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Pathology Oncology Research : POR 2024Colorectal carcinomas (CRC) are one of the most frequent malignancies worldwide. Based on gene expression profile analysis, CRCs can be classified into four distinct...
Colorectal carcinomas (CRC) are one of the most frequent malignancies worldwide. Based on gene expression profile analysis, CRCs can be classified into four distinct subtypes also known as the consensus molecular subtypes (CMS), which predict biological behaviour. Besides CMS, several other aspects of tumor microenvironment (TME) and systemic inflammatory response (SIR) influence the outcome of CRC patients. TME and inflammation have important role in the immune (CMS1) and mesenchymal (CMS4) subtypes, however, the relationship between these and systemic inflammation has not been assessed yet. Our objective was to evaluate the connection between CMS, TME and SIR, and to analyze the correlation between these markers and routinely used tumor markers, such as CEA (Carcinoembryonic Antigen) and CA19-9 (Carbohydrate Antigen 19-9). FFPE (Formalin Fixed Paraffin Embedded) samples of 185 CRC patients were collected. TME was described using tumor-stroma ratio (TSR), Klintrup-Makinen (KM) grade, and Glasgow Microenvironment Score (GMS). CMS classification was performed on tissue microarray using MLH1, PMS2, MSH2 and MSH6, and pan-cytokeratin, CDX2, FRMD6, HTR2B and ZEB1 immunohistochemical stains. Pre-operative tumor marker levels and inflammatory markers [C-reactive protein - CRP, albumin, absolute neutrophil count (ANC), absolute lymphocyte count (ALC), absolute platelet count (APC)] and patient history were retrieved using MedSolution database. Amongst TME-markers, TSR correlated most consistently with adverse clinicopathological features ( < 0.001) and overall survival ( < 0.001). Elevated CRP and modified Glasgow Prognostic Score (mGPS) were associated with worse outcome and aggressive phenotype, similarly to tumor markers CEA and CA19-9. Stroma-Tumor Marker score (STM score), a new combined score of CA19-9 and TSR delivered the second best prognostication after mGPS. Furthermore, CMS4 showed association with TSR and several laboratory markers (albumin and platelet derived factors), but not with other SIR descriptors. CMS did not show any association with CEA and CA19-9 tumor markers. More routinely available TME, SIR and tumor markers alone and in combination deliver reliable prognostic data for choosing the patients with higher risk for propagation. CMS4 is linked with high TSR and poor prognosis, but in overall, CMS-classification showed only limited effect on SIR- and tumor-markers.
Topics: Humans; Tumor Microenvironment; Colorectal Neoplasms; Biomarkers, Tumor; Female; Male; Aged; Middle Aged; Aged, 80 and over; Inflammation; Adult; Prognosis
PubMed: 38645565
DOI: 10.3389/pore.2024.1611574 -
Computational and Structural... Dec 2024Neuroblastoma (NB) is the most prevalent extracranial solid tumor in pediatric patients, and its treatment failure often associated with metastasis. In this study,...
Neuroblastoma (NB) is the most prevalent extracranial solid tumor in pediatric patients, and its treatment failure often associated with metastasis. In this study, LASSO, SVM-RFE, and random forest tree algorithms, was used to identify the pivotal gene involved in NB metastasis. NB cell lines (SK-N-AS and SK-N-BE2), in conjunction with NB tissue were used for further study. ABLIM3 was identified as the hub gene and can be an independent prognostic factor for patients with NB. The immunohistochemical analysis revealed that ABLIM3 is negatively correlated with the metastasis of NB. Patients with low expression of ABLIM3 had a poor prognosis. High ABLIM3 expression correlated with APC co-stimulation and Type1 IFN response, and TIDE analysis indicated that patients with low ABLIM3 expression exhibited enhanced responses to immunotherapy. Downregulation of ABLIM3 by shRNA transfection increased the migration and invasion ability of NB cells. Gene Set Enrichment Analysis (GSEA) revealed that genes associated with ABLIM3 were primarily enriched in the cell adhesion molecules (CAMs) pathway. RT-qPCR and western blot analyses demonstrated that downregulation of ABLIM3 led to decreased expression of ITGA3, ITGA8, and KRT19, the key components of CAMs. This study indicated that ABLIM3 can be an independent prognostic factor for NB patients, and CAMs may mediate the effect of ABLIM3 on the metastasis of NB, suggesting that ABLIM3 is a potential therapeutic target for NB metastasis, which provides a novel strategy for future research and treatment strategies for NB patients.
