Pathogenesis Of CRC Research Articles

Exploring the Gut Microbiome's Influence on Colorectal Cancer Development and Management: A Review of Current Knowledge and Future Directions

IntroductionColorectal cancer (CRC) is a significant global health concern, ranking as the third most commonly diagnosed cancer and the second leading cause of cancer-related deaths worldwide, with over 1.9 million new cases and nearly 935,000 deaths annually. The rise in CRC incidence is attributed to various lifestyle changes, including dietary shifts, sedentary behavior, and increased obesity rates. These factors underscore the urgent need for new preventive strategies targeting the underlying mechanisms of CRC development. PurposeThis review evaluates the intricate relationship between the gut microbiome and CRC, aiming to enhance our understanding of how microbial diversity and composition contribute to CRC pathogenesis. State of Knowledge Studies reveal a correlation between the onset and progression of CRC and changes in microbial diversity and specific taxa. In CRC patients, the presence of Fusobacterium nucleatum is linked to inflammation and poor prognosis, while Bacteroides fragilis is associated with promoting colitis and carcinogenesis. The Human Microbiome Project's findings reveal that unique microbial communities can impact inflammation and tumor growth. Meta-analyses underline the crucial role of microbial diversity, influenced by diet and health status, in cancer prevention and progression, particularly in CRC. ConclusionsUnderstanding the interactions between the microbiome, diet, and host health is crucial for developing targeted treatment strategies and precision diagnostics for CRC. Insights from microbiome research could significantly improve patient outcomes in CRC management. Further high-quality studies are essential to fully elucidate the therapeutic potential of the microbiome in CRC treatment.

PTOV1 facilitates colorectal cancer cell proliferation through activating AKT1 signaling pathway

BackgroundColorectal cancer is a predominant contributor to global cancer-related morbidity and mortality. The oncogene PTOV1 has been linked to various human malignancies, yet its specific role in CRC pathogenesis requires further elucidation. MethodsOur study used a comprehensive array of authoritative bioinformatics tools, such as TIMER, UCSC Xena, GEO, Human Protein Atlas, UALCAN, CIBERSORTx and others which used to investigate the complex effects of PTOV1 on gene expression profiles, diagnostic and prognostic biomarkers, tumor immunology, signaling pathways, epigenetic alterations, and genetic mutations. Gene expression validation was conducted using Western blot and qRT-PCR. The in vitro proliferative and migratory potentials of CRC cells were evaluated using CCK-8 assays, colony formation, and transwell migration assays, respectively. MSP was applied to assess the methylation status of the PTOV1 promoter region. ResultsOur results reveal a significant association between increased PTOV1 expression, driven by promoter hypomethylation, and poor patient prognosis in CRC. Elevated PTOV1 levels were positively correlated with the enrichment of diverse immune cell subsets and immune-related molecules within the tumor microenvironment. In vitro assays demonstrated that PTOV1 knockdown markedly reduced CRC cell proliferation, colony formation, and migration, while ectopic PTOV1 expression had the opposite effect. Importantly, PTOV1 was shown to regulate the PI3K-AKT signaling pathway, significantly influencing the phosphorylation of AKT1 and the expression of cell cycle regulators P21 and P27. The pharmacological inhibition of AKT1 phosphorylation using MK2206 effectively counteracted the proliferative effects induced by PTOV1 overexpression. ConclusionThe ability of PTOV1 to enhance CRC cell proliferation via modulation of the AKT1 signaling pathway establishes it as a potential therapeutic target and a promising biomarker for prognostic stratification in CRC.

