Triple-negative breast cancer (TNBC) primarily relies on traditional adjuvant chemotherapy and radiotherapy, which have significant side effects and are prone to drug resistance. Poly ADP-ribose polymerase inhibitor (PARPi) has been approved for TNBC patients with BRCA mutation, but some BRCA wild-type patients with homologous recombination deficiencies are also sensitive to PARPi. Therefore, it is important to identify potential molecules that influence PARPi sensitivity in BRCA wild-type TNBC and to explore their specific mechanisms. Through CRISPR-cas9 loss-of-function screening, the lncRNA MTUS2-AS1 was identified to be significantly correlated with PARPi sensitivity in BRCA wild-type TNBC cells. In vitro and in vivo experiments were performed to investigate its function and underlying mechanism. We found that MTUS2-AS1 knockdown suppressed DNA damage repair and enhanced the anticancer effects of PARPi in BRCA-wild TNBC cells. Mechanistically, MTUS2-AS1 upregulates DDX5 protein expression by maintaining its stability, thereby promoting R-loop resolution, and suppressing DNA damage. Knocking down MTUS2-AS1 accelerated DDX5 protein degradation, reduced DDX5 protein expression, inhibitd R-loop resolution, promoted DNA damage, and ultimately enhanced the PARPi sensitivity in TNBC cells. Our study provided new insights into exploring the key molecules and mechanisms influencing the sensitivity of PARPi treatment and had great significance for screening benefit population and expanding the indications of PARPi treatment.

Acute coronary syndrome, driven by vulnerable plaque (VP) instability, is a major cause of cardiovascular mortality. Current diagnostic methods for VPs are limited by invasiveness or low specificity, highlighting the need for non-invasive biomarkers. Using single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) from coronary artery disease (CAD) patients with VPs and controls, we identified circulating T cell-platelet aggregates (TPAs) significantly enriched in VP patients and linked to plaque instability via pro-inflammatory pathways. Through high dimensional weighted gene co-expression network analysis, we discovered TPAs' hub genes and demonstrated their role in plaque destabilization. Furthermore, employing machine learning, including Boruta, least absolute shrinkage and selection operator (LASSO) regression and support vector machine-recursive feature elimination (SVM-RFE), we screened for five blood biomarkers that can serve as diagnostic indicators for VPs. Our study demonstrates that TPAs are critically involved in VPs formation. Furthermore, we identified EPHB6, STAT1, RPL23, IKZF3 and AHCY as potential circulating biomarkers for non-invasive detection of VPs.

Acquired resistance to 5-fluorouracil (5-FU) curtails the survival benefit of chemotherapy in colorectal cancer (CRC). We asked whether a discrete subset of cancer-associated fibroblasts (CAFs) drives this phenotype. Multi-omic profiling of 24 CRC cohorts identified 10 collagen genes linked to poor outcome and 5-FU resistance; single-cell RNA-seq localized them to specific CAFs. Cellular communication modelling, in vitro proliferation, migration, apoptosis, and drug-sensitivity assays, together with CRISPR/Cas9 and siRNA perturbations, xenografts, and immunochemical analyses, examined the functional relevance of COL8A1-positive fibroblasts (COL8A1⁺Fibs) and their downstream signalling pathways. COL8A1⁺Fibs were enriched in advanced tumors and preferentially interacted with 5-FU-resistant malignant cells. Conditioned media from COL8A1⁺Fibs accelerated CRC cell growth, invasion, and 5-FU tolerance, and activated an epithelial–mesenchymal transition (EMT) programme. Secreted COL8A1 engaged integrin-β1 (ITGB1) on tumor cells; silencing ITGB1 or COL8A1 abrogated EMT induction, reduced proliferation, and restored 5-FU sensitivity in vitro and in vivo. COL8A1⁺Fibs orchestrate 5-FU resistance in CRC via a COL8A1/ITGB1-mediated EMT axis. Disrupting this stromal–tumor crosstalk represents a promising therapeutic strategy to overcome chemoresistance.