PubMed: 38645433
DOI: 10.1016/j.csbj.2024.04.024 -
Journal of Experimental & Clinical... Apr 2024Protein arginine methyltransferase 6 (PRMT6) plays a crucial role in various pathophysiological processes and diseases. Glioblastoma (GBM; WHO Grade 4 glioma) is the...
BACKGROUND
Protein arginine methyltransferase 6 (PRMT6) plays a crucial role in various pathophysiological processes and diseases. Glioblastoma (GBM; WHO Grade 4 glioma) is the most common and lethal primary brain tumor in adults, with a prognosis that is extremely poor, despite being less common than other systemic malignancies. Our current research finds PRMT6 upregulated in GBM, enhancing tumor malignancy. Yet, the specifics of PRMT6's regulatory processes and potential molecular mechanisms in GBM remain largely unexplored.
METHODS
PRMT6's expression and prognostic significance in GBM were assessed using glioma public databases, immunohistochemistry (IHC), and immunoblotting. Scratch and Transwell assays examined GBM cell migration and invasion. Immunoblotting evaluated the expression of epithelial-mesenchymal transition (EMT) and Wnt-β-catenin pathway-related proteins. Dual-luciferase reporter assays and ChIP-qPCR assessed the regulatory relationship between PRMT6 and YTHDF2. An in situ tumor model in nude mice evaluated in vivo conditions.
RESULTS
Bioinformatics analysis indicates high expression of PRMT6 and YTHDF2 in GBM, correlating with poor prognosis. Functional experiments show PRMT6 and YTHDF2 promote GBM migration, invasion, and EMT. Mechanistic experiments reveal PRMT6 and CDK9 co-regulate YTHDF2 expression. YTHDF2 binds and promotes the degradation of negative regulators APC and GSK3β mRNA of the Wnt-β-catenin pathway, activating it and consequently enhancing GBM malignancy.
CONCLUSIONS
Our results demonstrate the PRMT6-YTHDF2-Wnt-β-Catenin axis promotes GBM migration, invasion, and EMT in vitro and in vivo, potentially serving as a therapeutic target for GBM.
Topics: Animals; Mice; Glioblastoma; beta Catenin; Transcriptional Activation; Mice, Nude; Cell Line, Tumor; Transcription Factors; Glioma; Wnt Signaling Pathway; Epithelial-Mesenchymal Transition; Cell Proliferation; Cell Movement; Gene Expression Regulation, Neoplastic
PubMed: 38637831
DOI: 10.1186/s13046-024-03038-3 -
Heliyon Apr 2024Early mutation identification guides patients with colorectal cancer (CRC) toward targeted therapies. In the present study, 414 patients with CRC were enrolled, and...
Early mutation identification guides patients with colorectal cancer (CRC) toward targeted therapies. In the present study, 414 patients with CRC were enrolled, and amplicon-based targeted next-generation sequencing (NGS) was then performed to detect genomic alterations within the 73 cancer-related genes in the OncoAim panel. The overall mutation rate was 91.5 % (379/414). Gene mutations were detected in 38/73 genes tested. The most frequently mutated genes were (60.9 %), (46.6 %), (30.4 %), (15.9 %), (8.2 %), (6.8 %), (6.5 %), and (3.9 %). Compared with the wild type, mutations were associated with low microsatellite instability/microsatellite stability (MSI-L/MSS) ( = 0.007), tumor location ( = 0.043), and histological grade ( = 0.0009); mutations were associated with female gender ( = 0.026), distant metastasis ( = 0.023), TNM stage ( = 0.013), and histological grade ( = 0.004); mutations were associated with patients <64 years of age at diagnosis ( = 0.04); mutations were associated with tumor location ( = 4.97e-06) and female gender ( = 0.018); mutations were associated with tumor location ( = 0.033); mutations were associated with high MSI (MSI-H; = 6.968e-07), tumor location ( = 1.58e-06), and histological grade ( = 0.04). Mutations in 164 individuals were found to be pathogenic or likely pathogenic. A total of 26 patients harbored MSI-H tumors and they all had at least one detected gene mutation. Mutated genes were enriched in signaling pathways associated with CRC. The present findings have important implications for improving the personalized treatment of patients with CRC in China.
