Colorectal Cancer Progression Research Articles

Evolution of Colorectal Cancer Trends and Treatment Outcomes: A Comprehensive Retrospective Analysis (2019-2023) in West Kazakhstan.

To determine the demographic and clinical characteristics of individuals diagnosed with colorectal cancer. A retrospective study was conducted on 650 patients diagnosed with colorectal cancer in West Kazakhstan from 2019 to 2023. Statistical analysis was performed to explore the relationships between various factors and outcomes, using significance tests and regression techniques. The study included 650 colorectal cancer patients, with 59.7% males and 40.3% females. Age distribution showed 63.1% between 24-65 years and 36.9% over 65, with no gender-based age differences. Nationality significantly influenced patient composition (63.8% Kazakh, 36.2% Russian, P=0.03). KRAS mutations (76.0% negative) and tumor morphology (40% adenocarcinoma, P=0.02) displayed varied associations. Univariate logistic regression revealed links between demographic/clinical factors and cancer outcomes. Multivariate analysis emphasized age, stage of cancer, expansion, involvement of lymphatic and metastasis in cancer progression. Nomogram predictive modeling incorporated gender, tumor form, stage, and infiltration. Evaluation in a validation cohort showed good differentiation (AUC=0.6293) and calibration. The findings provide insights into colorectal cancer demographics, progression, treatment, and mortality, aiding personalized interventions. this study reveals critical insights into demographics, treatment, and prognosis. Emphasizing the complexity of CRC, the study highlights age, gender, and tumor characteristics' impact on progression and mortality. A developed nomogram model offers clinicians a practical tool for personalized treatment decisions, enhancing prognosis discussions with patients.

KLF4 Induces Colorectal Cancer by Promoting EMT via STAT3 Activation.

Krüppel-like factor 4 (KLF4) has been demonstrated to exert a pro-carcinogenic effect in solid tissues. However, the precise biological function and underlying mechanisms in colorectal cancer (CRC) remains elucidated. To investigate whether KLF4 participates in the proliferation and invasion of CRC. The expression of KLF4 was investigated using immunohistochemistry and immunoblotting. The clinical significance of KLF4 was evaluated. Furthermore, the effect of inhibiting or overexpressing KLF4 on tumor was examined. Immunoblotting and qPCR were used to detect Epithelial-mesenchymal transition-related proteins levels. Additionally, the molecular function of KLF4 is related to the STAT3 signaling pathway and was determined through JASPAR, GSEA analysis, and in vitro experiments. KLF4 exhibits down-regulated expression in CRC and is part of the vessel invasion, TNM stage, and worse prognosis. In vitro studies have shown that KLF4 promotes cellular proliferation and invasion, as well as EMT processes. Xenograft tumor models confirmed the oncogenic role of KLF4 in nude mice. Furthermore, GSEA and JASPAR databases analysis reveal that the binding of KLF4 to the signal transducer and activator of transcription 3 (STAT3) promoter site induces activation of p-STAT3 signaling. Subsequent targeting of STAT3 confirmed its pivotal role in mediating the oncogenic effects exerted by KLF4. The study suggests that KLF4 activates STAT3 signaling, inducing epithelial-mesenchymal transition, thereby promoting CRC progression.

Dual-Specificity Phosphatase 4 Promotes Malignant Features in Colorectal Cancer Through Cyclic-AMP Response Element Binding Protein/Protein KinaseCAMP-Activated Catalytic Subunit Beta Activation.

