Identification of the molecular subtypes and signatures to predict the prognosis, biological functions, and therapeutic response based on the anoikis‐related genes in colorectal cancer

Cancer Medicine, Journal Year: 2024, Volume and Issue: 13(10)

Published: May 1, 2024

Abstract Background Tumors that resist anoikis, a programmed cell death triggered by detachment from the extracellular matrix, promote metastasis; however, role of anoikis‐related genes (ARGs) in colorectal cancer (CRC) stratification, prognosis, and biological functions remains unclear. Methods We obtained transcriptomic profiles CRC 27 ARGs The Cancer Genome Atlas, Gene Expression Omnibus, MSigDB databases, respectively. tissue samples were classified into two clusters based on expression pattern ARGs, their functional differences explored. Hub screened using weighted gene co‐expression network analysis, univariate least absolute selection shrinkage operator validated lines, tissues, or Human Protein Atlas database. constructed an ARG‐risk model nomogram to predict prognosis patients with CRC, which was external cohort. Multifaceted landscapes, including stemness, tumor microenvironment (TME), immune landscape, drug sensitivity, between high‐ low‐risk groups examined. Results Patients divided C1 C2 clusters. Cluster exhibited higher TME scores, whereas cluster had favorable outcomes stemness index. Eight upregulated hub ( TIMP1 , P3H1 SPP1 HAMP IFI30 ADAM8 ITGAX APOC1 ) utilized construct risk model. qRT‐PCR, Western blotting, immunohistochemistry results consistent those bioinformatics analysis. high worse overall survival p < 0.01), increased TME, checkpoint expression, infiltration, mutation burden, susceptibility compared low risk. Conclusion Our offer novel stratification risk‐scoring system could immunophenotypes, thereby improving prognosis. This may facilitate personalized therapies.

Language: Английский

---

Methionine Metabolism Dictates PCSK9 Expression and Antitumor Potency of PD‐1 Blockade in MSS Colorectal Cancer

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: March 24, 2025

Abstract Nutrient metabolisms are vitally interrelated to cancer progression and immunotherapy. However, the mechanisms by which nutrient interact remodel immune surveillance within tumor microenvironment remain largely unexplored. Here it is demonstrated that methionine restriction inhibits expression of proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator cholesterol homeostasis potential target for immunotherapy, in colorectal (CRC) but not liver. Mechanistically, catabolized S‐adenosylmethionine (SAM), promoting mRNA transcription PCSK9 through increased DNA methyltransferase 1 (DNMT1)‐mediated methylation suppression sirtuin 6 (SIRT6) expression. Furthermore, both inhibition dietary (DMR) potentiate PD‐1 blockade therapy foster infiltration CD8 + T cells Colon 26 tumor‐bearing mice—a proficient mismatch repair (pMMR)/microsatellite stable (MSS) CRC model exhibits limited response anti‐PD‐1 therapy. Moreover, combining 5‐fluorouracil (5‐FU) chemotherapy with further augments therapeutic efficacy MSS CRC. The findings establish mechanistic link between amino acid metabolism where sense regulate expression, highlighting promising combination strategies may greatly benefit patients.

Language: Английский

---

Integrating transcriptomics and machine learning for immunotherapy assessment in colorectal cancer

Cell Death Discovery, Journal Year: 2024, Volume and Issue: 10(1)

Published: April 2, 2024

Abstract Colorectal cancer (CRC) is a highly prevalent and lethal malignancy worldwide. Although immunotherapy has substantially improved CRC outcomes, intolerance remains major concern among most patients. Considering the pivotal role of tumor microenvironment (TME) in progression treatment profiling TME at transcriptomic level can provide novel insights for developing strategies. Seventy-seven TME-associated signatures were acquired from previous studies. To elucidate variations prognosis, clinical features, genomic alterations, responses to CRC, we employed non-negative matrix factorization algorithm categorize 2595 samples 27 microarrays Gene Expression Omnibus database. Three machine learning techniques identify signature specific immunotherapy. Subsequently, mechanisms by which this interacts with subtypes investigated. Our findings revealed five distinct (TMESs; TMES1–TMES5) each exhibiting unique pattern response. TMES1, TMES4, TMES5 had relatively inferior TMES2 was associated poorest TMES3 superior outcome. Subsequent investigations that activated dendritic cells could enhance response rate, their augmentation effect closely activation CD8 + T cells. We successfully classified into TMESs, demonstrating varying rates Notably, application helped underlying contributing these differences. posit TMESs hold promising implications prognostic evaluation guidance strategies, thereby providing valuable inform decision-making.

Language: Английский

---

QPH-FR: A Novel Quinoa Peptide Enhances Chemosensitivity by Targeting Leucine-Rich Repeat-Containing G Protein-Coupled Receptor 5 in Colorectal Cancer

Journal of Agricultural and Food Chemistry, Journal Year: 2024, Volume and Issue: 72(31), P. 17417 - 17430

Published: July 24, 2024

Chemoresistance is one of the difficulties in treatment colorectal cancer (CRC), and enhanced stemness tumor cells underlying contributing factor. Leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) a classical marker CRC stem can be an important potential target for chemotherapy. Quinoa, protein-rich plant, offers as source high-quality active peptides. Novelly, study obtained quinoa protein hydrolysate (QPH) from whole grains by simulated digestion. In vivo experiments revealed that volume 5-FU+QPH group decreased 145.90 ± 13.35 to 94.49 13.05 mm3 5-FU group, suggesting QPH enhances chemosensitivity CRC. Further, most effective peptide QPH-FR 631 peptides was screened activity prediction, molecular docking, experimental validation. Mechanistically, competitively suppressed formation LGR5/RSPO1 complex binding LGR5, causing RNF43/ZNRF3 ubiquitinate FZD receptor, thereby suppressing Wnt/β-catenin signaling pathway exerting inhibition. summary, proposes novel elucidates mechanism which targets LGR5 enhance chemosensitivity, providing theoretical support development chemotherapeutic adjuvant drugs based on plant

Language: Английский

---

Role ofCD47gene expression in colorectal cancer: a comprehensive molecular profiling study

Journal for ImmunoTherapy of Cancer, Journal Year: 2024, Volume and Issue: 12(11), P. e010326 - e010326

Published: Oct. 1, 2024

Background In patients with colorectal cancer (CRC), the therapeutic effects of conventional immune checkpoint inhibitors targeting adaptive system are largely limited to those microsatellite instability-high tumors. Meanwhile, new immunotherapies innate attracting increasing attention. CD47 is a representative involved in evasion tumor cell phagocytosis by macrophages. This large-scale study comprehensively examined molecular significance gene expression CRC. Methods We analyzed next-generation sequencing data DNA and RNA from 14,287 CRC cases included set commercial Clinical Laboratory Improvement Amendments-certified laboratory (Caris Life Sciences). The were divided into two groups based on median value levels. profiles between compared, relationship survival outcomes was further examined. Results -high tumors, proportion consensus subtypes 1 4 significantly higher than -low levels damage-associated pattern-related genes showed positive correlation Major oncogenic pathways, such as mitogen-activated protein kinase, phosphoinositide 3-kinase, angiogenesis, transforming growth factor beta, activated Additionally, panel estimates cells constituting microenvironment (TME) Conclusions associated activation several pathways an immune-engaged TME. Our findings may provide valuable information for considering strategies checkpoints

Language: Английский

---