Pathogenesis Of Colorectal Cancer Research Articles

Natural Products and Derivatives Targeting Metabolic Reprogramming in Colorectal Cancer: A Comprehensive Review.

Metabolic reprogramming is a critical pathogenesis of colorectal cancer (CRC), referring to metabolic disorders that cancer cells make in response to the stimulating pressure. Metabolic reprogramming induces changes in genetic material and promotes CRC progression and has been proven to be an efficient target of CRC. As natural products have garnered interest due to notable pharmacological effects and potential in counteracting chemoresistance, an increasing body of research is delving into the impact of these natural products on the metabolic reprogramming associated with CRC. In this review, we collected published data from the Web of Science and PubMed, covering the period from January 1980 to October 2023. This article focuses on five central facets of metabolic alterations in cancer cells, glucose metabolism, mitochondrial oxidative phosphorylation (OXPHOS), amino acid metabolism, fatty acid synthesis, and nucleotide metabolism, to provide an overview of recent advancements in natural product interventions targeting metabolic reprogramming in CRC. Our analysis underscores the potential of natural products in disrupting the metabolic pathways of CRC, suggesting promising therapeutic targets for CRC and expanding treatment options for metabolic-associated ailments.

Exploring somatic mutations in POLE and POLD1: Their role in colorectal cancer pathogenesis and potential therapeutic strategies

Colorectal cancer (CRC) is one of the major causes of morbidity and mortality worldwide, resulting from the accumulation of genetic and epigenetic alterations in several oncogenes and tumor suppressor genes. Recent studies have identified germline and somatic mutations in the exonuclease domain regions of both epsilon polymerase (POLE) and delta polymerase (POLD1) genes in CRCs. We sought to examine the mutation of these genes in a series of sporadic CRCs. To do this, we extracted DNA from 100 primary CRC samples and 40 corresponding normal tissue samples, which had been previously characterized for clinicopathological and molecular features. We employed a combination of quick-multiplex consensus (QMC)-polymerase chain reaction (PCR) and co-amplification at lower denaturation temperature (COLD)-PCR, followed by high-resolution melting (HRM) analysis and Sanger sequencing, to investigate the exonuclease domain regions of POLE and POLD1 genes for somatic mutations that may potentially alter the proofreading activities of these genes. In silico predictions of the functional significance of the identified genetic alterations were performed using the protein variation effect analyzer, sorting intolerant from tolerant, and PON-P2 algorithms. We identified a total of eight new and non-recurrent somatic variants in the endonuclease domains of POLE and two in POLD1. Nine out of ten variants caused amino acid substitutions, whereas one resulted in a stop codon. Although no significant associations or correlations were found between the POLE/POLD1 mutations and the clinicopathological or molecular features of the CRC cases, most of the POLE/POLD1-mutated cases were microsatellite stable (90%) and aneuploid (80%). Furthermore, in silico analyses showed that nine of the ten variants would likely cause some adverse effect on protein function. Ten somatic variants with predicted proofreading activity-altering effects have been identified in the endonuclease domains of POLE and POLD1 in CRC using a combination of QMC-PCR, COLD-PCR, HRM analyses, and Sanger sequencing.

Biological function and potential application of PANoptosis-related genes in colorectal carcinogenesis

PANoptosis induces programmed cell death (PCD) through extensive crosstalk and is associated with development of cancer. However, the functional mechanisms, clinical significance, and potential applications of PANoptosis-related genes (PRGs) in colorectal cancer (CRC) have not been fully elucidated. Functional enrichment of key PRGs was analyzed based on databases, and relationships between key PRGs and the immune microenvironment, immune cell infiltration, chemotherapy drug sensitivity, tumor progression genes, single-cell cellular subgroups, signal transduction pathways, transcription factor regulation, and miRNA regulatory networks were systematically explored. This study identified 5 key PRGs associated with CRC: BCL10, CDKN2A, DAPK1, PYGM and TIMP1. Then, RT-PCR was used to verify expression of these genes in CRC cells and tissues. Clinical significance and prognostic value of key genes were further verified by multiple datasets. Analyses of the immune microenvironment, immune cell infiltration, chemotherapy drug sensitivity, tumor progression genes, single-cell cellular subgroups, and signal transduction pathways suggest a close relationship between these key genes and development of CRC. In addition, a novel prognostic nomogram model for CRC was successfully constructed by combining important clinical indicators and the key genes. In conclusion, our findings offer new insights for understanding the pathogenesis of CRC, predicting CRC prognosis, and identifying multiple therapeutic targets for future CRC therapy.