Previous studies have demonstrated that Dual-specificity phosphatase 4 (DUSP4) plays an important role in the progression of different tumor types. However, the role and mechanism of DUSP4 in colorectal cancer (CRC) remain unclear. We investigate the role and mechanisms of DUSP4 in CRC. Immunohistochemistry was used to investigate DUSP4 expression in CRC tissues. Cell proliferation, apoptosis and migration assays were used to validate DUSP4 function in vitro and in vivo. RNA-sequence assay was used to identify the target genes of DUSP4. Human phosphokinase array and inhibitor assays were used to explore the downstream signaling of DUSP4. DUSP4 expression was upregulated in CRC tissues relative to normal colorectal tissues, and DUSP4 expression showed a significant positive correlation with CRC stage. Consistently, we found that DUSP4 was highly expressed in colorectal cancer cells compared to normal cells. DUSP4 knockdown inhibits CRC cell proliferation, migration and promotes apoptosis. Furthermore, the ectopic expression of DUSP4 enhanced CRC cell proliferation, migration and diminished apoptosis in vitro and in vivo. Human phosphokinase array data showed that ectopic expression of DUSP4 promotes CREB activation. RNA-sequencing data showed that PRKACB acts as a downstream target gene of DUSP4/CREB and enhances CREB activation through PKA/cAMP signaling. In addition, xenograft model results demonstrated that DUSP4 promotes colorectal tumor progression via PRKACB/CREB activation in vivo. These findings suggest that DUSP4 promotes CRC progression. Therefore, it may be a promising therapeutic target for CRC.

Fighting the invisible foe in cancer therapy

In this issue of Cell Host & Microbe, Huang etal. determine that an oncogenic bacterium contributes to colorectal cancer progression and resistance to receptor tyrosine kinase inhibitors. These findings highlight the need for an integrative approach for cancer treatment that considers the influence of the microbiome.

MiR-29a expression negatively correlates with Bcl-2 levels in colorectal cancer and is correlated with better prognosis

MicroRNAs (miRNAs) are a class of small non-coding RNAs that act as important regulators of gene expression, involved in various biological pathways. Aberrant miRNAs expression is associated with the onset and progression of colorectal cancer (CRC). The aim of this study was to investigate the correlation between five miRNAs (miR-29a, miR-101, miR-125b, miR-146a, and miR-155), found to be deregulated in tissue samples of CRC patients, and clinicopathological characteristics and histological markers. Analysis of histological markers was performed by immunohistochemical staining of tumour tissues with Ki-67, p53, CD34, and Bcl-2. Our findings revealed a significant negative correlation between miR-29a expression and Bcl-2 levels. Furthermore, high miR-29a expression was associated with a lower incidence of distant metastasis in CRC patients. We observed negative correlations between miR-101 expression and the number of lymph nodes with metastasis, as well as the size of the largest metastasis; miR-125b expression and lymphovascular invasion; and miR-155 expression and mucus presence. Our survival analysis demonstrated that high miR-29a expression correlated with better progression-free survival of CRC patients, underscoring its potential as a prognostic marker. Our study unveiled intricate relationships between specific miRNA expressions and clinicopathological features in CRC, highlighting the potential utility of miR-29a as a valuable prognostic biomarker.

Circular RNA hsa_circ_0000467 promotes colorectal cancer progression by promoting eIF4A3-mediated c-Myc translation

BackgroundColorectal cancer (CRC) is the second most common malignant tumor worldwide, and its incidence rate increases annually. Early diagnosis and treatment are crucial for improving the prognosis of patients with colorectal cancer. Circular RNAs are noncoding RNAs with a closed-loop structure that play a significant role in tumor development. However, the role of circular RNAs in CRC is poorly understood.MethodsThe circular RNA hsa_circ_0000467 was screened in CRC circRNA microarrays using a bioinformatics analysis, and the expression of hsa_circ_0000467 in CRC tissues was determined by in situ hybridization. The associations between the expression level of hsa_circ_0000467 and the clinical characteristics of CRC patients were evaluated. Then, the role of hsa_circ_0000467 in CRC growth and metastasis was assessed by CCK8 assay, EdU assay, plate colony formation assay, wound healing assay, and Transwell assay in vitro and in a mouse model of CRC in vivo. Proteomic analysis and western blotting were performed to investigate the effect of hsa_circ_0000467 on c-Myc signaling. Polysome profiling, RT‒qPCR and dual-luciferase reporter assays were performed to determine the effect of hsa_circ_0000467 on c-Myc translation. RNA pull-down, RNA immunoprecipitation (RIP) and immunofluorescence staining were performed to assess the effect of hsa_circ_0000467 on eIF4A3 distribution.ResultsIn this study, we found that the circular RNA hsa_circ_0000467 is highly expressed in colorectal cancer and is significantly correlated with poor prognosis in CRC patients. In vitro and in vivo experiments revealed that hsa_circ_0000467 promotes the growth and metastasis of colorectal cancer cells. Mechanistically, hsa_circ_0000467 binds eIF4A3 to suppress its nuclear translocation. In addition, it can also act as a scaffold molecule that binds eIF4A3 and c-Myc mRNA to form complexes in the cytoplasm, thereby promoting the translation of c-Myc. In turn, c-Myc upregulates its downstream targets, including the cell cycle-related factors cyclin D2 and CDK4 and the tight junction-related factor ZEB1, and downregulates E-cadherin, which ultimately promotes the growth and metastasis of CRC.ConclusionsOur findings revealed that hsa_circRNA_0000467 plays a role in the progression of CRC by promoting eIF4A3-mediated c-Myc translation. This study provides a theoretical basis and molecular target for the diagnosis and treatment of CRC.