Environmental and Ingestible Toxins: A Review of their Role in the Development of Colon and Rectal Cancer

Objective: In this paper, we review the epidemiological evidence on the relationship between environmental and ingestible toxins and colorectal cancer. Data sources and date extraction: We searched PubMed, Embase, and Web of Science for epidemiological studies on environmental and ingestible toxins and colorectal cancer published before June 1, 2022. Results: Studies have reported positive associations between colorectal cancer and different persistent organic pollutants, non-persistent organic pollutants, polycyclic aromatic hydrocarbons, volatile organic compounds, and metals. Conclusion: While the pathogenesis of CRC is likely multifactorial including both modifiable lifestyle factors (e.g., dietary, smoking, physical activity) and nonmodifiable (genetic, colitis-associated) risk factors, the role of the environment may be an additional and frequently forgotten contributor.

The Role of Natural Products from Herbal Medicine in TLR4 Signaling for Colorectal Cancer Treatment.

The toll-like receptor 4 (TLR4) signaling pathway constitutes an intricate network of protein interactions primarily involved in inflammation and cancer. This pathway triggers intracellular signaling cascades, modulating transcription factors that regulate gene expression related to immunity and malignancy. Previous studies showed that colon cancer patients with low TLR4 expression exhibit extended survival times and the TLR4 signaling pathway holds a significant role in CRC pathogenesis. In recent years, traditional Chinese medicines (TCMs) have garnered substantial attention as an alternative therapeutic modality for CRC, primarily due to their multifaceted composition and ability to target multiple pathways. Emerging evidence indicates that specific TCM products, such as andrographolide, rosmarinic acid, baicalin, etc., have the potential to impede CRC development through the TLR4 signaling pathway. Here, we review the role and biochemical processes of the TLR4 signaling pathway in CRC, and natural products from TCMs affecting the TLR4 pathway. This review sheds light on potential treatment strategies utilizing natural TLR4 inhibitors for CRC, which contributes to the advancement of research and accelerates their clinical integration into CRC treatment.

Synergistic inhibition of CXCL8 following MRTX1133 treatment with ONC212 or 5-FU in KRAS G12D and G12V mutant CRC and PDAC cell lines.

e15196 Background: CXCL8, serves as a crucial multifunctional cytokine that plays a significant role in regulating tumor growth, invasion, and migration. Although in some cancers the critical role of CXCL8 in patient prognosis and disease progression is stablished but its role in CRC & PDAC patients is under investigation. High levels of CXCL8 in tumor microenvironment (TME) and association with cancer stem cell survival, immune surveillance escape & metastasis make it an interesting therapeutic target. Both CRC & PDAC are among the deadliest cancers with dismal prognosis. The need for novel therapeutics with a focus on TME is emerging. MRTX1133 was identified as an inhibitor of KRASG12D. ONC212 is a fluorinated imipridone with strong anti-cancer activity in nM range and preclinical efficacy against pancreatic and other malignancies. Here we report the synergistic inhibition of CXCL8 in both KRAS G12D & KRAS G12V cell lines with use of KRAS G12D inhibitor in combination with 5-FU or ONC212. Methods: Different CRC & PDAC cells were treated with MRTX1133 with 5-FU or ONC212 cytokine profiling at 48h time point was done. Human protein atlas was used for protein and RNA data &TCGA data for survival was used. Results: We previously have shown the synergistic inhibition of pERK and cytokine alteration between MRTX1133 KRAS G12D inhibitor with 5FU or ONC212 in both cell lines with KRAS G12D & KRAS G12V mutation (Tajiknia V et al. AACR 2023 annual meeting). In LS513 KRAS G12D CRC cell line, treatment of ONC212, MRTX1133 and combination of both showed a decrease of 52.36%,58.83% and 71.65% respectively in CXCL8 levels compared to control at 48h time point. In HPAF-II KRAS G12V PDAC cell line, treatment of ONC212, MRTX1133 and combination of both resulted in 38.69%, 64.44%, 57% inhibition of CXCL8 levels respectively compared to control. In SW480 KRAS G12V CRC cell line, treatment of ONC212, MRTX1133 and combination of both demonstrated 25.7%,47.3% and 66.5% inhibition in CXCL8 level respectively compared to control at 48h time point. Single treatment of MRTX1133 caused a decline in CXCL8/IL-8 levels by 30% while single treatment of 5-FU showed a 36% decrease, the combination of both resulted in more than 55% decrease compared to control in LS513 KRAS G12D cell line. In SW480 KRAS G12V cell line, combination of 5-FU & MRTX1133 showed 30% inhibition while in Capan-2 PDAC KRAS G12V cells the same combination showed a 48.2% reduction in CXCL8 compared to control at 48h time point. TCGA data for RNA shows low specificity of CXCL8 for cancer type but it is significantly high in CRC and PDAC. Protein concentration in the Pan-cancer cohort shows significant high level of CXCL8 in CRC. Conclusions: Considering the important role of KRAS mutations and CXCL8 in pathogenesis of CRC & PDAC, the effective inhibition of CXCL8 with the use of targeted therapy in combination could enhance treatment response and patient survival.