Investigation of pre and postoperative Th1/Th2 cytokine balance and novel cytokines in colorectal cancer patients

Colorectal cancer (CRC) is a major health problem worldwide and is usually detected in advanced stages, although it is highly treatable with early detection. The aim of this study was to examine the serum levels of various cytokines involved in the pathogenesis of CRC. The study included 29 patients and 30 healthy volunteers. Blood samples were collected twice from the patient group, before and after surgery, and these samples were evaluated for interleukin (IL) 4, 10, 23r, 37, 38, 40 and interferon (IFN) gamma levels. The results showed that IL-4 and IL-38 levels were significantly lower in the preoperative serum samples of the patient group compared to the control group (p < 0.001 and p = 0.01, respectively), while IL-4, IL-10, IL-38 and IL-40 levels increased significantly in the postoperative period (p = 0.004, p = 0.02, p = 0.03 and p = 0.004, respectively). These findings may contribute to the development of immunotherapy agents in the treatment of CRC. However, comprehensive studies on larger patient groups are needed to fully understand the role of cytokines in CRC pathogenesis.

Cross-modal integration of bulk RNA-seq and single-cell RNA sequencing data to reveal T-cell exhaustion in colorectal cancer.

Colorectal cancer (CRC) is a relatively common malignancy clinically and the second leading cause of cancer-related deaths. Recent studies have identified T-cell exhaustion as playing a crucial role in the pathogenesis of CRC. A long-standing challenge in the clinical management of CRC is to understand how T cells function during its progression and metastasis, and whether potential therapeutic targets for CRC treatment can be predicted through T cells. Here, we propose DeepTEX, a multi-omics deep learning approach that integrates cross-model data to investigate the heterogeneity of T-cell exhaustion in CRC. DeepTEX uses a domain adaptation model to align the data distributions from two different modalities and applies a cross-modal knowledge distillation model to predict the heterogeneity of T-cell exhaustion across diverse patients, identifying key functional pathways and genes. DeepTEX offers valuable insights into the application of deep learning in multi-omics, providing crucial data for exploring the stages of T-cell exhaustion associated with CRC and relevant therapeutic targets.

Unveiling the role of KRAS in Chinese colorectal cancer patients: a positive influence on tumor mutational burden.

One of the main challenges associated with the development of therapeutic and diagnostic strategies for patients with colorectal cancer (CRC) is the establishment of minimally invasive and efficient biomarkers. Pertinent genes in CRC have been identified through their functions in systematic mutagenesis screens. KRAS is considered a dominant mutated oncogene that contributes to pathogenesis of CRC. This study aimed to explore the genomic alternations of KRAS in a CRC population. Sequencing data of 94 Chinese patients with CRC were prospectively collected and analyzed using next-generation sequencing (NGS). The influence of KRAS and its associated subtype co-mutations on the expression level of the tumor mutational burden (TMB) was investigated. The objective of our study was to assess the potential prognostic significance of KRAS and other driving oncogenes in determining the clinical efficacy of immunotherapy. The gene mutation rates of TP53, APC, and KRAS were 81.91%, 71.28%, and 43.62%, respectively. Additionally, KRAS G12D displayed a relatively higher mutation rate than other KRAS-mutant subtypes. Increased TMB was observed in cases of KRAS and BRAF mutation combined with APC single mutation; furthermore, the expression of TMB in G12V was the highest, and G12D presented the lowest TMB in single KRAS-mutant subtypes or the combination with APC mutations. The TMB driven by KRAS co-mutations may have the potential to be used as a key biomarker for prediction of treatment outcomes of immune checkpoint inhibitors (ICIs) in patients with CRC, especially with APC co-mutation.

CD11b/CD86 involved in the microenvironment of colorectal cancer by promoting Wnt signaling activation.

