Role In Colorectal Cancer Research Articles

Systematic analysis of human colorectal cancer scRNA-seq revealed limited pro-tumoral IL-17 production potential in gamma delta T cells

Gamma delta T cells play a crucial role in anti-tumor immunity due to their cytotoxic properties. However, the role and extent of γδ T cells in production of pro-tumorigenic interleukin-17 (IL-17) within the tumor microenvironment of colorectal cancer (CRC) remains controversial. In this study, we re-analyzed nine published human CRC whole-tissue single-cell RNA sequencing datasets, identifying 18,483 γδ T cells out of 951,785 total cells, in the neoplastic or adjacent normal tissue of 165 human CRC patients. Our results confirm that tumor-infiltrating γδ T cells exhibit high cytotoxicity-related transcription in both tumor and adjacent normal tissues, but critically, none of the γδ T cell clusters showed IL-17 production potential. We also identified various γδ T cell subsets, including poised effector-like T cells, tissue-resident memory T cells, progenitor exhausted-like T cells, and exhausted T cells, and noted an increased expression of cytotoxic molecules in tumor-infiltrating γδ T cells compared to their normal area counterparts. We proposed anti-tumor γδ T effector cells may arise from tissue-resident progenitor cells based on the trajectory analysis. Our work demonstrates that γδ T cells in CRC primarily function as cytotoxic effector cells rather than IL-17 producers, mitigating the concerns about their potential pro-tumorigenic roles in CRC, highlighting the importance of accurately characterizing these cells for cancer immunotherapy research and the unneglectable cross-species discrepancy between the mouse and human immune system in the study of cancer immunology.

In-Depth Proteomic Analysis of Paraffin-Embedded Tissue Samples from Colorectal Cancer Patients Revealed TXNDC17 and SLC8A1 as Key Proteins Associated with the Disease.

A deeper understanding of colorectal cancer (CRC) biology would help to identify specific early diagnostic markers. Here, we conducted quantitative proteomics on FFPE healthy, adenoma, and adenocarcinoma tissue samples from six stage I sporadic CRC patients to identify dysregulated proteins during early CRC development. Two independent quantitative 10-plex TMT experiments were separately performed. After protein extraction, trypsin digestion, and labeling, proteins were identified and quantified by using a Q Exactive mass spectrometer. A total of 2681 proteins were identified and quantified after data analysis and bioinformatics with MaxQuant and the R program. Among them, 284 and 280 proteins showed significant upregulation and downregulation (expression ratio ≥1.5 or ≤0.67, p-value ≤0.05), respectively, in adenoma and/or adenocarcinoma compared to healthy tissue. Ten dysregulated proteins were selected to study their role in CRC by WB, IHC, TMA, and ELISA using tissue and plasma samples from CRC patients, individuals with premalignant colorectal lesions (adenomas), and healthy individuals. In vitro loss-of-function cell-based assays and in vivo experiments using three CRC cell lines with different metastatic properties assessed the important roles of SLC8A1 and TXNDC17 in CRC and liver metastasis. Additionally, SLC8A1 and TXNDC17 protein levels in plasma possessed the diagnostic ability of early CRC stages.

DST regulates cisplatin resistance in colorectal cancer via PI3K/Akt pathway.

Dystonin (DST), a potential tumor suppressor gene, plays a crucial role in regulating cancer cell proliferation and resistance to chemotherapy. However, DST's specific role in colorectal cancer (CRC) has not been thoroughly investigated, and this study aims to elucidate its molecular role in modulating cisplatin (DDP) resistance in CRC. DST expression was analyzed in CRC tumors, DDP-resistant CRC tissues, paracancer tissues, and normal tissues. Lentiviral overexpression and shRNA knockdown were conducted in advanced CRC and DDP-resistant cell lines to assess cell viability, apoptosis, invasion, migration, proliferation, and angiogenesis. Xenograft mouse models studied DST's impact on CRC tumor growth and DDP resistance in vivo. DST expression was significantly reduced in CRC tumor and DDP-resistant CRC tissues compared to paracancer and normal tissues (P < .001). Upregulating DST inhibited CRC and DDP-resistant cell viability, proliferation, invasion, and migration while promoting apoptosis. DST overexpression also reduced angiogenesis and attenuated DDP-induced cytotoxicity in CRC cells. Mechanistically, DST upregulation suppressed DDP resistance in CRC cells via the PI3K/Akt signaling pathway. DST upregulation reduced CRC tumor growth and mitigated DDP resistance, in vivo. DST plays a crucial role in limiting CRC progression and overcoming DDP resistance, suggesting potential for targeted CRC therapies.