Colorectal Cancer in Inflammatory Bowel Disease: A Review of the Role of Gut Microbiota and Bacterial Biofilms in Disease Pathogenesis.

The risk of colorectal cancer [CRC] is increased in patients with inflammatory bowel disease [IBD], particularly in extensive ulcerative colitis [UC] and Crohn's colitis. Gut microbiota have been implicated in the pathogenesis of CRC via multiple mechanisms, including the release of reactive oxygen species and genotoxins, and induction of inflammation, as well as activation of the immune response. Gut microbiota can enhance their carcinogenic and proinflammatory properties by organising into biofilms, potentially making them more resistant to the host's immune system and to antibiotics. Colonic biofilms have the capacity to invade colonic tissue and accelerate tumorigenesis in tumour-prone models of mice. In the context of IBD, the prevalence of biofilms has been estimated to be up to 95%. Although the relationship between chronic inflammation and molecular mediators that contribute to IBD-associated CRC is well established, the role of gut microbiota and biofilms in this sequence is not fully understood. Because CRC can still arise in the absence of histological inflammation, there is a growing interest in identifying chemopreventive agents against IBD-associated CRC. Commonly used in the treatment of UC, 5-aminosalicylates have antimicrobial and anticarcinogenic properties that might have a role in the chemoprevention of CRC via the inhibition or modulation of carcinogenic gut microbiota and potentially of biofilm formation. Whether biologics and other IBD-targeted therapies can decrease the progression towards dysplasia and CRC, via mechanisms independent of inflammation, is still unknown. Further research is warranted to identify potential new microbial targets in therapy for chemoprevention of dysplasia and CRC in IBD.

Characterization of Plasmids Isolated from Bacterial Flora of CRC Patients – Proof of Concept

Abstract Introduction Colorectal cancer (CRC) is one of the leading oncogenic disorders, both in terms of incidence and mortality. The etiology of the disease is certainly multifactorial. Various risk factors like alcohol consumption, smoking, CRC family history, inflammatory bowel disease, hormone therapy, aspirin/nonsteroidal anti-inflammatory drugs use, higher body mass index, consumption of red and/or processed meat, insufficient physical activity, and decreased intake of fruit and vegetables have been pointed out; however, there is not enough support evidence for a single particular causative mechanism. Recently, gut bacterial microbiota has been shown to influence significantly the pathogenesis of CRC. However, little attention is paid to the putative impact of plasmids in gut flora. Material and methods We have designed and tested the workflow for semi-selective isolation and amplification of random circular sequences. The exploitation of rolling circle amplification (RCA) with a random hexamers protocol is crucial for the outcome. Results Our results suggest that it is possible to isolate and amplify plasmid DNA from gut flora and further process, sequence, and identify them. Discussion Little is known about the interactions between bacterial plasmids and human cells. The collection of plasmid sequencing data and the comparison of CRC patients and healthy control sequences can be the first step to elucidating this phenomenon.