Colorectal cancer (CRC) is a malignancy that arises within the gastrointestinal tract. Despite ongoing research, the etiology and pathogenesis of CRC remain elusive; particularly, the distribution and characteristics of tumor-associated macrophages is currently an active area of investigation in understanding the pathological progression and prevention of CRC. This study utilized CRC patient surgical samples, mouse models of colitis-associated cancer, colonic organoid, and co-culture cell line to examine the changes in CD11b/CD86 at different pathological region and detect the Wnt signaling pathway activity. Our findings revealed a sensitive and increased expression of CD11b from the early to the advanced CRC tissues and correlated with poor prognosis, while CD86 expression was reduced in advanced CRC tissues. CD133 expression was also elevated in advanced CRC tissues and mainly co-localized with CD11b, suggesting a positive regulatory effect of CD11b and CD133 expression that may contribute to CRC progression. In AOM/DSS mouse models, activation of the Wnt signaling pathway was associated with increased CD133 and CD11b expression. Invitro, THP-1 cell was induced to high expression of CD11b, and the above conditional cultural medium enhanced HCT116 cell colony number and CD133 protein expression. Furthermore, colonic crypts from AOM/DSS mouse models were isolated to culture, and the colonic organoids exhibited dilation and significant increases expression of CD133 and β-Catenin/N-P-B-Catenin. CD11b might be an important factor to participate the progress of CRC. And the high CD11b of CRC microenviroment might potentially promote CD133 expression and associate with Wnt signal activation.

Effects of fecal microbiota transplantation combined with selenium on intestinal microbiota in mice with colorectal cancer

Colorectal cancer (CRC) is the third most common cancer in the world. With the development of high-throughput gene sequencing technology, homeostasis imbalance of the intestinal microbiota has been proven to play a key role in the pathogenesis of CRC. Furthermore, fecal bacteria transplantation (FMT) has been shown to alter the intestinal microecology, and is potentially an effective treatment for CRC. Sodium selenite plays an important role in anticancer adjuvant therapy due to its high pro-oxidation characteristics. In this study, a murine CRC tumor model was induced by AOM/DSS, and CRC mice were treated by FMT, sodium selenite, and FMT combined with sodium selenite. The results showed that FMT, sodium selenite, and FMT combined with sodium selenite inhibited the occurrence of CRC in mice, increased the abundance of beneficial intestinal bacteria, produced different microorganisms, and changed the metabolic pathways of the intestinal microbiota. In summary, FMT, sodium selenite, and FMT combined with sodium selenite can inhibit the occurrence of CRC by increasing the abundance of beneficial bacteria and regulating phenotypes and metabolic pathways. Notably, the effect of FMT combined with sodium selenite in reducing the number of tumors, protecting intestinal tissues, and restoring the diversity and richness of the intestinal microbiota is superior to that of FMT alone or sodium selenite alone. The results of this study provide new ideas for the application of FMT and selenium in the treatment of CRC.

The current role of dendritic cells in the progression and treatment of colorectal cancer.

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related deaths worldwide. Dendritic cells (DCs) constitute a heterogeneous group of antigen-presenting cells that are important for initiating and regulating both innate and adaptive immune responses. As a crucial component of the immune system, DCs have a pivotal role in the pathogenesis and clinical treatment of CRC. DCs cross-present tumor-related antigens to activate T cells and trigger an antitumor immune response. However, the antitumor immune function of DCs is impaired and immune tolerance is promoted due to the presence of the tumor microenvironment. This review systematically elucidates the specific characteristics and functions of different DC subsets, as well as the role that DCs play in the immune response and tolerance within the CRC microenvironment. Moreover, how DCs contribute to the progression of CRC and potential therapies to enhance antitumor immunity on the basis of existing data are also discussed, which will provide new perspectives and approaches for immunotherapy in patients with CRC.

Antioxidant Role of Probiotics in Inflammation-Induced Colorectal Cancer.