PubMed: 38623252
DOI: 10.1016/j.heliyon.2024.e29299 -
Nutrients Apr 2024Colorectal cancer (CRC), a major global health concern, may be influenced by dietary protein digestibility impacting gut microbiota and metabolites, which is crucial for...
Colorectal cancer (CRC), a major global health concern, may be influenced by dietary protein digestibility impacting gut microbiota and metabolites, which is crucial for cancer therapy effectiveness. This study explored the effects of a casein protein diet (CTL) versus a free amino acid (FAA)-based diet on CRC progression, gut microbiota, and metabolites using carcinogen-induced (AOM/DSS) and spontaneous genetically induced ( mice) CRC mouse models. Comprehensive approaches including 16s rRNA gene sequencing, transcriptomics, metabolomics, and immunohistochemistry were utilized. We found that the FAA significantly attenuated CRC progression, evidenced by reduced colonic shortening and histopathological alterations compared to the CTL diet. Notably, the FAA enriched beneficial gut bacteria like and and reversed CRC-associated dysbiosis. Metabolomic analysis highlighted an increase in ornithine cycle metabolites and specific fatty acids, such as Docosapentaenoic acid (DPA), in FAA-fed mice. Transcriptomic analysis revealed that FAA up-regulated Egl-9 family hypoxia inducible factor 3 (Egln 3) and downregulated several cancer-associated pathways including Hippo, mTOR, and Wnt signaling. Additionally, DPA was found to significantly induce EGLN 3 expression in CRC cell lines. These results suggest that FAA modulate gut microbial composition, enhance protective metabolites, improve gut barrier functions, and inhibit carcinogenic pathways.
Topics: Animals; Mice; Gastrointestinal Microbiome; RNA, Ribosomal, 16S; Carcinogenesis; Cell Transformation, Neoplastic; Carcinogens; Amino Acids; Colorectal Neoplasms
PubMed: 38613073
DOI: 10.3390/nu16071040 -
International Journal of Molecular... Mar 2024Cell division cycle 23 (CDC23) is a component of the tetratricopeptide repeat (TPR) subunit in the anaphase-promoting complex or cyclosome (APC/C) complex, which...
Cell division cycle 23 (CDC23) is a component of the tetratricopeptide repeat (TPR) subunit in the anaphase-promoting complex or cyclosome (APC/C) complex, which participates in the regulation of mitosis in eukaryotes. However, the regulatory model and mechanism by which the CDC23 gene regulates muscle production in pigs are largely unknown. In this study, we investigated the expression of CDC23 in pigs, and the results indicated that CDC23 is widely expressed in various tissues and organs. In vitro cell experiments have demonstrated that CDC23 promotes the proliferation of myoblasts, as well as significantly positively regulating the differentiation of skeletal muscle satellite cells. In addition, Gene Set Enrichment Analysis (GSEA) revealed a significant downregulation of the cell cycle pathway during the differentiation process of skeletal muscle satellite cells. The protein-protein interaction (PPI) network showed a high degree of interaction between genes related to the cell cycle pathway and CDC23. Subsequently, in differentiated myocytes induced after overexpression of CDC23, the level of CDC23 exhibited a significant negative correlation with the expression of key factors in the cell cycle pathway, suggesting that CDC23 may be involved in the inhibition of the cell cycle signaling pathway in order to promote the differentiation process. In summary, we preliminarily determined the function of CDC23 with the aim of providing new insights into molecular regulation during porcine skeletal muscle development.