Advances in microRNAs as Emerging Biomarkers for Colorectal Cancer Early Detection and Diagnosis.

Colorectal cancer (CRC) remains the second most common cause of cancer-related mortality worldwide, necessitating advancements in early detection and innovative treatment strategies. MicroRNAs (miRNAs), small non-coding RNAs involved in gene regulation, have emerged as crucial players in the pathogenesis of CRC. This review synthesizes the latest findings on miRNA deregulated in precancerous lesions and in CRC. By examining the deregulation patterns of miRNAs across different stages of CRC development, this review highlights their potential as diagnostic tools. We specifically analyse the roles and diagnostic relevance of four miRNAs-miR-15b, miR-21, miR-31, and miR-146a-that consistently exhibit altered expression in CRC. The current knowledge of their role in key oncogenic pathways, drug resistance, and clinical relevance is discussed. Despite challenges posed by the heterogeneity of the research findings on miRNA deregulation and their role in CRC, integrating miRNA diagnostics into current screening methods holds promise for enhancing personalized medicine approaches. This review emphasizes the transformative potential of miRNAs in CRC diagnosis, paving the way for improved patient outcomes and novel therapeutic paradigms.

Lower expressions of MIR34A and MIR31 in colo-rectal cancer are associated with an enriched immune microenvironment

IntroductionMicroRNAs (MIRs) play a crucial role in colorectal cancer (CRC) development and metastasis by regulating immune responses. Tumour-infiltrating lymphocytes (TILs) are an important predictive factor in many cancers, but, their association with microRNAs have not been studied well in colorectal cancer. Three microRNAs (MIR34A, MIR31 & MIR21), the roles of which in tumorigenesis is well-studied and which also possess immunomodulatory effect, were identified by extensive literature search. Of these, MIR34A acts as a tumour suppressor, MIR21 is considered an onco-MIR, and MIR31 displays both tumour-suppressing and oncogenic properties, making it ambiguous. This study examines the relationship between these three micro-RNAs and TILs in CRC. Materials & methodsConducted over 18 months at a tertiary cancer care hospital in southern India, this unicentric observational study included 69 cases. These cases were analyzed for miR expression using q-RT-PCR, TILs density through hematoxylin & eosin(H&E) slide examination, and p53 and beta-catenin expression via immunohistochemistry (IHC). Correlations between non-parametric variables were assessed using Chi-square and Spearman correlation tests. ResultsThe study found significantly higher MIR34A expression in patients aged 60 years and less (26/41, p=0.024) and a higher prevalence of MIR21 in male patients (23/35, p=0.012). TILs at the tumour advancing front were categorized as low (≤10 %) or high (≥15 %). Among the 36 cases with low TILs, high MIR34A and high MIR31 expressions were observed in 24 cases (p=0.016) and 23 cases (p=0.03), respectively. Conversely, 21 of 33 cases with high TILs had low expressions of both MIR34A and MIR31. High TILs were more common in early-stage CRC (TNM stages I-IIIA), with 20 out of 28 cases, compared to 28 of 41 cases in later stages (IIIB-IVC) exhibiting low TILs (p=0.003). Aberrant p53 expression correlated with lower MIR34A levels, consistent with TCGA data. ConclusionLower MIR34A and MIR31 levels are associated with higher TILs density in CRC. Unlike other cancers where MIR34A has anti-tumour effects, there was no statistically significant correlation between its expression and the pT or TNM stages in this study. Increased TILs being a good prognostic indicator, this suggests MIR34A and MIR31 may help CRC cells evade immune surveillance. Aberrant p53 expression downregulates MIR34A, underscoring the therapeutic potential of miRs.