The Role of Adipocytes Recruited as Part of Tumor Microenvironment in Promoting Colorectal Cancer Metastases.

Adipose tissue dysfunction, which is associated with an increased risk of colorectal cancer (CRC), is a significant factor in the pathophysiology of obesity. Obesity-related inflammation and extracellular matrix (ECM) remodeling promote colorectal cancer metastasis (CRCM) by shaping the tumor microenvironment (TME). When CRC occurs, the metabolic symbiosis of tumor cells recruits adjacent adipocytes into the TME to supply energy. Meanwhile, abundant immune cells, from adipose tissue and blood, are recruited into the TME, which is stimulated by pro-inflammatory factors and triggers a chronic local pro-inflammatory TME. Dysregulated ECM proteins and cell surface adhesion molecules enhance ECM remodeling and further increase contractibility between tumor and stromal cells, which promotes epithelial-mesenchymal transition (EMT). EMT increases tumor migration and invasion into surrounding tissues or vessels and accelerates CRCM. Colorectal symbiotic microbiota also plays an important role in the promotion of CRCM. In this review, we provide adipose tissue and its contributions to CRC, with a special emphasis on the role of adipocytes, macrophages, neutrophils, T cells, ECM, and symbiotic gut microbiota in the progression of CRC and their contributions to the CRC microenvironment. We highlight the interactions between adipocytes and tumor cells, and potential therapeutic approaches to target these interactions.

Exposure to trichloromethane via drinking water promotes progression of colorectal cancer by activating IRE1α/XBP1 pathway of endoplasmic reticulum stress

Trichloromethane (TCM), a commonly recognized disinfection by-product formed during the chlorination of water, has been associated with the onset of colorectal cancer (CRC) in humans. Despite this, the impact of TCM on the progression of CRC remains uncertain. In this investigation, it was observed that exposure to TCM could augment the migratory capabilities of CRC cells and facilitate the advancement of colorectal tumors. To delve deeper into the mechanism responsible for TCM-induced CRC progression, we performed RNA-Seq analysis at cellular and animal levels after TCM exposure. Both the KEGG and GO enrichment analyses indicated the activation of endoplasmic reticulum stress (ERS) and the regulation of the cytoskeleton. Subsequently, we confirmed the activation of the IRE1α/XBP1 pathway of ERS through western blot and RT-qPCR. Additionally, we observed the aggregation of cytoskeletal proteins F-actin and β-tubulin at the cell membrane periphery and the development of cellular pseudopods using immunofluorescence following exposure to TCM in vitro. The downregulation of IRE1α and XBP1 through siRNA interference resulted in the disruption of cell cytoskeleton rearrangement and impaired cell migration capability. Conversely, treatment with TCM mitigated this inhibitory effect. Moreover, chronic exposure to low concentration of TCM also triggered CRC cell migration by causing cytoskeletal reorganization, a process controlled by the IRE1α/XBP1 axis. Our study concludes that TCM exposure induces cell migration through the activation of ERS, which in turn regulates cytoskeleton rearrangement. This study offers novel insights into the mechanism through which TCM facilitates the progression of CRC.