Colorectal cancer (CRC) continues to be a significant contributor to global morbidity and mortality. Emerging evidence indicates that disturbances in gut microbial composition, the formation of reactive oxygen species (ROS), and the resulting inflammation can lead to DNA damage, driving the pathogenesis and progression of CRC. Notably, bacterial metabolites can either protect against or contribute to oxidative stress by modulating the activity of antioxidant enzymes and influencing signaling pathways that govern ROS-induced inflammation. Additionally, microbiota byproducts, when supplemented through probiotics, can affect tumor microenvironments to enhance treatment efficacy and selectively mediate the ROS-induced destruction of CRC cells. This review aims to discuss the mechanisms by which taxonomical shifts in gut microbiota and related metabolites such as short-chain fatty acids, secondary bile acids, and trimethylamine-N-oxide influence ROS concentrations to safeguard or promote the onset of inflammation-mediated CRC. Additionally, we focus on the role of probiotic species in modulating ROS-mediated signaling pathways that influence both oxidative status and inflammation, such as Nrf2-Keap1, NF-κB, and NLRP3 to mitigate carcinogenesis. Overall, a deeper understanding of the role of gut microbiota on oxidative stress may aid in delaying or preventing the onset of CRC and offer new avenues for adjunct, CRC-specific therapeutic interventions such as cancer immunotherapy.

Chinese national clinical practice guidelines on prevention, diagnosis and treatment of early colorectal cancer.

The incidence and mortality of colorectal cancer (CRC) in China are increasing in recent years. The clarified pathogenesis and detectable precancerous lesions of CRC make it possible to prevent, screen, and diagnose CRC at an early stage. With the development of endoscopic and surgical techniques, the choice of treatment for early CRC is also worth further discussion, and accordingly, a standard follow-up program after treatment needs to be established. This clinical practice guideline (CPG) was developed following the recommended process of the World Health Organization, adopting Grading of Recommendations Assessment, Development and Evaluation (GRADE) in assessing evidence quality, and using the Evidence to Decision framework to formulate clinical recommendations, thereby minimizing bias and increasing transparency of the CPG development process. We used the Reporting Items for practice Guidelines in HealThcare (RIGHT) statement and Appraisal of Guidelines for Research and Evaluation II (AGREE II) as reporting and conduct guides to ensure the guideline's completeness and transparency. This CPG comprises 46 recommendations concerning prevention, screening, diagnosis, treatment, and surveillance of CRC. In these recommendations, we have indicated protective and risk factors for CRC and made recommendations for chemoprevention. We proposed a suitable screening program for CRC based on the Chinese context. We also provided normative statements for the diagnosis, treatment, and surveillance of CRC based on existing clinical evidence and guidelines. The 46 recommendations in this CPG are formed with consideration for stakeholders' values and preferences, feasibility, and acceptability. Recommendations are generalizable to resource-limited settings with similar CRC epidemiology pattern as China.

Diet and epigenetics of colon carcinogenesis: A review article

The following article includes a chart illustrating the dietary components of various food classes that are involved in the pathogenesis of colorectal cancer (CRC), as well as information on the key players in the digestive tract microbiota and the many dysfunctions involved in the onset or progression of CRC. With its complex course throughout history, colorectal cancer has advanced the understanding of its initiation and improvement. The understanding of how colorectal cancer starts and improves through eating less has advanced over time. By and enormous, the utilization of ruddy and organized meats has been related to an expanded chance of start. These meats contain compounds such as nitrates and nitrites that can serve as diagram carcinogens inside the colon. Understanding how diets affect epigenetic modifications inside the intestinal mucosa is particularly important since abnormally methylated genes may serve as early detection and prognostic markers for colon cancer. Epigenetic changes, such as changes in methylation, are potentially reversible and, therefore, offer interesting targets for supportive and preventative therapy, unlike intrinsic changes in cancer. The growing role of microbial metabolites and a few clearly beneficial dietary additions in the management of CRC are outlined in this article.

Triglyceride-Glucose Index, Modifiable Lifestyle, and Risk of Colorectal Cancer: A Prospective Analysis of the Korean Genome and Epidemiology Study.