Mitotic spindle positioning protein serves as prognostic biomarker in patients with colorectal cancer

Background Colorectal cancer (CRC) ranks among the most aggressive types of cancer globally. Currently, clinical tumor prognostic biomarkers still lack accuracy. Mitotic spindle positioning (MISP) protein connects microtubules to the actin cytoskeleton and adhesive plaques, playing a critical role in spindle positioning, orientation, and the process of cell division. MISP can regulate the malignant biological functions of pancreatic cancer and intrahepatic cholangiocarcinoma and it acts as biomarker for prognosis, but its role in CRC remains unclear. Methods This study has collected 37 CRC tissue samples and 37 corresponding adjacent nontumor tissue samples, and 57 additional CRC tissues samples. Clinical data were obtained from the patients with CRC. MISP mRNA and protein expression levels were analyzed in normal control and CRC tissues using the GEPIA and Human Protein Atlas website. MISP protein levels in the collected tissues were analyzed using immunohistochemistry. Results MISP mRNA and protein expression levels were significantly increased in CRC tissues compared to adjacent nontumor tissues. Higher MISP protein levels were associated with distant metastasis, recurrence, and lower survival rates. Kaplan–Meier analysis showed that high expression levels of MISP protein were associated with recurrence and death in CRC patients. In addition, a high expression level of MISP protein, lymph node metastasis, and distance metastasis were risk factors for recurrence and a poor prognosis in patients with CRC. Conclusion Elevated MISP protein correlated with tumor metastasis, recurrence, and lower survival rates in patients with CRC, and thus, MISP has the potential to become a prognostic marker for CRC.

USP7 facilitates deubiquitination of LRRC42 in colorectal cancer to accelerate tumorigenesis and augment Wnt/β-catenin signaling

Colorectal cancer is a prevalent malignancy with an increasing incidence worldwide. Leucine-rich repeat-containing protein 42 (LRRC42) is known to be dysregulated in tumor tissues, yet its role in colorectal cancer remains largely unexplored. Herein, the function of LRRC42 in colorectal cancer was investigated using clinical samples, cellular experiments, animal models, and multiple omics techniques. The results demonstrated that LRRC42 was highly expressed in colorectal cancer tissues and was associated with poor clinical outcomes. Silencing LRRC42 suppressed cell proliferation, induced G0/G1 phase arrest, and promoted apoptosis by reducing Bcl2 expression while elevating the expression of Bax, cleaved PARP and cleaved caspase 3. Conversely, LRRC42 overexpression exhibited the opposite effects. Consistent findings were observed in vivo. Additionally, ubiquitin specific peptidase 7 was identified as a potential LRRC42-interacting protein through immunoprecipitation-mass spectrometry, with ubiquitin specific peptidase 7 stabilizing LRRC42 expression by promoting its deubiquitination. Notably, LRRC42 overexpression partially reversed the effects of ubiquitin specific peptidase 7 silencing on tumor cell proliferation and apoptosis. mRNA sequencing analysis revealed that differentially expressed genes in LRRC42 overexpressing cells were linked to Wnt signaling pathway, suggesting that LRRC42 overexpression may activate this pathway. Furthermore, LRRC42 was proved to elevate the levels of ki67, cyclin D1 and WNT3, while reducing the level of p-β-catenin. These findings suggest that LRRC42 perhaps serve as a potential oncogenic factor in colorectal cancer, regulated by ubiquitin specific peptidase 7 and capable of activating Wnt/β-catenin signaling pathway.

KRAS mutation promotes the colonization of Fusobacterium nucleatum in colorectal cancer by down-regulating SERTAD4.

This study explores and verifies potential molecular targets through which KRAS mutations regulate the colonization of Fusobacterium nucleatum (FN) in colorectal cancer (CRC). This study combined multiple bioinformatics methods and biological assays. Through The Cancer Genome Atlas, Gene Expression Omnibus, Human Protein Atlas, immunohistochemistry, and co-culture assays, we further confirmed the differential expression of SERTAD4 in CRC. We delved deeper into examining how expression of SERTAD4 is linked with immune cell infiltration and the enrichment of potential pathways. Lastly, through bacterial phenotypic assays, we validated the function of SERTAD4. As a molecule associated with KRAS mutations and FN infection, the expression levels of SERTAD4 were downregulated in CRC. The diagnostic efficacy of SERTAD4 for CRC is not inferior to that of CEA. Low expression of SERTAD4 is associated with poorer overall survival in CRC. Correlation analysis found that increased expression of SERTAD4 is associated with various immune cell infiltrations and immune checkpoint genes. Finally, bacterial adhesion and invasion assays verify that SERTAD4 inhibits the adhesion and invasion abilities of FN in CRC. This study demonstrates that SERTAD4 exerts a protective role in CRC by inhibiting the colonization of FN.