Spatial transcriptome and single-cell reveal the role of nucleotide metabolism in colorectal cancer progression and tumor microenvironment

BackgroundThe intricacies of nucleotide metabolism within tumor cells specific to colorectal cancer (CRC) remain insufficiently characterized. A nuanced examination of particular tumor clusters and their dynamic interplay with the tumor microenvironment (TME) may yield profound insights into these therapeutically auspicious communicative networks.MethodsBy integrating ten types of single-cell enrichment scoring methods, we carried out enrichment analysis on CRC cell types, which was validated through four additional single-cell cohorts. Groups of tumor cells were determined using the average values of the scores. Using cellphonedb, monocle, inferCNV, SCENIC, and Cytotrace, functional analyses were performed. Utilizing the RCTD approach, single-cell groupings were mapped onto spatial transcriptomics, analyzing cell dependency and pathway activity to distinguish between tumor cell subtypes. Differential expression analysis identified core genes in nucleotide metabolism, with single-cell and spatial transcriptomics analyses elucidating the function of these genes in tumor cells and the immune microenvironment. Prognostic models were developed from bulk transcriptome cohorts to forecast responses to immune therapy. Laboratory experiments were conducted to verify the biological function of the core gene.ResultsNucleotide metabolism is significantly elevated in tumor cells, dividing them into two groups: NUhighepi and NUlowepi. The phenotype NUhighepi was discerned to exhibit pronounced malignant attributes. Utilizing the analytical tool stlearn for cell-to-cell communication assessment, it was ascertained that NUhighepi engages in intimate interactions with fibroblasts. Corroborating this observation, spatial transcriptome cell interaction assessment through MISTy unveiled a particular reliance of NUhighepi on fibroblasts. Subsequently, we pinpointed NME1, a key gene in nucleotide metabolism, affirming its role in thwarting metastasis via in vitro examination. Utilizing multiple machine learning algorithms, a stable prognostic model (NRS) has been developed, capable of predicting survival and responses to immune therapy. In addition, targeted drugs have been identified for both high and low scoring groups. Laboratory experiments have revealed that NME1 can inhibit the proliferation and invasion of CRC tumor cells.ConclusionOur study elucidates the potential pro-tumor mechanism of NUhighepi and the role of NME1 in inhibiting metastasis, further deepening the understanding of the role of nucleotide metabolism in colorectal cancer, and providing valuable targets for disrupting its properties.

Obesity and Colorectal Cancer: A Narrative Review.

Background and Objectives: Cancer is a multicausal disease, and environmental, cultural, socioeconomic, lifestyle, and genetic factors can influence the risk of developing cancer. Colorectal cancer (CRC) stands as the third most common cancer globally. Some countries have observed a rise in the incidence of CRC, especially among young people. This increase is associated with lifestyle changes over the last few decades, including changes in diet patterns, a sedentary lifestyle, and obesity. Currently, obesity and overweight account for approximately 39% of the world's population and increase the risk of overall mortality of certain cancer types. This study aims to conduct a literature review examining the association between obesity and CRC. Materials and Methods: This narrative review explored the pathophysiological mechanisms, treatment strategies, and challenges related to obesity and CRC. Results: Several studies have established a clear causal relationship between obesity and CRC, showing that individuals with morbid obesity are at a higher risk of developing colorectal cancer. The adipose tissue, particularly the visceral, secretes proinflammatory cytokines, such as TNF-alpha, interleukin-6, and C-reactive protein. Chronic inflammation is closely linked to cancer initiation and progression, with a complex interplay of molecular mechanisms underlying this association. Obesity can complicate the treatment of CRC due to several factors, reducing the therapeutic effectiveness and increasing the risk for adverse events during treatment. Dietary modification, calorie restriction, and other types of weight-control strategies can reduce the risk of CRC development and improve treatment outcomes. Conclusions: Obesity is intricately linked to CRC development and progression, making it a crucial target for intervention, whether through diet therapy, physical exercises, medical therapy, or bariatric surgery.