Insulin-mediated pathways plausibly explain the pathogenesis of colorectal cancer (CRC). The triglyceride-glucose index (TyG) is a surrogate of insulin resistance (IR), but its association with CRC in the Korean population has not been evaluated. From the 2004-2013 Korean Genome and Epidemiology Study, 98,800 participants aged 40-69 years were followed through 2020. Data on CRC incidence were obtained from the Korean National Cancer Center registry. Cox regression models and restricted cubic splines were fitted to examine the association between the TyG; In [(triglycerides) × (fasting glucose)/2] and CRC incidence. Joint effects of modifiable lifestyle factors and TyG on CRC risk were also investigated. Median follow-up time was 10.6 years, and 699 CRC cases were observed. A unit-increment in TyG was associated with increased risk of CRC combined (hazard ratio, HR: 1.28, and 95% confidence interval, CI: 1.12-1.46), colon (1.29, 1.10-1.54), and rectal cancer (1.24, 1.01-1.52). Associations were dose-dependent, with linear associations observed for CRC and colon, but non-linear associations were observed for rectal cancer. A high TyG index (above 8.4) combined with overweight/obesity was linked to an increased risk of CRC (1.31, 1.07-1.61) and colon cancer (1.33, 1.03-1.72). When combined with low fruit and vegetable intake, the risks were higher for CRC (1.40, 1.12-1.74) and colon cancer (1.57, 1.18-2.09). Combined with high red meat consumption, the risks were elevated for CRC (1.32, 1.05-1.65) and colon cancer (1.52, 1.15-2.02). A high TyG index was associated with a higher risk of colorectal cancer, and the risk was highest among participants with a high BMI, low fruit and vegetable intake, and high intake of red meat, suggesting a role of both insulin resistance and modifiable lifestyle in colorectal cancer development.

Downregulation of circ-RAPGEF5 inhibits colorectal cancer progression by reducing the expression of polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3).

Circular RNA (circRNA) plays a crucial role in the pathogenesis and progression of colorectal cancer (CRC). However, the current understanding of the emerging function and mechanism of circ-RAPGEF5 in CRC remains poorly understood. We first evaluated the expression level of circ-RAPGEF5 in CRC tissues and cells by quantitative real-time polymerase chain reaction (qRT-PCR). Then, we analyzed cell proliferation (EdU and colony formation assay), migration (cell wound healing assay), invasion (transwell assay), and apoptosis (flow cytometry assay). To further elucidate the mechanism of circ-RAPGEF5 in CRC, bioinformatics tools, Dual-luciferase reporter assay, Ago2 RNA immunoprecipitation assay, and RNA pull-down assay were employed. Moreover, we established a CRC transplantation tumor model to evaluate the effect of circ-RAPGEF5 on tumor growth in vivo. circ-RAPGEF5 was significantly upregulated in CRC tissues and CRC cells. Furthermore, the downregulation of circ-RAPGEF5 restrained CRC cell proliferation, migration, and invasion, and promoted cell apoptosis in vitro. Mechanistically, circ-RAPGEF5 accelerated the malignant behaviors of CRC cells by sponging miR-545-5p, which targeted polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3). In addition, we revealed that circ-RAPGEF5 silence curbed tumor growth in vivo. These findings revealed that circ-RAPGEF5 played an oncogenic role through the miR-545-5p/GALNT3 axis in CRC progression, providing potential therapeutic targets for the treatment of CRC.

Hydrophilic materials based on hydrogel polymers for enrichment of glycopeptides from serum of colorectal cancer patients.

In this work, a composite hydrogel material consisting of chitosan-based composite hydrogel was prepared by a simple and rapid synthetic method and will be named three-dimensional (3D)-IL-COF-1@CS hydrogel. Possessing a stable 3D network structure and outstanding hydrophilicity, the novel hydrogel is capable of capturing glycopeptides. The 3D-IL-COF-1@CS hydrogel showed good sensitivity (0.1 fmol/µL) and selectivity (1:2000). In addition, 19 glycopeptides were captured in standard samples. In the analysis of human serum, 148 glycopeptides assigned to 72 glycoproteins were assayed in the serum of normal individuals, and 245 glycopeptides corresponding to 100 glycoproteins were found in the serum of colorectal cancer (CRC) patients. More importantly, several functional programs based on Gene Ontology analysis supported molecular biological processes that may be relevant to the pathogenesis of CRC, including aging, fibrinogen complex, and arylesterase activity. The low cost, simplicity, rapid synthesis, and good enrichment performance have a great future in glycoproteomics analysis and related diseases.