Background:Ventricular pre-excitation can cause left ventricular (LV) mechanical dyssynchrony and dysfunction. However, the specific impact of accessory pathway (AP) location on LV mechanics remains incompletely characterized. This study utilized two-dimensional speckle-tracking echocardiography (2D-STE) to quantify and compare LV deformation and synchrony across these anatomical subgroups. Methods:We retrospectively analyzed 91 patients with Wolff-Parkinson-White (WPW) syndrome (age 38.2±1.4 years) and 56 matched controls using 2D-STE. Global and regional LV deformation and synchrony were compared across AP-location groups: septal (n=34), right (n=38), and left (n=19). LV deformation parameters included circumferential strain (CS), longitudinal strain (LS), and radial strain (RS). LV synchrony was assessed by peak strain dispersion (PSD) of LV segments for each strain direction. Results:All patient groups (septal: -19.0%±0.7%, right: -19.3%±0.6%, and left AP: -19.2%±0.8%) had lower global CS (GCS) compared with controls (-23.1%±0.4%, all P<0.001). The septal AP group showed lower global LS (GLS) (-17.2%±0.5%), global RS (GRS) (30.1%±2.0%), and prolonged GLS-PSD (51.3±3.1 ms) than the left AP group and controls (P<0.05). The right AP group exhibited lower GLS (-17.5%±0.5%) than the left AP group (-19.6%±0.5%, P<0.05) and prolonged GLS-PSD (46.7±2.5 ms) compared with controls (31.6±1.1 ms, P<0.001). The left AP group showed GLS (-19.6%±0.5%), GRS (40.0%±2.6%), and GLS-PSD (40.1±2.3 ms) that were not significantly different from controls (all P>0.05). LV ejection fraction (LVEF) was lower in septal (59.2%±1.2%) and right AP groups (59.8%±1.0%) vs. controls (65.0%±0.3%; P<0.001). LVEF correlated negatively with GLS (r=-0.53, P<0.001) and with GLS-PSD (r=-0.41, P<0.001). Conclusions:LV mechanical dysfunction in WPW syndrome varies by AP location. Septal and right APs lead to widespread strain impairment, dyssynchrony, and lower LVEF, whereas left APs mainly reduce CS. Reduced LVEF is closely associated with impaired LV mechanics and dyssynchrony.

Inflammatory bowel disease (IBD) is a chronic and clinically important intestinal disorder with rapidly rising global incidence and prevalence. While biological therapies targeting tumor necrosis factor-alpha (TNF-alpha), a key cytokine in IBD pathogenesis, have shown clinical efficacy, their use is often limited by systemic adverse effects. RNA interference (RNAi) offers a promising strategy for precise gene silencing, yet its therapeutic application is constrained by the poor stability and inefficient in vivo delivery of small interfering RNA (siRNA). To overcome these challenges, we developed a macrophage-targeted, colon-specific liposomal system for delivering TNF-alpha siRNA. The liposomes were functionalized with mannose to selectively engage the mannose receptor (MR, CD206), highly expressed on macrophages, and coated with Eudragit S100 (ES100), a pH-responsive polymer that shields siRNA from gastrointestinal degradation and enables site-specific release in the colon. The resulting ES100-coated, mannose-modified liposomes (EML/siRNA) demonstrated enhanced cellular uptake and efficient siRNA delivery to macrophages both in vitro and in vivo. In animal models of IBD, treatment with EML/siRNA significantly downregulated pro-inflammatory cytokine, alleviated intestinal inflammation, and promoted mucosal tissue repair, as evidenced by histopathological analysis. This study introduces a dual-functional nanotherapeutic platform that combines targeted RNAi-mediated TNF-alpha silencing with colon-specific delivery and mucosal protection, offering a promising and refined therapeutic strategy for IBD.