Cyclophilin J limits linear ubiquitin signaling and controls colorectal cancer progression

Exorbitant sustained inflammation is closely linked to inflammation-associated disorders, including cancer. The initiation of gastrointestinal cancers such as colorectal cancer (CRC) is frequently accelerated by uncontrollable chronic inflammation which is triggered by excessive activation of nuclear factor kappa-B (NF-κB) signaling. Linear ubiquitin chains play an important role in activating canonical NF-κB pathway. The only known E3 complex, linear ubiquitin assembly complex (LUBAC) is responsible for the synthesis of linear ubiquitin chains, thus leading to the activation of NF-κB axis and promoting the development of inflammation and inflammation-associated cancers. We report here cyclophilin J (CYPJ) is a negative regulator of the LUBAC. The N-terminus of CYPJ binds to the second Npl4-like zinc finger (NZF2) domain of HOIP and the ubiquitin-like (UBL) domain of SHARPIN to disrupt the interaction between HOIP and SHARPIN and thus restrains linear ubiquitin chain synthesis and NF-κB activation. Cypj-deficient mice are highly susceptible to dextran sulfate sodium (DSS)-induced colitis and DSS plus azoxymethane (AOM)-induced colon cancer. Moreover, CYPJ expression is induced by hypoxia. Patients with high expression of both CYPJ and hypoxia-inducible factor-1α (HIF-1α) have longer overall survival and progression-free survival. These results implicate CYPJ as an unexpected robust attenuator of inflammation-driven tumorigenesis that exerts its effects by controlling linear ubiquitin chain synthesis in NF-κB signal pathway.

Expression Pattern of PDE4B, PDE4D, and SFRP5 Markers in Colorectal Cancer.

Background and Objectives: Colorectal cancer (CRC) is the most frequently diagnosed malignant disease of the gastrointestinal system, and new diagnostic and prognostic markers are needed to elucidate the complete tumor profile. Materials and Methods: We used CRC tumor tissues (Dukes' A-D) and adjacent noncancerous tissues of 43 patients. Immunohistochemistry was used to examine the expression of phosphodiesterase 4B (PDE4B), phosphodiesterase 4D (PDE4D), and secreted frizzled related protein 5 (SFRP5) markers. We also analyzed the expression levels of PDE4B, PDE4D, and SFRP5 in CRC tissues compared to control tissues using RNA-sequencing data from the UCSC Xena browser. Results: In CRC stages, the distribution of PDE4B-positive cells varied, with differing percentages between epithelium and lamina propria. Statistically significant differences were found in the number of PDE4B-positive epithelial cells between healthy controls and all CRC stages, as well as between different CRC stages. Similarly, significant differences were observed in the number of PDE4B-positive cells in the lamina propria between healthy controls and all CRC stages, as well as between different CRC stages. CRC stage Dukes' C exhibited a significantly higher number of PDE4B-positive cells in the lamina propria compared to CRC stage Dukes' B. Significant differences were noted in the number of PDE4D-positive epithelial cells between healthy controls and CRC stages Dukes' A, B, and D, as well as between CRC stage Dukes' C and stages A, B, and D. CRC stage Dukes' A had significantly more PDE4D-positive cells in the lamina propria compared to stage D. Significant differences were also observed in the number of SFRP5-positive cells in the lamina propria between healthy controls and all CRC stages, as well as between CRC stages Dukes' A and D. While the expression of PDE4D varied across CRC stages, the expression of SFRP5 remained consistently strong in both epithelium and lamina propria, with significant differences noted mainly in the lamina propria. The expression levels of PDE4B, PDE4D, and SFRP5 reveal significant differences in the expression of these genes between CRC patients and healthy controls, with notable implications for patient prognosis. Namely, our results demonstrate that PDE4B, PDE4D, and SFRP5 are significantly under-expressed in CRC tissues compared to control tissues. The Kaplan-Meier survival analysis and the log-rank (Mantel-Cox) test revealed distinct prognostic implications where patients with lower expression levels of SFRP5 exhibited significantly longer overall survival. The data align with our immunohistochemical results and might suggest a potential tumor-suppressive role for these genes in CRC. Conclusions: Considering significantly lower gene expression, aligned with our immunohistochemical data in tumor tissue in comparison to the control tissue, as well as the significantly poorer survival rate in the case of its higher expression, we can hypothesize that SFRP5 is the most promising biomarker for CRC out of the observed proteins. These findings suggest alterations in PDE4B, PDE4D, and SFRP5 expression during CRC progression, as well as between different stages of CRC, with potential implications for understanding the molecular mechanisms involved in CRC development and progression.