Cancer-Associated Fibroblasts Expressing Sulfatase 1 Facilitate VEGFA-Dependent Microenvironmental Remodeling to Support Colorectal Cancer.

Tumor stroma plays a critical role in fostering tumor progression and metastasis. Cancer-associated fibroblasts (CAF) are a major component of the tumor stroma. Identifying the key molecular determinants for the protumor properties of CAFs could enable the development of more effective treatment strategies. In this study, through analyses of single-cell sequencing data, we identified a population of CAFs expressing high levels of sulfatase 1 (SULF1), which was associated with poor prognosis in patients with colorectal cancer. Colorectal cancer models using mice with conditional SULF1 knockout in fibroblasts revealed the tumor-supportive function of SULF1+ CAFs. Mechanistically, SULF1+ CAFs enhanced the release of VEGFA from heparan sulfate proteoglycan. The increased bioavailability of VEGFA initiated the deposition of extracellular matrix and enhanced angiogenesis. In addition, intestinal microbiota-produced butyrate suppressed SULF1 expression in CAFs through its histone deacetylase (HDAC) inhibitory activity. The insufficient butyrate production in patients with colorectal cancer increased the abundance of SULF1+ CAFs, thereby promoting tumor progression. Importantly, tumor growth inhibition by HDAC was dependent on SULF1 expression in CAFs, and patients with colorectal cancer with more SULF1+ CAFs were more responsive to treatment with the HDAC inhibitor chidamide. Collectively, these findings unveil the critical role of SULF1+ CAFs in colorectal cancer and provide a strategy to stratify patients with colorectal cancer for HDAC inhibitor treatment. Significance: SULF1+ cancer-associated fibroblasts play a tumor-promoting role in colorectal cancer by stimulating extracellular matrix deposition and angiogenesis and can serve as a biomarker for the therapeutic response to HDAC inhibitors in patients.

Trefoil Factor 3 in human serum as a predictor of disease activity in Egyptian ulcerative colitis patients and its role in colorectal cancer

Ulcerative colitis (UC), a chronic idiopathic inflammatory disease, is caused by abnormal immune response to intestinal microflora. Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality. The gold standard to establish diagnosis and assess disease activity remains endoscopy and histopathology. Non-invasive biomarkers are required for timely diagnosis of CRC and to assess disease activity as endoscopic assessment is not accepted by most patients. Enhanced trefoil factor 3 (TFF3) expression is seen following gastrointestinal tract injury. In the current study, the significance of serum TFF3 as a potential diagnostic biomarker of disease activity in naїve UC patients, and its diagnostic accuracy in CRC patients were investigated. We collected serum and fecal samples from 20 cases with active UC, 20 CRC patients, and 20 normal controls. TFF3 levels were higher in patients with active UC than in controls (p&lt;0.001). TFF3 cut-off value of 7.9 ng/ml could predict disease activity with sensitivity and specificity of 90% and 100%, respectively. However, the combination of TFF3, C-reactive protein (CRP), and fecal calprotectin (FC) was able to predict disease activity better than each biomarker alone by raising the sensitivity and specificity to 100%. There was no correlation between TFF3, FC, and endoscopic activity in UC assessed by ulcerative colitis endoscopic index of severity (UCEIS). In the CRC patient group, the serum level of TFF3 was significantly higher when compared to controls (p=0.012). TFF3 and the degree of dysplasia were significantly correlated (r=0.496, p=0.026). At a cut-off value of 5.9 ng/ml, serum TFF3 had a diagnostic sensitivity and specificity for CRC of 82% and 90%, respectively. In conclusion, serum TFF3 may be used as a non-invasive biomarker to predict disease activity in UC both alone and in combination with CRP and FC and it could have a potential role in diagnosis of CRC.

Phytochemicals and colorectal cancer: About polyphenols

Dietary consumption of polyphenols, found in fruits and vegetables, has been associated with a potentially protective role in colorectal cancer (CRC). To establish the state of knowledge regarding advances in polyphenols, CCR and action mechanisms a systematic review and an analysis of information available until 2021 were made. Results indicate that only some polyphenols have in vitro, preclinical and clinical studies. These studies showed that polyphenols will inhibit human CRC cell invasion, migration, metastasis formation, tumor growth. Action mechanisms involve signaling pathways that modulate genes, proteins, markers or cell death inductors, like the AMPK pathway, caspases, Bcl-2, p-Akt, and NF-kB, lysosomal and mitochondrial dysfunction, cellular cycle arrest, among the best known and implied in CRC. Overall, in vitro, preclinical and clinical data on phytochemicals against CRC are still not sufficient and therefore the preventive or therapeutic impacts of dietary phytochemicals on CRC development deserve further research.