Abstract 5859: PLK1 predicts aggressive behavior in CRC patients and its inhibition reverse chemoresistance in CRC cells

Abstract Polo-like kinase 1 (PLK1) is a serine/threonine-protein kinase, that is involved in multiple stages of cell cycle progression in mammals. Dysregulation of PLK1 has been found in a variety of human cancers and was associated with poor prognoses in various cancers. However, its role in the pathogenesis of CRC from Middle Eastern ethnicity has not yet been explored. Therefore, we examined the expression of PLK1 protein in a large cohort of over 1000 Middle Eastern CRC cases by immunohistochemistry. Correlation with clinico-pathological parameters were performed. PLK1 overexpression was noted in 60.3% (693/1149) CRC cases and was significantly associated with larger tumor size (T3/T4 tumors), lymphnode metastasis, Stage III tumors, MSI-H status and p-ERK1/2 over-expression. Interestingly, on multivariate logistic regression analysis, we found that PLK1 was an independent predictor of lymphnode metastasis. However, no association was noted between PLK1 expression and clinical outcomes (DFS, RFS, OS, CSS). Our in vitro experimentation revealed that CRC cells expressing high levels of PLK1 exhibited resistance to 5-Fu treatment, whereas cells with low PLK1 expression demonstrated sensitivity to the treatment. To explore the role of PLK1 on chemoresistance, we inhibited PLK1 using specific inhibitor, volasertib and we showed that volasertib effectively reversed 5-Fu resistance in these cells. Furthermore, knockdown of PLK1 reduced the progression of epithelial-to-mesenchymal transition (EMT) and the stem cell-like properties in 5-Fu resistant cells, showing the role of PLK1 on inducing EMT and stemness in CRC. Interestingly, the forced expression of PLK1 triggered the activation of the CRAF-MEK-ERK-ZEB1 signaling cascade, whereas its inhibition led to the suppression of this cascade. In addition, we showed that silencing of ERK1/2 reversed the chemoresistance, EMT and stemness of PLK1 expressing CRC cell lines. Our findings underscore the significant role of PLK1 in conferring chemoresistance, and targeting PLK1 could represent a viable therapeutic approach for the treatment of patients with an aggressive subtype of CRC. Citation Format: Divya Padmaja, Maha Al-Rasheed, Pratheesh Kumar Poyil, Abdul K. Siraj, Sandeep Kumar Parvathareddy, Wael Haqawi, Fouad Al-Dayel, Khawla S. Al-Kuraya. PLK1 predicts aggressive behavior in CRC patients and its inhibition reverse chemoresistance in CRC cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5859.

Abstract 4401: GATA6 is a novel regulator of gene expression and 3D genome in colorectal cancer

Abstract Colorectal cancer (CRC) is one of the most lethal and prevalent malignancies with elusive molecular causes. While the abnormal activity of transcription factors has been reported as a vital component of cancer progression, the mechanism through which they function remains unclear. Here, through the analysis of primary human CRC tissue data, we identified GATA6 as a CRC specific regulator, whose expression upregulation is potentially associated with promoter hypomethylation. In the human genome, GATA6 showed preferential binding at tumor specific active enhancers. Through both auxin-inducible degron (AID) and CRISPR knockout, we showed that GATA6 depletion severely impaired clonogenicity and proliferation. GATA6 depletion caused the loss of CRC specific open chromatin, suggesting a specific regulatory role of GATA6 in CRC pathogenesis. Interestingly, we also discovered the co-occupancy of GATA6 with CTCF and its direct involvement in promoter enhancer loops, suggesting the possibility that GATA6 mediate transcriptional regulation through 3D genome. The loss of GATA6 led to alterations in E-P chromatin interactions of a panel of oncogenes, accompanied by the oncogene downregulation. Finally, we showed that GATA6 loss is detrimental to the xenograft tumor growth and thereby rescued mice survival. Taken together, we unrevealed a novel mechanism by which GATA6 contributes to CRC. Citation Format: Huijue Lyu, Xintong Chen, Yang Cheng, Te Zhang, Ping Wang, Josiah Hiu-yuen Wong, Juan Wang, Lena Stasiak, Leyu Sun, Guangyu Yang, Lu Wang, Feng Yue. GATA6 is a novel regulator of gene expression and 3D genome in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4401.