Gut microbiota affects the activation of STING pathway and thus participates in the progression of colorectal cancer

BackgroundMore and more studies showed that gut microbiota was closely related to the development of colorectal cancer (CRC). However, the specific pathway of gut microbiota regulating CRC development is still unknown.MethodsWe collected fecal samples from 14 CRC patients and 20 normal volunteers for 16 S sequencing analysis. At the same time, 14 CRC patients’ tumors and their adjacent tissues were collected for the detection of STING pathway related protein level. Mice were injected with azoxymethane (AOM) to establish an animal model of CRC, and antibiotics were given at the same time to evaluate the influence of gut microbiota on STING pathway and whether it was involved in regulating the tumor development of CRC mice.ResultsThe sequencing results showed that compared with the normal group, the gut microbiota gut microbiota of CRC patients changed significantly at different species classification levels. At the level of genus, Akkermansia, Ligilactobacillus and Subdoligranulum increased the most in CRC patients, while Bacteroides and Dialister decreased sharply. The expression of STING-related protein was significantly down-regulated in CRC tumor tissues. Antibiotic treatment of CRC mice can promote the development of tumor and inhibit the activation of STING pathway.ConclusionGut microbiota participates in CRC progress by mediating STING pathway activation.

Integrative Omics Uncovers Low Tumorous Magnesium Content as A Driver Factor of Colorectal Cancer.

Magnesium (Mg) deficiency is associated with increased risk and malignancy in colorectal cancer (CRC), yet the underlying mechanisms remain elusive. Here, we used genomic, proteomic, and phosphoproteomic data to elucidate the impact of Mg deficiency on CRC. Genomic analysis identified 160 genes with higher mutation frequencies in Low-Mg tumors, including key driver genes such as KMT2C and ERBB3. Unexpectedly, initiation driver genes of CRC, such as TP53 and APC, displayed higher mutation frequencies in High-Mg tumors. Additionally, proteomic and phosphoproteomic data indicated that low Mg content in tumors may activate epithelial-mesenchymal transition (EMT) by modulating inflammation or remodeling the phosphoproteome of cancer cells. Notably, we observed a negative correlation between the phosphorylation of DBN1 at S142 (DBN1S142p) and Mg content. A mutation in S142 to D (DBN1S142D) mimicking DBN1S142p upregulated MMP2 and enhanced cell migration, while treatment with MgCl2 reduced DBN1S142p, thereby reversing this phenotype. Mechanistically, Mg2+ attenuated the DBN1-ACTN4 interaction by decreasing DBN1S142p, which in turn enhanced the binding of ACTN4 to F-actin and promoted F-actin polymerization, ultimately reducing MMP2 expression. These findings shed new light on the crucial role of Mg deficiency in CRC progression and suggest that Mg supplementation may be a promising preventive and therapeutic strategy for CRC.

Identification and validation of metastasis-related gene ZG16 in the prognosis and progression in colorectal cancer.