Exploitation of porphyrin-based titanium-rich porous organic polymers for targeted phosphopeptide enrichment from the serum of colorectal cancer individuals.

Aporphyrin-based titanium-rich porous organic polymer (Th-PPOPs@Ti4+) was designed based on immobilized metal ion affinity chromatography technique and successfully applied to phosphopeptide enrichment with 5,10,15,20-tetrakis(4-carboxyphenyl) porphine tetramethyl ester (TCPTE), 2,3-dihydroxyterephthalaldehyde (DHTA), and 2,3,4-trihydroxybenzaldehyde (THBA) as raw materials. Th-PPOPs@Ti4+ exhibited remarkable sensitivity (0.5 fmol),highselectivity (β-casein: BSA = 1:2000, molar ratio), outstanding recovery (95.0 ± 1.9%), reusability (10 times), and superior loading capacity (143mg·g-1). In addition, Th-PPOPs@Ti4+ exhibited excellent ability to specifically capture phosphopeptides from the serum of colorectal cancer (CRC) individuals and normal subjects. Sixty phosphopeptides assigned to 35 phosphoproteins were obtained from the serum of CRC individuals, and 43 phosphopeptides allocated to 28 phosphoproteins were extracted in the serum of healthy individuals via nano-LC-MS/MS. Gene ontology assays revealed that the detected phosphoproteins may be inextricably tied to CRC-associated events, including response to estrogen, inflammatory response, and heparin binding, suggesting that it is possible that these correlative pathways may be implicated in the pathogenesis of CRC.

IL-10 polymorphism genotypes, haplotypes, and diplotypes are associated with colorectal cancer predisposition and outcome in Tunisian population

Background and aimAs the presence of single nucleotide polymorphisms (SNPs) in the interleukin (IL)-10 gene continues to be a major challenge in the development of effective therapies for digestive cancers, this case-control study was conducted to assess the possible influence of genotype, haplotype and diplotype for two SNPs (−1082A/G (rs1800896) and −592A/C (rs1800872)) located in the promoter region of IL-10 gene on the incidence, severity and prognosis of colorectal cancer (CRC) in Tunisians. MethodsIL-10 gene SNPs were analyzed in 130 CRC cases and 165 healthy subjects (HS) using PCR-SSP. ResultsFor the IL-10 -1082A/G SNP, the comparison of genotype frequencies between cases and HS groups showed that the G allele significantly reduced CRC risk under the recessive model (GG vs. AA + AG: OR [95%CI] = 0.44 [0.21–0.93], p = 0.03). Conversely, a positive association was observed between the codominant model (AG vs. AA + GG) and high susceptibility (OR [95%CI] = 1.65 [1.02–2.63], p = 0.04). After stratification by disease site, the recessive model was also found to reduce susceptibility to colon cancer (OR [95%CI] = 0.18 [0.04–0.72], p = 0 0.01), while the homozygote model (AA vs. GG) was suggested as a risk factor (OR [95%CI] = 5.16 [1.31–23.26], p = 0.02). Furthermore, the codominant model (AG vs. AA + GG) doubled the risk of rectum cancer (OR [95%CI] = 1.98 [1.07–3.70], p = 0.03). For the IL-10 -592A/C SNP, the codominant model (AC vs. AA + CC) has a protective effect against the development of CRC (OR [95%CI] = 0.59 [0.36–0.94], p = 0.03). The IL-10 gene haplotype was not associated with CRC risk. A stratified analysis by disease site demonstrated that the presence of Hap3 (−1082G and −592C alleles) specifically reduced the risk of developing colon cancer (OR [95%CI] = 0.51 [0.32–0.80], p = 0.003). Moreover, homozygous Hap3/Hap3 diplotype significantly reduced susceptibility to CRC (OR [95%CI] = 0.35 [0.14–0.85], p = 0.02). Interestingly, this diplotype has not been identified in colon cancer patients. Kaplan-Meier analysis showed that the homozygous Hap2/Hap2 diplotype was significantly associated with decreased overall survival (Log-rank: p = 0.01). This association was also observed in the colon cancer subgroup (Log-rank: p = 0.001). ConclusionOur findings provide preliminary indications that the −1082A/G and −592/AC SNPs within the IL-10 gene may exhibit significant associations with the pathogenesis and prognostic outcomes of CRC. However, further investigations are still warranted to validate and establish the veracity of our findings.