Disruption of the intestinal clock drives dysbiosis and impaired barrier function in colorectal cancer.

Diet is a robust entrainment cue that regulates diurnal rhythms of the gut microbiome. We and others have shown that disruption of the circadian clock drives the progression of colorectal cancer (CRC). While certain bacterial species have been suggested to play driver roles in CRC, it is unknown whether the intestinal clock impinges on the microbiome to accelerate CRC pathogenesis. To address this, genetic disruption of the circadian clock, in an Apc-driven mouse model of CRC, was used to define the impact on the gut microbiome. When clock disruption is combined with CRC, metagenomic sequencing identified dysregulation of many bacterial genera including Bacteroides, Helicobacter, and Megasphaera. We identify functional changes to microbial pathways including dysregulated nucleic acid, amino acid, and carbohydrate metabolism, as well as disruption of intestinal barrier function. Our findings suggest that clock disruption impinges on microbiota composition and intestinal permeability that may contribute to CRC pathogenesis.

Unraveling molecular and clinical aspects of ALKBH5 as dual role in colorectal cancer.

This study investigates the dual role of ALKBH5, an eraser enzyme, in colorectal cancer (CRC), focusing on how N6-methyladenosine (m6A) mutations influence CRC development and progression. We reviewed various studies that highlighted the role of ALKBH5 in colorectal cancer (CRC). This includes the impact of ALKBH5 on tumor cell behavior including immune system interactions, invasion, and proliferation in CRC. We also looked into how ALKBH5 acts as a tumor suppressor under different conditions analyzed clinical data to assess the impact of ALKBH5 expression on outcomes in colorectal cancer patients. In CRC, ALKBH5 plays a dual role. In certain situations, it inhibits the progression of the tumor, but in other circumstances, it promotes tumor growth and immunosuppression. The interaction with RABA5 plays a role in the development of CRC. Having elevated levels of ALKBH5 has been associated with unfavorable patient outcomes, such as reduced survival rates and more advanced cancer stages. Various factors, including tumor differentiation, TNM stages, and carcinoembryonic antigen (CEA) levels, be linked to ALKBH5 expression. ALKBH5 plays a complicated and situation-specific role in colorectal cancer (CRC). Targeting ALKBH5 could result in novel therapy options that balance its tumor-promoting and tumor-fighting properties in CRC. Further research into m6A alterations and ALKBH5 could enhance CRC treatment approaches and patient outcomes.

Unraveling the Regulatory Role of HuR/microRNA Axis in Colorectal Cancer Tumorigenesis.

Colorectal cancer (CRC) remains a significant global health burden with high incidence and mortality. MicroRNAs (miRNAs) are small non-protein coding transcripts, conserved throughout evolution, with an important role in CRC tumorigenesis, and are either upregulated or downregulated in various cancers. RNA-binding proteins (RBPs) are known as essential regulators of miRNA activity. Human antigen R (HuR) is a prominent RBP known to drive tumorigenesis with a pivotal role in CRC. In this review, we discuss the regulatory role of the HuR/miRNA axis in CRC. Interestingly, miRNAs can directly target HuR, altering its expression and activity. However, HuR can also stabilize or degrade miRNAs, forming complex feedback loops that either activate or block CRC-associated signaling pathways. Dysregulation of the HuR/miRNA axis contributes to CRC initiation and progression. Additionally, HuR-miRNA regulation by other small non-coding RNAs, circular RNA (circRNAs), or long-non-coding RNAs (lncRNAs) is also explored here. Understanding this HuR-miRNA interplay could reveal novel biomarkers with better diagnostic or prognostic accuracy.