Topics: Animals; Anaphase-Promoting Complex-Cyclosome; Muscle Cells; Muscle, Skeletal; Satellite Cells, Skeletal Muscle; Swine
PubMed: 38612477
DOI: 10.3390/ijms25073664 -
Frontiers in Cell and Developmental... 2024To study the genetic variation leading to the arrest phenotype of pronuclear (PN) zygotes. We recruited a family characterized by recurrent PN arrest during...
To study the genetic variation leading to the arrest phenotype of pronuclear (PN) zygotes. We recruited a family characterized by recurrent PN arrest during fertilization (IVF) and intracytoplasmic sperm injection cycles (ICSI) and performed whole-exome sequencing for 2 individuals. The transcriptome profiles of PN-arrest zygotes were assessed by single-cell RNA sequencing analysis. The variants were then validated by PCR amplification and Sanger sequencing in the affected individuals and other family members. A family characterized by recurrent PN arrest during IVF and ICSI cycles were enrolled after giving written informed consent. Peripheral blood samples were taken for DNA extraction. Three PN-arrest zygotes from patient III-3 were used for single-cell RNA-seq as described. This phenotype was reproduced after multiple cycles of egg retrieval and after trying different fertilization methods and multiple ovulation regimens. The mutant genes of whole exon sequencing were screened and verified. The missense variant c. C1630T (p.R544W) in was responsible for a phenotype characterized by paternal transmission. controls Ca oscillation, which is required for oocyte activation after fertilization. Single-cell transcriptome profiling of PN-arrest zygotes revealed defective established translation, RNA processing and cell cycle, which explained the failure of complete oocyte activation. Furthermore, we identified proximal genes involved in Ca oscillation-cytostatic factor-anaphase-promoting complex (Ca oscillation-CSF-APC) signaling, including upregulated , and and downregulated and . The findings indicate abnormal spontaneous Ca oscillations leading to oocytes with prolonged low CSF level and high APC level, which resulted in defective nuclear envelope breakdown and DNA replication. We have identified an RGS12 variant as the potential cause of female infertility characterized by arrest at the PN stage during multiple IVF and ICSI.
PubMed: 38606321
DOI: 10.3389/fcell.2024.1280797 -
Frontiers in Oncology 2024Altered lipid metabolism is a well-recognized feature of solid cancers, including colorectal cancer. In colorectal cancer, upregulation of lipid metabolism contributes... (Review)
Review
Altered lipid metabolism is a well-recognized feature of solid cancers, including colorectal cancer. In colorectal cancer, upregulation of lipid metabolism contributes to initiation, progression, and metastasis; thus, aberrant lipid metabolism contributes to a poor patient outcome. The inactivating mutation of , a vital tumor suppressor in the Wnt signaling pathway, is a key event that occurs early in the majority of colorectal cancer cases. The potential crosstalk between lipid metabolism and APC-driven colorectal cancer is poorly understood. This review collectively highlights and summarizes the limited understanding between mutations in and the upregulation of Wnt/beta-catenin signaling and lipid metabolism. The interconnection between inactivation and aberrant lipid metabolism activates Wnt/beta-catenin signaling which causes transcriptome, epigenetic, and microbiome changes to promote colorectal cancer initiation and progression. Furthermore, the downstream effects of this collaborative effort between aberrant Wnt/beta-catenin signaling and lipid metabolism are enhanced stemness, cellular proliferation, prooncogenic signaling, and survival. Understanding the mechanistic link between inactivation and alterations in lipid metabolism may foster identification of new therapeutic targets to enable development of more efficacious strategies for prevention and/or treatment of colorectal cancer.
PubMed: 38590663
DOI: 10.3389/fonc.2024.1343061 -
Journal of Translational Medicine Apr 2024The mesenchymal subtype of colorectal cancer (CRC), associated with poor prognosis, is characterized by abundant expression of the cellular prion protein PrP, which...