Background: Metabolic reprogramming is a hallmark of colorectal cancer (CRC), yet the molecular regulators that orchestrate this process remain incompletely understood. Although many long non-coding RNAs (lncRNAs) possess protein-coding potential, their translational products and metabolic functions have been largely overlooked. Here, we identify MUCP1, a microprotein encoded by the lncRNA MUC20-OT1, as a critical regulator of mitochondrial metabolism and epigenetic remodeling in CRC. Methods: Multi-omics data were integrated to identify MUC20-OT1 as a candidate lncRNA encoding a functional microprotein. Fusion reporter plasmids, mass spectrometry, and immunoblotting were used to validate MUCP1 translation and mitochondrial localization. Functional assays, metabolomic profiling, 13C5-glutamine isotope tracing, subcellular succinate quantification, CUT&Tag, and xenograft models were performed to investigate the role of MUCP1 in facilitating mitochondrial succinate export and maintaining glutamine metabolism homeostasis. Results: The microprotein MUCP1, encoded by the lncRNA MUC20-OT1, serves as an auxiliary regulator of SLC25A10-mediated mitochondrial succinate transport. MUCP1 is upregulated during CRC progression and localizes in the mitochondrial outer membrane, where it facilitates the balance of mitochondrial succinate metabolism. Elevated extramitochondrial succinate subsequently enhances H3K4me3 histone modifications, promoting the transcription of enzymes involved in glutamine metabolism and sustaining the high metabolic demands of CRC cells. Conclusions: This study identifies MUCP1 as a novel lncRNA-encoded microprotein that maintains metabolic homeostasis in CRC by coupling mitochondrial succinate transport to histone methylation. MUCP1 might be a promising metabolic vulnerability and therapeutic target in CRC.

The Golgi apparatus plays a key role in innate immune signaling, but its exact role in depression-related neuroinflammation remains unclear. The role of Dymeclin (DYM), a Golgi structural protein, in stress-related psychiatric disorders needs further clarification. This study aims to investigate whether DYM participates in the development of chronic stress-induced depression by regulating Golgi function. A mouse depression model was developed with chronic unpredictable mild stress (CUMS), followed by a rescue experiment using stereotactic injection of DYM-overexpressing lentiviruses into the hippocampus. Depression-associated behaviors, hippocampal metabolites, Golgi apparatus function, and inflammatory markers were examined using mass spectrometry, immunofluorescence, electron microscopy, and immunoprecipitation techniques. Overexpression of DYM mitigated depressive-like behaviors induced by CUMS in mice. Additionally, it enhanced the structural integrity of the Golgi apparatus, suppressed NLRP3 inflammasome activation, reduced levels of central and peripheral inflammatory factors, and partially ameliorated hippocampal metabolic disturbances. In vitro experiments further confirmed that DYM overexpression inhibited LPS-induced NLRP3 upregulation and inflammatory factor release in microglia. This study reveals that chronic stress causes depressive-like behaviors by reducing hippocampal DYM expression, leading to Golgi dysfunction and triggering NLRP3 inflammasome-related neuroinflammation and metabolic issues. This finding broadens the traditional framework of depression research, which has primarily focused on neurons and monoamine neurotransmitters, by underscoring the pivotal role of Golgi organelle homeostasis in mediating the interactions among stress, neuro-immune, and metabolic processes. Our research indicates that targeting the DYM/Golgi pathway could offer new treatment strategies and a theoretical foundation for reducing depression-related neuroinflammation and metabolic issues. Drugs targeting the structural stability of the Golgi apparatus may serve as potential candidates for novel antidepressants in the future.

ABSTRACT Getah virus (GETV) is an emerging mosquito-borne alphavirus that poses a growing threat to animal and public health. However, the molecular mechanisms underlying its pathogenesis and immune evasion remain poorly defined. This study demonstrated that GETV infection suppressed the activation of interferon β (IFN-β) or IFN-stimulated response element after poly(I:C) stimulation. By screening nine viral proteins (non-structural proteins 1–4 [nsP1–4] and C-E3-E2-6K-E1), we discovered that the nsP2 protein of GETV could effectively inhibit the production of IFN-β and IFN-stimulated genes. Subsequently, we discovered that nsP2 disrupted the retinoic acid-inducible gene I-like receptor signaling pathway by causing widespread cellular shutoff and directly targeting inhibitor of kappa-B kinase ε (IKKε). Mechanistically, the inhibitory function of nsP2 is contingent upon the protein’s structural integrity and the presence of proline 717 and nuclear localization signal-related residues. Additionally, we illustrated that nsP2 markedly inhibited TRAF2-induced K63-linked polyubiquitination and phosphorylation of IKKε, which is essential for activating IKKε. Altogether, the present study elucidated a new mechanism in which GETV modulates the host’s antiviral immunity.IMPORTANCEGetah virus (GETV), a multi-host alphavirus of the Togaviridae family, imposes a significant economic burden on the swine industry by causing fever, diarrhea, reproductive disorders in sows, and elevated mortality in newborn piglets. Here, we reveal that GETV non-structural protein 2 antagonizes interferon β (IFN-β) production through a dual mechanism: it induces broad cellular shutoff and directly interacts with inhibitor of kappa-B kinase ε (IKKε) to prevent its activation. This strategy effectively disrupts type I IFN responses by suppressing antiviral gene expression, such as IKKε, IFN-I, and IFN-stimulated genes, and impairing retinoic acid-inducible gene I-like receptor signaling activation. Our findings not only uncover a novel mechanism of GETV immune evasion but also establish the rationale for novel therapeutic targets, suggesting a new avenue for the treatment and intervention of GETV infection.

