing syndromes. This... (Review)
Review
The advancement of CRISPR mediated gene engineering provides an opportunity to improve upon preclinical human cell line models of cancer predisposing syndromes. This review focuses on using CRISPR/Cas9 genome editing tools to model various human cancer predisposition syndromes. We examine the genetic mutations associated with neurofibromatosis type 1, Li-Fraumeni syndrome, Gorlin syndrome, BRCA mutant breast and ovarian cancers, and APC mutant cancers. Furthermore, we discuss the possibilities of using next-generation CRISPR-derived precision gene editing tools to introduce a variety of genetic lesions into human cell lines. The goal is to improve the quality of preclinical models surrounding these cancer predisposition syndromes through dissecting the effects of these mutations on the development of cancer and to provide new insights into the underlying mechanisms of these cancer predisposition syndromes. These studies demonstrate the continued utility and improvement of CRISPR/Cas9-induced human cell line models in studying the genetic basis of cancer.
Topics: Humans; CRISPR-Cas Systems; Syndrome; Gene Editing; Disease Susceptibility; Cell Line; Neoplasms
PubMed: 36959711
DOI: 10.1002/gcc.23140 -
Journal of Orthopaedic Surgery and... Oct 2023To investigate the ferroptosis-related long non-coding RNAs (FRLncs) implicated in influencing the prognostic and immune microenvironment in osteosarcoma (OS), and to...
OBJECTIVE
To investigate the ferroptosis-related long non-coding RNAs (FRLncs) implicated in influencing the prognostic and immune microenvironment in osteosarcoma (OS), and to establish a foundational framework for informing clinical decision making pertaining to OS management.
METHODS
Transcriptome data and clinical data pertaining to 86 cases of OS, the GSE19276, GSE16088 and GSE33382 datasets, and a list of ferroptosis-related genes (FRGs) were used to establish a risk prognostic model through comprehensive analysis. The identification of OS-related differentially expressed FRGs was achieved through an integrated analysis encompassing the aforementioned 86 OS transcriptome data and the GSE19276, GSE16088 and GSE33382 datasets. Concurrently, OS-related FRLncs were ascertained via co-expression analysis. To establish a risk prognostic model for OS, Univariate Cox regression analysis and Lasso Cox regression analysis were employed. Subsequently, a comprehensive evaluation was conducted, comprising risk curve analysis, survival analysis, receiver operating characteristic curve analysis and independent prognosis analysis. Model validation with distinct clinical subgroups was performed to assess the applicability of the risk prognostic model to diverse patient categories. Moreover, single sample gene set enrichment analysis (ssGSEA) was conducted to investigate variations in immune cell populations and immune functions within the context of the risk prognostic model. Furthermore, an analysis of immune checkpoint differentials yielded insights into immune checkpoint-related genes linked to OS prognosis. Finally, the risk prognosis model was verified by dividing the samples into train group and test group.
RESULTS
We identified a set of seven FRLncs that exhibit potential as prognostic markers and influence factors of the immune microenvironment in the context of OS. This ensemble encompasses three high-risk FRLncs, denoted as APTR, AC105914.2 and AL139246.5, alongside four low-risk FRLncs, designated as DSCR8, LOH12CR2, AC027307.2 and AC025048.2. Furthermore, our analysis revealed notable down-regulation in the high-risk group across four distinct immune cell types, namely neutrophils, natural killer cells, plasmacytoid dendritic cells and tumor-infiltrating lymphocytes. This down-regulation was also reflected in four key immune functions, antigen-presenting cell (APC)-co-stimulation, checkpoint, cytolytic activity and T cell co-inhibition. Additionally, we identified seven immune checkpoint-associated genes with significant implications for OS prognosis, including CD200R1, HAVCR2, LGALS9, CD27, LAIR1, LAG3 and TNFSF4.
CONCLUSION
The findings of this study have identified FRLncs capable of influencing OS prognosis and immune microenvironment, as well as immune checkpoint-related genes that are linked to OS prognosis. These discoveries establish a substantive foundation for further investigations into OS survival and offer valuable insights for informing clinical decision making in this context.
Topics: Humans; RNA, Long Noncoding; Ferroptosis; Osteosarcoma; Prognosis; Bone Neoplasms; Tumor Microenvironment; OX40 Ligand
PubMed: 37858131
DOI: 10.1186/s13018-023-04286-3 -
Nature Reviews. Microbiology May 2024Bacteriocins are potent antimicrobial peptides that are produced by bacteria. Since their discovery almost a century ago, diverse peptides have been discovered and... (Review)
Review
Bacteriocins are potent antimicrobial peptides that are produced by bacteria. Since their discovery almost a century ago, diverse peptides have been discovered and described, and some are currently used as commercial food preservatives. Many bacteriocins exhibit extensively post-translationally modified structures encoded on complex gene clusters, whereas others have simple linear structures. The molecular structures, mechanisms of action and resistance have been determined for a number of bacteriocins, but most remain incompletely characterized. These gene-encoded peptides are amenable to bioengineering strategies and heterologous expression, enabling metagenomic mining and modification of novel antimicrobials. The ongoing global antimicrobial resistance crisis demands that novel therapeutics be developed to combat infectious pathogens. New compounds that are target-specific and compatible with the resident microbiota would be valuable alternatives to current antimicrobials. As bacteriocins can be broad or narrow spectrum in nature, they are promising tools for this purpose. However, few bacteriocins have gone beyond preclinical trials and none is currently used therapeutically in humans. In this Review, we explore the broad diversity in bacteriocin structure and function, describe identification and optimization methods and discuss the reasons behind the lack of translation beyond the laboratory of these potentially valuable antimicrobials.