BACKGROUND
The mesenchymal subtype of colorectal cancer (CRC), associated with poor prognosis, is characterized by abundant expression of the cellular prion protein PrP, which represents a candidate therapeutic target. How PrP is induced in CRC remains elusive. This study aims to elucidate the signaling pathways governing PrP expression and to shed light on the gene regulatory networks linked to PrP.
METHODS
We performed in silico analyses on diverse datasets of in vitro, ex vivo and in vivo models of mouse CRC and patient cohorts. We mined ChIPseq studies and performed promoter analysis. CRC cell lines were manipulated through genetic and pharmacological approaches. We created mice combining conditional inactivation of Apc in intestinal epithelial cells and overexpression of the human prion protein gene PRNP. Bio-informatic analyses were carried out in two randomized control trials totalizing over 3000 CRC patients.
RESULTS
In silico analyses combined with cell-based assays identified the Wnt-β-catenin and glucocorticoid pathways as upstream regulators of PRNP expression, with subtle differences between mouse and human. We uncover multiple feedback loops between PrP and these two pathways, which translate into an aggravation of CRC pathogenesis in mouse. In stage III CRC patients, the signature defined by PRNP-CTNNB1-NR3C1, encoding PrP, β-catenin and the glucocorticoid receptor respectively, is overrepresented in the poor-prognosis, mesenchymal subtype and associates with reduced time to recurrence.
CONCLUSIONS
An unleashed PrP-dependent vicious circle is pathognomonic of poor prognosis, mesenchymal CRC. Patients from this aggressive subtype of CRC may benefit from therapies targeting the PRNP-CTNNB1-NR3C1 axis.
Topics: Humans; Mice; Animals; Prion Proteins; beta Catenin; Glucocorticoids; Colonic Neoplasms; Colorectal Neoplasms; Phenotype; Prognosis; Wnt Signaling Pathway; Gene Expression Regulation, Neoplastic; Cell Line, Tumor
PubMed: 38589873
DOI: 10.1186/s12967-024-05164-0 -
Molecular Genetics & Genomic Medicine Apr 2024Congenital insensitivity to pain with anhidrosis (CIPA) is an extremely rare autosomal recessive disorder caused by loss-of-function mutations of the NTRK1 gene,... (Review)
Review
BACKGROUND
Congenital insensitivity to pain with anhidrosis (CIPA) is an extremely rare autosomal recessive disorder caused by loss-of-function mutations of the NTRK1 gene, affecting the autonomic and sensory nervous system. Clinical manifestation is varied and includes recurrent fever, pain insensitivity, anhidrosis, self-mutilating behavior, and intellectual disability.
METHODS
Clinical and genetic features were assessed in two males and one female with genetically confirmed CIPA using exome or genome sequencing.
RESULTS
CIPA symptoms including recurrent fever, pain insensitivity, and anhidrosis manifested at the age of 1 year (age range: 0.3-8 years). Two patients exhibited self-mutilation tendencies, intellectual disability, and developmental delay. Four NTRK1 (NM_002529.3) mutations, c.851-33T>A (p.?), c.2020G>T (p.Asp674Tyr), c.2303C>T (p.Pro768Leu), and c.574-156_850+1113del (exons 5-7 del) were identified. Two patients exhibited early onset and severe phenotype, being homozygous for c.851-33T>A (p.?) mutations and compound heterozygous for c.851-33T>A (p.?) and c.2020G>T (p.Asp674Tyr) mutation of NTRK1. The third patient with compound heterozygous mutations of c.2303C>T (p.Pro768Leu) and c.574-156_850+1113del (exons 5-7 del) displayed a late onset and milder clinical manifestation.
CONCLUSION
All three patients exhibited variable phenotypes and disease severity. This research enriches our understanding of clinical and genetic aspects of CIPA, highlighting variable phenotypes and disease severity.
Topics: Child; Child, Preschool; Female; Humans; Infant; Male; Channelopathies; Hereditary Sensory and Autonomic Neuropathies; Hypohidrosis; Indoles; Intellectual Disability; Pain; Pain Insensitivity, Congenital; Propionates
PubMed: 38581121
DOI: 10.1002/mgg3.2430