IL-1R signaling drives enteric glia-macrophage interactions in colorectal cancer

Enteric glia have been recently recognized as key components of the colonic tumor microenvironment indicating their potential role in colorectal cancer pathogenesis. Although enteric glia modulate immune responses in other intestinal diseases, their interaction with the colorectal cancer immune cell compartment remains unclear. Through a combination of single-cell and bulk RNA-sequencing, both in murine models and patients, here we find that enteric glia acquire an immunomodulatory phenotype by bi-directional communication with tumor-infiltrating monocytes. The latter direct a reactive enteric glial cell phenotypic and functional switch via glial IL-1R signaling. In turn, tumor glia promote monocyte differentiation towards pro-tumorigenic SPP1+ tumor-associated macrophages by IL-6 release. Enteric glia cell abundancy correlates with worse disease outcomes in preclinical models and colorectal cancer patients. Thereby, our study reveals a neuroimmune interaction between enteric glia and tumor-associated macrophages in the colorectal tumor microenvironment, providing insights into colorectal cancer pathogenesis.

Integrated systematic functional screen and fine-mapping decipher the role and genetic regulation of RPS19 in colorectal cancer development.

Despite genome-wide association studies (GWAS) have identified more than 200 risk loci associated with colorectal cancer (CRC), the causal genes or risk variants within these loci and their biological functions remain not fully revealed. Recently, the genomic locus 19q13.2, with the lead SNP rs1800469 was identified as a crucial CRC risk locus in Asian populations. However, the functional mechanism of this region has not been fully elucidated. Here we employed an RNA interfering-based on-chip approach to screen for the genes essential for cell proliferation in the CRC risk locus 19q13.2. Notably, we found that RPS19 exhibited the most significant effect among the identified genes and acted as a critical oncogene facilitating CRC cell proliferation. Subsequently, combining integrative fine-mapping analysis and a large-scale population study consisting of 6027 cases and 6099 controls, we prioritized rs1025497 as a potential causal candidate for CRC risk, demonstrating that rs1025497[A] allele significantly reduced the risk of CRC (OR 0.70, 95% confidence interval = 0.56-0.83, P = 1.12 × 10-6), which was further validated in UK Biobank cohort comprising 5,313 cases and 21,252 controls. Mechanistically, we experimentally elucidated that variant rs1025497 might acted as an allele-specific silencer, inhibiting the expression level of oncogene RPS19 mediated by the transcription suppressive factor HBP1. Taken together, our sturdy unveils the significant role of RPS19 during CRC pathogenesis and delineates its distal regulatory mechanism mediated by rs1025497, advancing our understanding of the etiology of CRC and provided new insights into the personalized medicine of human cancer.

Protein phosphatase 6 promotes stemness of colorectal cancer cells.

Colorectal cancer (CRC) remains a significant global health concern, demanding a more profound comprehension of its molecular foundations for the development of improved therapeutic strategies. This study aimed to elucidate the role of protein phosphatase 6 (PP6), a member of the type 2A protein phosphatase family, in CRC. Protein phosphatase 6 functions as a heterotrimer with a catalytic subunit (PP6c), regulatory subunits (PP6Rs; PP6R1, PP6R2, and PP6R3), and scaffold subunits (ANKRD28, ANKRD44, and ANKRD52). Elevated PP6c expression has been identified in CRC tissues compared to normal mucosa, aligning with its potential involvement in CRC pathogenesis. PP6c knockdown resulted in decreased colony-forming ability and invivo proliferation of various CRC cell lines. Transcriptome analysis revealed that PP6c knockdown resulted in altered expression of genes associated with cancer stemness. Notably, the PP6c-PP6R3 complex is a key player in regulating cancer stem cell (CSC) markers. Additionally, increased PP6c expression was observed in CSC-like cells induced by sphere formation, implicating the role of PP6c in CSC maintenance. This study highlights the role of PP6c in CRC and suggests that it is a potential therapeutic target disrupting a pathway critical for CRC progression and stem cell maintenance.