Transfer RNA-derived small RNAs (tsRNAs) are a novel class of small non-coding RNAs abundant in the bloodstream of cancer patients and involved in various physiological and pathological processes. However, the regulatory mechanisms and clinical significance of tsRNAs in colorectal cancer (CRC) remain unclear. In this study, PANDORA-seq was used as an exploratory screen of CRC tissues, paired adjacent tissues, and CRC plasma samples, followed by validation in larger independent cohorts. Quantitative real-time PCR quantified mt-5'-tiRNA-Tyr levels in tissues, plasma, and cells. Functional assays assessed the role of mt-5'-tiRNA-Tyr in CRC. Mechanistic studies utilized RNA pull-down, mass spectrometry, RNA immunoprecipitation, western blotting, and Co-immunoprecipitation. Results revealed that mt-5'-tiRNA-Tyr was significantly upregulated in CRC plasma and tissues. In vitro and in vivo studies demonstrated its oncogenic potential. Mechanistic assays showed that mt-5'-tiRNA-Tyr was enriched with HARS2 in RNA pull-down/RIP assays and associated with reduced HARS2-mt-tRNA-His association, increased HARS2 K91 succinylation, impaired mitochondrial protein translation, and mitochondrial damage. Moreover, succinate accumulation creates a positive feedback loop that enhances CRC proliferation. This study identifies a novel oncogenic tsRNA and uncovers a mechanism by which mt-5'-tiRNA-Tyr promotes CRC proliferation through HARS2 succinylation, supporting further evaluation of plasma mt-5'-tiRNA-Tyr as a candidate circulating biomarker for CRC.

Colorectal cancer (CRC) is one of the most common malignancies. Hypoxia can promote the occurrence and development of CRC. However, how hypoxia regulates the CRC immune microenvironment needs to be further explored. The bulk RNA sequencing data and clinicopathological information of CRC patients were enrolled from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. The single-cell RNA sequencing (scRNA-seq) datasets of CRC were collected from and analyzed from the GEO database and the ArrayExpress database. The score of the hypoxia gene set was estimated using the "ssGSEA" algorithm in the "GSVA" R package. The functional characteristics of CAF subtypes were studied by bioinformatics analysis and in vitro experiments, and a prognostic model was constructed based on machine learning correlation. Hypoxia is associated with poor prognosis in CRC patients. Periostin (POSTN) + Fib is a cancer-associated fibroblast (CAF) closely associated with hypoxia, and high infiltration of POSTN + Fib is associated with adverse outcomes in overall survival (OS) and relapse-free survival (RFS) in CRC patients. Hypoxia can induce POSTN expression and secretion in CAFs. Hypoxia-induced increase of POSTN expression in CAFs can significantly promote the migration and proliferation of CRC cells. Hypoxia-induced increase of POSTN expression in CAFs can significantly promote the proliferation and migration of CRC cells. The POSTN+Fib Hypoxia-Related Risk Model (PFHRM) can predict the survival and immunotherapy response of CRC patients. Our study identified a POSTN+Fib cell subpopulation closely associated with hypoxia, which promotes the malignant progression of CRC. The development of PFHRM provides a theoretical basis for improving patient survival and prognosis.