Correlation between gut microbiota dysbiosis and colorectal cancer: review

Introduction and Purpose: The human gut microbiota, comprising a diverse consortium of approximately 100 trillion microorganisms, is integral to maintaining health and modulating disease processes. Its development begins at birth, influenced by maternal microbiota and environmental factors. Dysbiosis, defined as an imbalance in the gut microbial composition, has been implicated in a range of gastrointestinal pathologies, including colorectal cancer (CRC). This review endeavors to elucidate the relationship between gut microbiota and CRC, examining the impact of specific bacterial taxa on the pathogenesis CRC. Description of the State of Knowledge: Gut microbiota encompasses a multitude of microbial species, with their composition differing along the gastrointestinal tract. Healthy gut microbiota perform essential functions such as pathogen protection, metabolic processes, and immune system modulation. Factors like diet and genetics significantly influence microbial composition. Dysbiosis contributes to CRC through inflammation, genotoxin production, and immune modulation. Specific bacteria, such as Fusobacterium nucleatum and Bacteroides fragilis, are associated with CRC. Mechanisms of carcinogenesis include bacterial adherence, invasion of epithelial cells, and activation of pro-inflammatory pathways. Summary:Understanding the gut microbiota's role in CRC highlights the importance of maintaining a balanced microbiome for cancer prevention. Dietary interventions promoting beneficial bacteria and reducing harmful species could mitigate CRC risk. Further research should prioritize the identification of microbial biomarkers for early CRC detection and the development of therapeutic strategies aimed at modulating the gut microbiota. These efforts will enhance CRC prevention and treatment modalities.

Unveiling the hidden link between oral flora and colorectal cancer: a bidirectional Mendelian randomization analysis and meta-analysis.

The impact of oral flora on intestinal micro-environment and related diseases has been widely reported, but its role in colorectal cancer (CRC) remains elusive. A Two-sample Mendelian Randomization (TSMR) analysis was conducted to explore the causal relationship between oral flora and CRC, with the Inverse-Variance Weighted (IVW) serving as the primary method for evaluating this causal relationship. Data on the oral flora were derived from human samples from the tongue and saliva, with all cohort populations originating from Asia. In addition, 2 independent external cohorts were used to validate the positive results and perform a meta-analysis of the final results. Lastly, to balance the effect of positive oral flora on CRC, a Multivariate Mendelian Randomization (MVMR) analysis was also performed. The TSMR analysis revealed that 17 oral flora may have a causal relationship with CRC in the training cohort. Among them, s Haemophilus, g Fusobacterium, s Metamycoplasma salivarium, and s Mogibacterium pumilum were validated in two testing cohorts. Intriguingly, after integrating the results of the 3 cohorts for meta-analysis, 16 associations remained significant. In the training cohort, MVMR analysis demonstrated that s Capnocytophaga ochracea and s Metamycoplasma salivarium retained statistical significance. In one of the testing cohorts, s Metamycoplasma salivarium, s Streptococcus anginosus, and s Streptococcus sanguinis retained statistical significance. In the other testing cohort, s Metamycoplasma salivarium, s Haemophilus, and g Fusobacterium remained significant. s Haemophilus, g Fusobacterium, s Metamycoplasma salivarium, and s Mogibacterium pumilum have a solid causal relationship with the occurrence and development of CRC.

Comprehensive analysis of cuproptosis-related genes involved in prognosis and tumor microenvironment infiltration of colorectal cancer.

Colorectal cancer (CRC) is a common malignancy, with high incidence and high mortality rates. Cuproptosis, a novel form of copper-induced programmed cell death, contributes to tumor progression. However, whether cuproptosis-related genes (CRGs) play a role in CRC remains unclear. This study aims to elucidate the role of CRGs in CRC development, patient prognosis, and immune response. We performed bioinformatics analysis of the differential expression of CRGs between CRC and normal tissues. Least absolute shrinkage and selection operator (LASSO), and univariate and multivariate Cox analyses were employed to identify risk factors, which were used to construct a risk score model. Patients with CRC were categorized into high- and low-risk groups based on their median risk scores. Receiver operating characteristic curve analysis was used to verify the predictive accuracy of the risk model. A nomogram was developed for CRC through univariate and multivariate Cox regression analyses. The chemotherapeutic drug sensitivity was compared between patients with high and low CDKN2A/DLAT expression using the Wilcoxon rank-sum test. Spearman's correlation and TISIDB database analyses were conducted to determine relationships between CDKN2A or DLAT and immune cell infiltration. Eight of ten identified CRGs exhibited significant differential expression between CRC and normal tissues. Among the eight significant differential expression CRGs, CDKN2A and DLAT were identified as independent risk factors for predicting overall survival (OS) in CRC. Patients with CRC in the low-risk group had longer OS than those in the high-risk group. The risk score model had good predictive accuracy for OS. Based on CDKN2A, DLAT and some clinical characteristics, a prognostic nomogram was developed to predict OS for CRC patients and showed good predictive ability. CDKN2A and DLAT expressions were significantly associated with chemotherapeutic drug sensitivity and immune cell infiltration in CRC, and the molecular subtypes and immune subtypes differed between CDKN2A and DLAT. Our research revealed the prognostic value of CRGs, particularly CDKN2A and DLAT, in CRC and demonstrated the relationship between CDKN2A/DLAT and immune infiltration in CRC, thereby contributing to the outcome evaluation of patients with CRC and identifying novel targets for CRC immunotherapy.