Abstract 1806: Induction of KRAS G13D dimers as a therapeutic strategy for colorectal cancer

Abstract Colorectal cancer (CRC) is the third leading cause of cancer deaths. Most CRCs arise from polyps in the colon/rectum that acquire gene mutations, including frequent activation of the oncogene Kirsten rat sarcoma virus (KRAS) observed in 40% of cases, particularly at codons 12, 13, and 61. KRAS oligomerization is critical for MAPK pathway signaling, which drives CRC pathogenesis. This study evaluated compounds that bind mutant KRAS G13D to induce non-physiological dimerization. Screening of a 4.1 billion compound DNA-encoded library led to the identification of pyridinylpiperazine/quinoline compounds. These compounds demonstrated the ability to induce RAS dimer formation, subsequently reducing MAPK signaling, exhibiting similarities to BI-2852, which is known to induce formation of non-physiologic RAS dimers. Structure-activity studies yielded indole, piperidine, and morpholine variants showing improved activity in thermal shift assays (DSF) and in cell-based assays evaluating RAS signaling (p-ERK inhibition). Citation Format: Deekshi Angira, anbo Li, Zhiwei Zhou, Seungheon Lee, Joseph Ready, Kenneth Westover. Induction of KRAS G13D dimers as a therapeutic strategy for colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1806.

KRAS and P53 Gene Mutation Patterns Linked to Colorectal Cancer in Sudan

Background: Molecular pathogenesis of CRC represents a major target for understanding and controlling of the disease in the Sudan. Therefore, the present study aimed to explore the clinicopathological pattern of CRC in the Sudan with specific emphases in the role KRAS and P53 genes mutations. Methodology: This study was carried out in El-Obeid, North Kordofan state, Sudan, using CRC samples from patients who presented to the Al-Obeid teaching hospital between 2017 and 2022 and had a biopsy for histopathological diagnosis. This series featured everyone who has CRC. Results: The most prevalent CRC subtype is adenocarcinoma, which is followed by mucinous adenocarcinoma and metastatic adenocarcinoma, which constitute 74%, 20%, and 6%, respectively. KRAS mutation was found in 40% patients 48% males and 33.3% females). P53 mutation was found in 46% individuals 43.5% men and 48% females. Positive correlations between KRAS and P53 were found in 26% cases, while negative correlations were found in 40% cases. Conclusion: Many CRC patients in Sudan present at advanced stages of the illness and at a younger age, necessitating early screening measures. CRC patients have been discovered to have KRAS, P53, or both mutations. As a result, precise preventative and therapeutic methods are considered essential.

Molecular mechanisms of colorectal cancer formation and their significance (literature review)

Colorectal cancer remains an urgent problem of oncological proctology and requires active efforts to study risk factors, mechanisms for the formulation and search for genetic components that play a key role in determining the prognosis of the disease. This article analyzes the molecular mechanisms of colorectal cancer formation, factors of transformation of adenoma formation, pathogenesis and molecular nature of CRC. Subtypes based on transcription signatures allow for better refinement and provide insight into the development of subtype-specific treatment methods, which, in turn, can contribute to more effective treatment of this disease.