Colorectal cancer (CRC) is a common gastrointestinal cancer with poor response to therapy and high metastatic risk. Cancer-associated fibroblasts (CAFs) support tumor progression, but their functional heterogeneity remains poorly understood. We integrated multi-omics data from 10,164 samples, including single-cell, bulk, spatial transcriptomics, and proteomics, to identify and characterize CAF subpopulations. Functional validation was performed using molecular assays, in vivo models, and drug screening. We identified a COL10A1-positive fibroblast subpopulation (COL10A1+Fib) associated with CRC progression and poor patient prognosis. COL10A1+Fib promotes tumor cell proliferation, immune suppression, and metastasis. Mechanistically, COL10A1+Fib facilitates epithelial–mesenchymal transition (EMT) in CRC cells via COL10A1 secretion and induces M2 macrophage polarization through the COL10A1/CD18/JAK1/STAT3 signaling axis. In turn, M2 macrophages enhance COL10A1 expression in fibroblasts via the TGF-β/RUNX2 pathway, forming a pro-tumorigenic feedback loop. The DNA-PKcs inhibitor NU7441 reduces COL10A1 expression, suppresses CAF activity, and reverses EMT and M2 polarization. Pan-cancer analysis suggests that COL10A1+Fib may have similar functional roles across multiple major solid tumors. Our study identifies a CAF subpopulation, COL10A1+Fib, associated with CRC progression and immune suppression, suggesting it as a potential therapeutic target in CRC and possibly other malignancies.

Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality worldwide. Tumor epithelial cells play a crucial role in shaping the tumor microenvironment (TME) and driving cancer progression. This study utilized a multi-omics approach, integrating data from 21 multi-center CRC cohorts (n = 2,767), including single-cell transcriptomics, bulk transcriptomics, spatial transcriptomics, and proteomics. Bioinformatic analyses were combined with in vitro and in vivo experiments for validation. A distinct epithelial subpopulation, ERO1A-positive epithelial cells (ERO1A + Epi), was identified and found to be significantly enriched in advanced-stage CRC, correlating with poor prognosis. ERO1A + Epi cells promoted proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) in vitro, while in vivo models confirmed their role in tumor growth and liver metastasis. Spatial and intercellular interaction analyses revealed that ERO1A + Epi cells interact with CTHRC1 + cancer-associated fibroblasts (CTHRC1 + CAFs) and SPP1 + macrophages via MDK-LRP1, MIF-(CD74 + CD44), and APP-CD74 signaling pathways, fostering a pro-tumorigenic TME. Co-culture experiments demonstrated that ERO1A + Epi enhances the expression of CTHRC1 and SPP1. A risk prediction model (ETSRM) based on the ERO1A + Epi_TME_Score demonstrated superior prognostic accuracy over 111 existing CRC models. Integrating ETSRM with TNM staging further enhanced survival prediction. Our findings identify ERO1A + Epi as a significant driver of colorectal cancer progression. The ERO1A + Epi_TME_Score-based ETSRM provides a robust prognostic tool, offering new insights into CRC pathogenesis and highlighting potential therapeutic targets for improved patient outcomes. Summarizes ERO1A-positive tumor epithelial cells in colorectal cancer progression: a multi-omics perspective.

BACKGROUND:Preoperative chemotherapy (PC) is an important component of Colorectal cancer (CRC) treatment, but its effects on the biological functions of fibroblasts and epithelial cells in CRC are unclear. METHODS:This study utilized bulk, single-cell, and spatial transcriptomic sequencing data from 22 independent cohorts of CRC. Through bioinformatics analysis and in vitro experiments, the research investigated the impact of PC on fibroblast and epithelial cells in CRC. Subpopulations associated with PC and CRC prognosis were identified, and a predictive model was constructed using machine learning. RESULTS:PC significantly attenuated the pathways related to tumor progression in fibroblasts and epithelial cells. NOTCH3 + Fibroblast (NOTCH3 + Fib), TNNT1 + Epithelial (TNNT1 + Epi), and HSPA1A + Epithelial (HSPA1A + Epi) subpopulations were identified in the adjacent spatial region and were associated with poor prognosis in CRC. PC effectively diminished the presence of these subpopulations, concurrently inhibiting pathway activity and intercellular crosstalk. A risk signature model, named the Preoperative Chemotherapy Risk Signature Model (PCRSM), was constructed using machine learning. PCRSM emerged as an independent prognostic indicator for CRC, impacting both overall survival (OS) and recurrence-free survival (RFS), surpassing the performance of 89 previously published CRC risk signatures. Additionally, patients with a high PCRSM risk score showed sensitivity to fluorouracil-based adjuvant chemotherapy (FOLFOX) but resistance to single chemotherapy drugs (such as Bevacizumab and Oxaliplatin). Furthermore, this study predicted that patients with high PCRSM were resistant to anti-PD1therapy. CONCLUSION:In conclusion, this study identified three cell subpopulations (NOTCH3 + Fib, TNNT1 + Epi, and HSPA1A + Epi) associated with PC, which can be targeted to improve the prognosis of CRC patients. The PCRSM model shows promise in enhancing the survival and treatment of CRC patients.