TRIM72 inhibits cell migration and epithelial-mesenchymal transition by attenuating FAK/akt signaling in colorectal cancer

TRIM72 (MG53), a membrane repair protein with E3-ligase activity, plays a crucial role in colorectal cancer (CRC). This study examined TRIM72 expression in primary CRC tumors and paired liver metastases using RT-PCR. Findings revealed significantly lower TRIM72 levels in liver metastases compared to primary tumors (p < 0.001). Aberrant TRIM72 expression correlated with lymph node metastasis and advanced clinical stages. Overexpression of TRIM72 inhibited CRC cell migration, intravasation, and EMT in vitro and in vivo, while TRIM72 knockout increased migration and invasion. TRIM72 interacted with Focal Adhesion Kinase (FAK), implicating the FAK/Akt signaling axis in colon cancer spread. Lower TRIM72 levels were associated with reduced survival rates, highlighting its potential as a prognostic marker and therapeutic target in CRC.

Targeting m7G-enriched circKDM1A prevents colorectal cancer progression.

Plenty of circRNAs have been reported to play an important role in colorectal cancer (CRC), while the reason of abnormal circRNA expression in cancer still keep elusive. Here, we found that m7G RNA modifications were enriched in some circRNAs, these m7G modifications in circRNAs were catalyzed by METTL1, and the GG motif was the main site preference for m7G modifications in circRNAs. We further confirmed that METTL1 played a cancer-promoting role in CRC. We then screened a highly expressed circRNA, called circKDM1A, and found that METTL1 prevented the degradation of circKDM1A by m7G modification. CircKDM1A was further verified to promote proliferation, invasion and migration of CRC in vivo and in vitro. Its cancer-promoting ability was weakened after the m7G site mutation. CircKDM1A was verified to activate AKT pathway by upregulating PDK1, consequently promoting CRC progression. These results suggest that m7G-modified circRNA promotes CRC progression via activating AKT pathway. Our study uncovers an essential physiological function and mechanism of METTL1-mediated m7G modification in the regulation of circRNA stability and cancer progression.

Identification of a Novel 4-gene Prognostic Model Related to Neutrophil Extracellular Traps for Colorectal Cancer.

Colorectal cancer (CRC) is a significant global health concern, and understanding the molecular mechanisms underlying CRC progression and prognosis is crucial. Neutrophil extracellular traps (NETs) have been implicated in various cancers, but their role in CRC and its clinical implications remain to be elucidated. Transcriptomic data from TCGA of CRC patients were analyzed to assess NETs enrichment and "NETs formation" pathway scores in NETs_high and NETs_low groups. Univariate Cox regression was used to identify prognosis-associated genes with the Log-Rank test for selection. Patients in the TCGA database were randomly split into training and testing sets to build a prognostic model with LASSO Cox regression. Model diagnostic performance was evaluated using Kaplan-Meier curves and receiver operating characteristic analysis. Single-sample gene set enrichment analysis (ssGSEA) was used to determine the abundance of 23 immune cells. ESTIMATE was used to calculate ImmuneScore and ESTIMATEScore, characterizing immune features of CRC samples. The NETs_high group in CRC showed significantly better survival than the NETs_low group. A robust prognostic model based on PRKRIP1, SERTAD2, ELFN1, and LINC00672 accurately predicted patient outcomes. NETs_high samples exhibited a more enriched immune environment with higher immune cell infiltration levels, as well as ImmuneScore and ESTIMATEScore. PRKRIP1, SERTAD2, ELFN1, and LINC00672 were significantly correlated with key immune cell types. Additionally, 18 drugs displayed differential sensitivity between NETs_high and NETs_low groups, with Daporinad and Selumetinib as potential therapeutic options. Our findings may catalyze the development of personalized treatment modalities and bestow invaluable insights into the intricate dynamics governing CRC progression.