Association study for the role of MMP8 gene polymorphisms in Colorectal cancer susceptibility

BackgroundColorectal cancer (CRC) is one of the most common malignant tumors, influenced by several genetic loci in its clinical phenotypes. The aim of this study was to determine the relationship between the MMP8 gene polymorphism and CRC risk in the Chinese Han population.MethodThis study recruited 688 CRC patients and 690 healthy controls. The relationship between MMP8 polymorphism and CRC susceptibility was assessed by calculating the odds ratio (OR) and 95% confidence interval (CI) after stratifying by age, gender, body mass index (BMI), smoking, and alcohol consumption under a multi-genetic model.ResultsMMP8 rs3740938 was associated with increased CRC predisposition (p = 0.016, OR = 1.24, 95% CI: 1.04–1.48), and this association was detected particularly in subjects aged > 60 years, females, people with BMI > 24 kg/m2, smokers, and drinkers. Moreover, rs3740938 was found to be associated with the pathological type of rectal cancer.ConclusionsOur results first displayed that rs3740938 in MMP8 was a risk factor for CRC predisposition. This finding may provide a new biological perspective for understanding the role of the MMP8 gene in CRC pathogenesis.

Early-Onset Colon Cancer: A Narrative Review of Its Pathogenesis, Clinical Presentation, Treatment, and Prognosis.

Colon cancer remains a leading cause of cancer-related deaths, and there has been a rise in the incidence of early-onset colon cancer or colon cancer diagnosed before the age of 50 years old. Early-onset colon cancerhas several differences in clinical presentation, as well as histopathology, geneticalteration, and molecular profiling. Early-onset colon cancer can be differentiated into familial type that includes hereditary familial syndrome and sporadic type. Demographic variance also exists in both developing and developed countries. Due to the rising incidence of colon cancer diagnosed in younger age, it is imperative to examine the available evidence regarding the mortality rate of early-onset colon cancer. Colon cancer is affected by numerous modifiable and non-modifiable risk factors. Increasing obesity and lifestyle disorders in the younger population, such as smoking, may influence this increasing trend. There are existing guidelines for colon cancer screening in both average-risk and high-risk individuals.This narrative review aims to highlight the pathogenesis of early-onset CRC; its clinical presentation, treatment, prognosis; and how it differs from late-onset CRC.

Unmasking the Silent Threat: Colorectal Cancer’s Alarming Surge in India’s Young Adults

Abstract Colorectal cancer (CRC) incidence is rising in young population in India due to increasing influence of Western food habits and increase in sedentary lifestyles. Due to unhealthy eating habits and sedentary lifestyle, obesity is another problem faced by the youth of our country. Physical inactivity, overweight and obesity, red and processed meat consumption, and smoking and excessive alcohol consumption are the factors which have been responsible for the complex etiology and pathogenesis of CRC. These factors individually or synergistically may help in the rapid progression and multistep development of this disease. This review article is aimed to raise the concern of the harmful effect of Western culture on our health and create awareness to adopt a healthy lifestyle and maintain ideal weight. Efforts should be made to increase screening and raise awareness about eating and drinking habits along with lifestyle modification to decrease the rate of CRC.

Evaluation of the Association Between CRNDE Plasma Expression Level, KRAS, NRAS, and BRAF Variants in Patients with advanced CRC

Colorectal cancer is one of the most common types of cancer. CRNDE is a novel-defined lncRNA. We evaluated the possibility of using CRDNE circulating lncRNA as a noninvasive biomarker. Also, we examined the effect of circulating CRNDE lncRNA on the pathogenesis of CRC and its association with the KRAS, NRAS, and BRAF somatic variants commonly observed in CRC. In this study, we enrolled plasma and FFPE tissue samples of 50 advanced CRC patients and plasma samples of 31 individuals in the control group of similar ages. Then, we performed plasma extraction, total RNA isolation, cDNA synthesis, and circulating lncRNA expression analysis, respectively. Also, we carried out KRAS, NRAS, and BRAF somatic variant analysis from FFPE tissues. Our results showed that the expression level of CRNDE (p= 0.002) were significantly upregulated in the CRC when it was compared to with the control group. The calculated area under the curve of the receiver operating characteristic was 0.70. We found a statistically significant difference between the KRAS somatic variants and the circulating CRNDE lncRNA (p= 0.031). This study demonstrated that CRNDE circulating lncRNAs may be used as a potential non-invasive biomarker in CRC. In our study, it was determined that there is a significant relationship between the frequently observed KRAS somatic variants and CRNDE in advanced-stage CRC cases. To the best of our knowledge, this is the first study to show the association of CRNDE circulating lncRNA with advanced CRC. Moreover, it is the first study to show a relationship between the KRAS somatic variants between circulating CRNDE lncRNA in advanced CRC. Keywords: CRNDE, Circulating lncRNA, KRAS, CRC, RT-PCR

Could Microplastics Be a Driver for Early Onset Colorectal Cancer?