Colorectal cancer (CRC) is one of the most serious gastrointestinal tumors. The survival rate of patients with advanced stages is meager, so it is urgent to identify new diagnostic biomarkers with high sensitivity and specificity. tRNA-derived small RNAs (tsRNAs) are an emerging class of small non-coding RNAs that are highly abundant in the blood of cancer patients and are associated with various physiological and pathological processes. Therefore, the clinical value of tsRNAs in diagnosing CRC requires further investigation. In this study, we identified the differential expression profiles of tsRNAs in CRC tissues via Pandora sequencing. We selected 5'-tiRNA-His that were significantly highly expressed in CRC plasma and tissues for further investigation. Interestingly, the expression level of 5'-tiRNA-His was increased dramatically in the plasma of CRC patients and correlated with various clinicopathologic parameters. ROC analysis revealed that 5'-tiRNA-His had good diagnostic value in diagnosing CRC patients, superior to that of CEA, CA199, and CA724, and could significantly differentiate patients with CRC from healthy donors and patients with intestinal polyps. Moreover, 5'-tiRNA-His still had good diagnostic efficacy in the diagnosis of patients with early-stage CRC, and the diagnostic efficacy was further elevated when combined with clinically used tumor markers. In conclusion, our study identified plasma 5'-tiRNA-His as a promising biomarker for diagnosing and screening CRC.

Colorectal cancer (CRC) is a prevalent malignancy, yet the role of lactylation in its progression remains unclear. This study investigates High Mobility Group Box 2 positive tumor epithelial cells (HMGB2+Epi), a lactylation-associated subpopulation. By integrating multi-omics data, including proteomics, single-cell, spatial, and bulk transcriptomics, we explored the function of HMGB2+Epi in CRC. Elevated lactylation levels in CRC tissues were correlated with poor prognosis. Single-cell analysis identified HMGB2+Epi as a central lactylation-enriched subpopulation. Functionally, HMGB2 enhanced the Warburg effect, promoting CRC cell proliferation, migration, and invasion. HMGB2 knockout reduced lactylation levels and inhibited tumor progression. Mechanistically, NFYB directly bound to the HMGB2 promoter, forming the NFYB-HMGB2 axis that drives lactylation and metabolic reprogramming. Cell-cell communication analysis revealed enhanced interactions between HMGB2+Epi and fibroblasts, endothelial cells, and T/NK cells. Molecular dynamics and in-vitro assays suggest that BI-2536 downregulates HMGB2 and lactylation in CRC cells. A risk model based on HMGB2+Epi outperformed 125 previously published models in independent cohorts. In summary, HMGB2+Epi represents a key lactylation-enriched subgroup, with the NFYB-HMGB2 axis driving CRC progression via lactylation. BI-2536 as a tool compound implicating the HMGB2-lactylation axis, and the HMGB2+Epi-based risk model provides a novel target for precision CRC therapy.