Metastasis remains the leading cause of mortality among colorectal cancer (CRC) patients. Identification of new metastasis-related genes are critical to improve colorectal cancer prognosis. Data on mRNA expression in metastatic and primary CRC was obtained from the Gene Expression Omnibus (GEO) database, including GSE81986, GSE41568, GSE71222, GSE21510, and GSE14333. Additionally, data concerning mRNA expression in colon cancer (COAD) and adjacent normal tissues were acquired from The Cancer Genome Atlas (TCGA) database. Hub genes were identified by weighted gene co-expression network analysis (WGCNA) and differential gene expression analysis. Moreover, we assessed the impact of hub gene expression on both overall survival (OS) and disease-free survival (DFS) in patients and identified ZG16 as a potential target. We generated CRC cell lines transfected with lentivirus OE-ZG16 to investigate proliferation, invasion, and migration in vitro. To further elucidate the involvement of ZG16, we utilized gene set enrichment analysis (GSEA) to identify enriched pathways, which were subsequently validated via Western blot analysis. Five datasets containing primary and metastatic CRC samples from GEO database and CRC samples from TCGA database were included in this study and 29 hub genes were identified by WGCNA and differentially expressed gene (DEG) analysis. Low expression of the hub genes (CLCA1 and ZG16) was associated with poor DFS and OS. We confirmed the low expression of ZG16 in CRC using external database and IHC analysis at both transcriptional and protein levels. In addition, the expression of ZG16 was notably elevated in NCM460 cells in comparison to CRC cell lines. The overexpression of ZG16 in CRC cells has been shown to inhibit the proliferation, invasion, and migration of CRC cells. Furthermore, the overexpression of ZG16 has been found to suppress the activation of the epithelial-mesenchymal transition (EMT) and Wnt/β-catenin signaling pathways in CRC. ZG16 may serve as a promising therapeutic target for metastatic CRC treatment.

Exposure to microcystin-LR promotes the progression of colitis-associated colorectal cancer by inducing barrier disruption and gut microbiota dysbiosis

Microcystins (MCs) are secondary metabolites generated by cyanobacterial blooms, among which microcystin-LR (MC-LR) stands out as the most widely distributed variant in aquatic environments. However, the effects of MC-LR on the colorectum and its role in promoting colorectal tumor progression remain unclear. Therefore, this study aims to scrutinize the impact of MC-LR on a mice model of colitis-associated colorectal cancer and elucidate the potential underlying molecular mechanisms. In this study, we used AOM/DSS mice and orally administered MC-LR at doses of 40 µg/kg or 200 µg/kg. Exposure to MC-LR increased tumor burden, promoted tumor growth, shortened colon size, and decreased goblet cell numbers and tight junction protein levels in intestinal tissues. Additionally, exposure to MC-LR induced alterations in the structure of gut microbiota in the mouse colon, characterized by an increase in the relative abundance of Escherichia_coli and Shigella_sonnei, and a decline in the relative abundance of Akkermansia_muciniphila. Transcriptomic analysis revealed that MC-LR exposure activated the IL-17 signaling pathway in mouse colorectal tissues and participated in inflammation regulation and immune response. Immunofluorescence results demonstrated an increase in T-helper 17 (Th17) cell levels in mouse colorectal tumors following MC-LR exposure. The results from RT-qPCR revealed that MC-LR induced the upregulation of IL-6, IL-1β, IL-10, IL-17A, TNF-α, CXCL1, CXCL2, CXCL5 and CCL20. The novelty of this study lies in its comprehensive approach to understanding the mechanisms by which MC-LR may contribute to CRC progression, offering new perspectives and valuable reference points for establishing guidance standards regarding MC-LR in drinking water. Our findings suggest that even at guideline value, MC-LR can have profound effects on susceptible mice, emphasizing the need for a reevaluation of guideline value and a deeper understanding of the role of environmental toxins in cancer progression.