Introduction: The incidence of colorectal cancer in those under 50 years of age (early onset colorectal cancer (EOCRC)) is increasing throughout the world. This has predominantly been an increase in distal colonic and rectal cancers, which are biologically similar to late onset colorectal cancer (LOCRC) but with higher rates of mucinous or signet ring histology, or poorly differentiated cancers. The epidemiology of this change suggests that it is a cohort effect since 1960, and is most likely driven by an environmental cause. We explore the possible role of microplastics as a driver for this change. Review: The development of sporadic colorectal cancer is likely facilitated by the interaction of gut bacteria and the intestinal wall. Normally, a complex layer of luminal mucus provides colonocytes with a level of protection from the effects of these bacteria and their toxins. Plastics were first developed in the early 1900s. After 1945 they became more widely used, with a resultant dramatic increase in plastic pollution and their breakdown to microplastics. Microplastics (MPs) are consumed by humans from an early age and in increasingly large quantities. As MPs pass through the gastrointestinal tract they interact with the normal physiological mechanism of the body, particularly in the colon and rectum, where they may interact with the protective colonic mucus layer. We describe several possible mechanisms of how microplastics may disrupt this mucus layer, thus reducing its protective effect and increasing the likelihood of colorectal cancer. Conclusions: The epidemiology of increase in EOCRC suggests an environmental driver. This increase in EOCRC matches the time sequence in which we could expect to see an effect of rapid increase of MPs in the environment and, as such, we have explored possible mechanisms for this effect. We suggest that it is possible that the MPs damage the barrier integrity of the colonic mucus layer, thus reducing its protective effect. MPs in CRC pathogenesis warrants further investigation. Future directions: Further clarification needs to be sought regarding the interaction between MPs, gut microbiota and the mucus layer. This will need to be modelled in long-term animal studies to better understand how chronic consumption of environmentally-acquired MPs may contribute to an increased risk of colorectal carcinogenesis.

Circular RNA hsa_circ_0064559 affects tumor cell growth and progression of colorectal cancer

BackgroundColorectal cancer (CRC) is the second leading cause of cancer-related deaths globally. It is essential to identify new CRC-associated therapeutic targets and diagnostic biomarkers. Previous studies have demonstrated that a series of circular RNAs (circRNAs) play a crucial role in CRC pathogenesis. This study assessed the potential of hsa_circ_0064559 in tumor cell growth and progression of CRC.MethodsSix pairs of matched CRC and normal colorectal tissue samples were sequenced using the Affymetrix Clariom D array. Using RNA interference, the expression of thirteen circRNAs was knocked down in CRC cells. The proliferation of CRC cell lines (RKO and SW620 cells) was detected using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay. Apoptosis and cell cycle were determined by flow-cytometric analysis. An in vivo study uses nude mice to establish a CRC mouse model. The differentially expressed genes were analyzed using Affymetrix primeview human GeneChip array and verified by polymerase chain reaction.ResultsAffymetrix Clariom D array analysis revealed that thirteen circRNAs were upregulated in CRC. The proliferation of CRC cell lines was decreased, while the proportion of apoptotic and G1 phase cells was higher after hsa_circ_0064559 knockdown. In vivo xenograft nude mice model revealed that the volume and weight of the tumor were reduced by hsa_circ_0064559 knockdown. In Affymetrix primeview human GeneChip array, we found six upregulated genes (STAT1, ATF2, TNFRSF10B, TGFBR2, BAX, and SQSTM1) and two downregulated genes (SLC4A7 and CD274) related to apoptosis and proliferation of colorectal cancer cells after hsa_circ_0064559 knockdown.ConclusionsThe hsa_circ_0064559 knockdown could inhibit the proliferation, promote apoptosis in CRC cell lines in vitro, and inhibit the development of CRC tumors in vivo. The mechanism may be related to activating a wide range of signaling pathways. The hsa_circ_0064559 may be a potential biomarker for early diagnosis or prognosis of CRC and a novel drug target for CRC therapy.