The recombinant oncolytic adenovirus is a novel anticancer agent to replicate selectively in colon cancer cell lines. Loss of imprinting (LOI) of insulin-like growth factor 2 (IGF2) gene is an epigenetic abnormality phenomenon. We utilized the IGF2 LOI in gene therapy for the malignant tumor cell lines. We investigated the tumoricidal effects of IGF2 LOI on four cell lines by oncolytic adenovirus, and constructed novel adenovirus vectors Ad312-E1A and Ad312-EGFP. The expression of E1A was monitored by real-time PCR and western blot analysis. The viability and apoptosis of colorectal cells infected with Ad312-E1A were tested by CCK-8 and flow cytometry. In addition, we established a colorectal cancer model in nude mice. The results showed that HCT-8 and HT-29 with IGF2 LOI were infected with Ad312-EGFP and then produced the EGFP. Nevertheless, SW480 and GES-1, which were IGF2 MOI, did not produce the EGFP. The Ad312-E1A obviously reduced the cell viability and induced apoptosis in HCT-8 and HT-29 in vitro, and successfully suppressed tumor growth in HT-29 xenografts in nude mice. In summary, the conditionally replicative adenovirus with loss of IGF2 imprinting system has a positive effect on gene therapy.

Colorectal cancer (CRC) ranks among the most aggressive malignancies globally, with advanced-stage patients exhibiting notably low survival rates. Consequently, there is an urgent imperative to identify novel biomarkers characterized by high sensitivity and specificity. Ribosomal RNA-derived small RNAs (rsRNAs), which originate from ribosomal RNAs, represent the most prevalent small noncoding RNAs (sncRNAs) in CRC tissues and plasma. Thus, the development of a diagnostic panel comprising multiple rsRNAs holds considerable significance for CRC diagnosis. Utilizing PANDORA-seq, we have, for the first time, delineated a novel sncRNA expression profile in CRC tissues and plasma, identifying rsRNAs as the predominant sncRNAs within these contexts. We identified six rsRNAs that were significantly upregulated in CRC plasma and subsequently constructed a co-diagnostic panel. This panel demonstrated an area under the curve (AUC) value of 0.898, which increased to 0.942 when combined with clinically utilized tumor markers, indicating robust diagnostic efficacy. Our study is the first to establish that rsRNAs are the most abundantly expressed sncRNAs in CRC tissues and plasma. We have developed an rsRNA panel with substantial diagnostic efficacy in CRC plasma, presenting promising potential as diagnostic biomarkers.

BACKGROUND:In China, CRC incidence is escalating. The main hurdles are heterogeneity and drug resistance. This research delves into cellular senescence in CRC, aiming to devise a prognostic model and pinpoint mechanisms impacting drug resistance.METHODS:Mendelian randomization (MR) analysis confirmed the association between CRC and cellular aging. The Cancer Genome Atlas (TCGA)-CRC data served as the training set, with GSE38832 and GSE39582 as validation sets. Various bioinformatics methods were employed to construct and validate a risk model. CRC cells with NADPH Oxidase 4 (NOX4) knockout were generated using CRISPR-Cas9 technology. Protein blotting and colony formation assays elucidated the role of NOX4 in CRC cell aging and drug resistance.RESULTS:A prognostic model, derived from dataset analysis, uncovered a link between high-risk groups and cancer progression. Notable differences in the tumor microenvironment were observed between risk groups. Finally, NOX4 was found to be linked with aging and drug resistance in CRC.CONCLUSION:This research presents a novel senescence-based CRC prognosis model. It identifies NOX4's role in CRC drug resistance, suggesting it is a potential treatment target.

Millions of people worldwide die from malignant tumors every year, and the current clinical treatment is still based on radiotherapy and chemotherapy. Immunotherapy-adjuvant chemotherapy is widely applied, yet resistance to various factors persists in the management of advanced malignancies. Recently researchers have gradually discovered that the integrity of primary cilia is closely related to many diseases. The phenotypic changes in primary cilia are found in some cases of progeria, tumorigenesis, and drug resistance. Primary cilia seem to mediate signaling during these diseases. Hedgehog inhibitors have emerged in recent years to treat tumors by controlling signaling proteins on primary cilia. There is evidence for the use of anti-tumor drugs to treat senescence-related disease. Considering the close relationship between aging and obesity, as well as the obesity is the phenotype of many ciliopathies. Therefore, we speculate that some anti-tumor or anti-aging drugs can treat ciliopathies. Additionally, there is evidence suggesting that anti-aging drugs for tumor treatment, in which the process may be mediated by cilia. This review elucidates for the first time that cilia may be involved in the regulation of senescence, metabolic, tumorigenesis, and tumor resistance and hypothesizes that cilia can be regulated to treat these diseases in the future.