PubMed: 38730101
DOI: 10.1038/s41579-024-01045-x -
Frontiers in Immunology 2023Familial adenomatous polyposis (FAP) is an inherited disease characterized by the development of large number of colorectal adenomas with high risk of evolving into...
Familial adenomatous polyposis (FAP) is an inherited disease characterized by the development of large number of colorectal adenomas with high risk of evolving into colorectal tumors. Mutations of the gene is often at the origin of this disease, as well as of a high percentage of spontaneous colorectal tumors. is therefore considered a tumor suppressor gene. While the role of in intestinal epithelium homeostasis is well characterized, its importance in immune responses remains ill defined. Our recent work indicates that the APC protein is involved in various phases of both CD4 and CD8 T cells responses. This prompted us to investigate an array of immune cell features in FAP subjects carrying mutations. A group of 12 FAP subjects and age and sex-matched healthy controls were studied. We characterized the immune cell repertoire in peripheral blood and the capacity of immune cells to respond to different stimuli either in whole blood or in purified T cells. A variety of experimental approaches were used, including, pultiparamater flow cytometry, NanosString gene expression profiling, Multiplex and regular ELISA, confocal microscopy and computer-based image analyis methods. We found that the percentage of several T and natural killer (NK) cell populations, the expression of several genes induced upon innate or adaptive immune stimulation and the production of several cytokines and chemokines was different. Moreover, the capacity of T cells to migrate in response to chemokine was consistently altered. Finally, immunological synapses between FAP cytotoxic T cells and tumor target cells were more poorly structured. Our findings of this pilot study suggest that mild but multiple immune cell dysfunctions, together with intestinal epithelial dysplasia in FAP subjects, may facilitate the long-term polyposis and colorectal tumor development. Although at an initial discovery phase due to the limited sample size of this rare disease cohort, our findings open new perspectives to consider immune cell abnormalities into polyposis pathology.
Topics: Humans; Adenomatous Polyposis Coli; Cell Movement; Colorectal Neoplasms; Genes, APC; Mutation; Pilot Projects; T-Lymphocytes
PubMed: 37533857
DOI: 10.3389/fimmu.2023.1163466 -
Frontiers in Endocrinology 2023Hyperthyroidism in Chinese children is relatively high and has been increasing in recent years, which has a significant impact on their healthy development....
OBJECTIVE
Hyperthyroidism in Chinese children is relatively high and has been increasing in recent years, which has a significant impact on their healthy development. Hyperthyroidism is a polygenic disorder that presents greater challenges in terms of prediction and treatment than monogenic diseases. This study aims to elucidate the associated functions and gene sets of mutated genes in children with hyperthyroidism in terms of the gene ontology through GO enrichment analysis and in terms of biological signaling pathways through KEGG enrichment analysis, thereby enhancing our understanding of the expected effects of multiple mutated genes on hyperthyroidism in children.
METHODS
Whole-exome sequencing was performed on the DNA samples of children with hyperthyroidism. Screening for pathogenic genes related to hyperthyroidism in affected children was performed using the publicly available disease databases Malacards, MutationView, and Clinvar, and the functions and influences of the identified pathogenic genes were analyzed using statistical analysis and the gene enrichment approach.
RESULTS
Through GO enrichment analysis, it was found that the most significant gene ontology enrichment was the function "hormone activity" in terms of gene ontology molecular function. The corresponding mutated genes set that has common effects on hyperthyroidism in children included TG, CALCA, POMC, CGA, PTH, GHRL, FBN1, TRH, PRL, LEP, ADIPOQ, INS, GH1. The second most significant gene ontology enrichment was the function "response to peptide hormone" in terms of biological process. The corresponding mutated genes set that has common effects on hyperthyroidism in children included LRP6, TSC2, KANK1, COL1A1, CDKN1B, POMC, STAT1, MEN1, APC, GHRL, TSHR, GJB2, FBN1, GPT, LEP, ADIPOQ, INS, GH1. Through KEGG enrichment analysis, it was found that the most significant biological signaling pathway enrichment was the pathway "Thyroid hormone signaling pathway" function. The corresponding mutated genes set that has common effects on hyperthyroidism in children included NOTCH3, MYH7, TSC2, STAT1, MED13L, MAP2K2, SLCO1C1, SLC16A2, and THRB. The second most significant biological signaling pathway enrichment was the pathway "Hypertrophic cardiomyopathy" in terms of biological process. The corresponding mutated genes set that has common effects on hyperthyroidism in children included IGF1, CACNA1S, MYH7, IL6, TTN, CACNB2, LAMA2, and DMD.
CONCLUSION
The mutated genes in children with hyperthyroidism were closely linked to function involved in "hormone activity" and "response to peptide hormone" in terms of the biological signaling pathway, and to the functional pathways involved in "Thyroid hormone signaling pathway" and "Hypertrophic cardiomyopathy" in terms of the biological signaling pathway.
Topics: Humans; Child; Computational Biology; Pro-Opiomelanocortin; Hyperthyroidism; Thyroid Hormones; Cardiomyopathies; Cytoskeletal Proteins; Adaptor Proteins, Signal Transducing; Organic Anion Transporters; Monocarboxylic Acid Transporters; Symporters
PubMed: 37876543
DOI: 10.3389/fendo.2023.1213465