Streptococcus gallolyticus infection: A neglected marker for colorectal cancer?

Background and study aimsColorectal cancer (CRC) is the second most common cancer in Malaysia and mostly detected at advanced stages due to lack of awareness of CRC symptoms and signs. CRC pathogenesis is multifactorial, and there is ambiguous evidence on association of Streptococcus gallolyticus infection with CRC that needs further attention.Thus, a case–control study was conducted to determine whether S. gallolyticus infection is a predictor for CRC occurrence among patients attending Sultan Ahmad Shah Medical Centre@IIUM (SASMEC@IIUM). Patients and methodsA total of 33 stool samples from patients diagnosed with CRC and 80 from patients without CRC attending surgical clinic of SASMEC@IIUM were collected and analyzed with iFOBT test and PCR assay to detect S. gallolyticus. ResultsIn this study, the proportion of S. gallolyticus infection was higher among patients with CRC (48.5%) compared with the control group (20%). Univariate analysis shows that occult blood in stool, S. gallolyticus infection and family history were significantly associated with the development of CRC (P < 0.05). Using the multivariate logistic regression model, positive stool PCR for S. gallolyticus had the lowest relative standard error and almost five times the odds of developing CRC after adjusting other factors (adjusted odds ratio = 4.7, 95% confidence interval = 1.7–12.6, relative standard error = 59.6%). ConclusionThis finding suggests that S. gallolyticus infection was the strongest predictor of CRC’s development in our study and potentially serves as a predictive marker for early detection of disease progression.

Berberine is a suppressor of Hedgehog signaling cascade in colorectal cancer

BackgroundColorectal cancer (CRC) is a malignant affliction that burdens people globally. Overactivated Hedgehog signal is highly implicated in CRC pathogenesis. Phytochemical berberine exerts strong potency on CRC, with molecular mechanism elusive. PurposeWe sought to study berberine's anti-CRC action and explore its underlying mechanism based on Hedgehog signaling cascade. MethodsIn CRC HCT116 cells and SW480 cells treated with berberine, the proliferation, migration, invasion, clonogenesis, apoptosis and cell cycle were measured, with determination of Hedgehog signaling pathway activity. Following establishment of mouse model of HCT116 xenograft tumor, the efficacies of berberine on carcinogenesis, pathological manifestation and malignant phenotypes of CRC were examined, with analysis of Hedgehog signaling axis in HCT116 xenograft tumor tissues. Additionally, toxicological study of berberine was conducted on zebrafish. ResultsBerberine was discovered to suppress the proliferation, migration, invasion and clonogenesis of HCT116 cells and SW480 cells. Furthermore, berberine caused cell apoptosis and blockaded cell cycle at phase G0/G1 in CRC cells, with dampened Hedgehog signaling cascade. In HCT116 xenograft tumor of nude mice, berberine inhibited tumor growth, alleviated pathological score, and promoted apoptosis and cell cycle arrest in tumor tissues, through constraining Hedgehog signaling. The toxicological study of berberine on zebrafish indicated that berberine incurred damage to the liver and heart of zebrafish at high dosage and prolonged administration. ConclusionsTaken together, berberine may inhibit the malignant phenotypes of CRC through diminishing Hedgehog signaling cascade. However, the potential adverse reactions should be taken into account upon abuse of berberine.