Enhanced therapeutic impact of Shikonin-encapsulated exosomes in the inhibition of colorectal cancer progression

Colorectal cancer (CRC) is a prevalent malignancy with high mortality rates and poor prognosis. Shikonin (SHK) has demonstrated extensive anti-tumor activity across various cancers, yet its clinical application is hindered by poor solubility, limited bioavailability, and high toxicity. This study aims to develop SHK-loaded exosomes (SHK-Exos) and assess their efficacy in CRC progression. Exosomes were isolated using ultracentrifugation and characterized via TEM, NTA, and western blotting. Their cellular internalization was confirmed through confocal microscopy post PKH67 labeling. Effects on cell behaviors were assessed using CCK-8 and Transwell assays. Cell cycle and apoptosis were analyzed via flow cytometry. A xenograft tumor model evaluated in vivo therapeutic potential, and tumor tissues were examined using H&E staining and in vivo imaging. SHK-Exos demonstrated effective cell targeting and internalization in CRC cells. In vitro, SHK-Exos surpassed free SHK in inhibiting aggressive cellular behaviors and promoting apoptosis, while in vivo studies showed substantial efficacy in reducing tumor growth with excellent tumor targeting and minimal toxicity. Employing SHK-Exos effectively impedes CRC progression in vitro and in vivo, offering significant therapeutic potential. This research underscores the advantages of using autologous exosomes as a drug carrier, enhancing efficacy and reducing toxicity.

Defensins: Exploring Their Opposing Roles in Colorectal Cancer Progression.

Colorectal cancer (CRC) represents a significant global healthcare burden, with a particularly concerning rising incidence among younger adults. This trend may highlight potential links between diet, gut microbiome, and CRC risk. Novel therapeutic options have been increasingly based on the understanding of molecular mechanisms and pathways. The PI3K/AKT/mTOR pathway, a crucial cell growth regulator, offers a promising target for CRC therapy. mTOR, a key component within this pathway, controls cell growth, survival, and metabolism. Understanding the specific roles of defensins, particularly human β-Defensin 1 (HBD-1), in CRC is crucial. HBD-1 exhibits potent antimicrobial activity and may influence CRC development. Deciphering defensin expression patterns in CRC holds the promise of improved understanding of tumorigenesis, which may pave the way for improved diagnostics and therapies. This article reviews recent advances in understanding regarding how HBD-1 influences CRC initiation and progression, highlighting the molecular mechanisms by which it impacts CRC. Further, we describe the interaction between defensins and mTOR pathway in CRC.

FEV-mediated WNT2 transcription is involved in the progression of colorectal cancer via the Wnt signaling.

The online version contains supplementary material available at 10.1007/s10616-024-00643-0.

Investigating the impact of SMAD2 and SMAD4 downregulation in colorectal cancer and their correlation with immune markers, prognosis, and drug resistance and sensitivity.

While many genes linked to colorectal cancer (CRC) contribute to cancer development, a thorough investigation is needed to explore crucial hub genes yet to be fully studied. A pivotal pathway in CRC is transforming growth factor-beta (TGF-β). This study aimed to assess SMAD2 and SMAD4 gene expression from this pathway. Counted data from the Cancer Genome Atlas (TCGA) were examined, comparing 483 tumor and 41 normal samples. Using clinical data, genes impacting overall survival (OS) were evaluated. GSE39582 was employed to confirmed the levels of genes in CRC compared to the normal samples. Additionally, employing unhealthy samples and the RT-qPCR means our outcomes was validated. Finally, PharmacoGx information were utilized to connect the levels of potential genes to drug tolerance and susceptibility. Our findings showed SMAD2 and SMAD4 levels in TGF-β signaling were more significant than other pathway genes. Our findings indicated that the protein levels of these genes were lower in malignant tissues than in healthy tissues. Results revealed a significant correlation between low levels of SMAD2 and unfavorable OS in CRC individuals. RT-qPCR results demonstrated decreased expressions of both SMAD2 and SMAD4 in cancer tissues compared to elevated levels in adjacent normal samples. Our results showed significant association between selected genes and immune cell infiltration markers such as CD8+, and B-cells. Our results indicated a potential association among the levels of SMAD2 and SMAD4 genes and tolerance and susceptibility to Nilotinib and Panobinostat drugs. Reduced expression of SMAD2 and SMAD4 may be pivotal in CRC progression, impacting downstream genes unrelated to patient OS. These findings suggest a potential role for SMAD2 and SMAD4 as predictive markers for drug response in CRC patients.