Development Of Colorectal Cancer Research Articles

Plasma ghrelin and risks of sex-specific, site-specific, and early-onset colorectal cancer: A Mendelian randomization analysis.

Epidemiological and laboratory-based studies have provided conflicting evidence for a role of ghrelin in colorectal cancer (CRC) development. We conducted two-sample Mendelian randomization (MR) analyses to evaluate evidence for an association of circulating ghrelin and CRC risk overall and by sex, cancer subsite and age at diagnosis. Genetic instruments proxying plasma total ghrelin levels were obtained from a recent genome-wide association study of 54,219 participants. Summary data for CRC risk were obtained from a recent meta-analysis of several genetic consortia (up to 73,673 cases and 86,854 controls). A two-sample MR approach and several sensitivity analyses were applied. We found no evidence for an association of genetically-predicted plasma total ghrelin levels and CRC risk (0.95, 95% confidence interval: 0.81-1.12; R2 of ghrelin genetic instruments: 4.6%), with similarly null results observed when stratified by sex, anatomical subsite, and for early-onset CRC. Our study suggests that plasma ghrelin levels are unlikely to have a causal relationship with overall, early-onset, and sex- and cancer subsite-stratified CRC risk. This large-scale analysis adds to the growing body of evidence that plasma total ghrelin levels are not associated with CRC risk.

Targeting CREB-binding protein (CBP) abrogates colorectal cancer stemness through epigenetic regulation of C-MYC.

Colorectal cancer (CRC) is a common cancer worldwide with an increasing annual incidence. Cancer stem cells (CSCs) play important roles in the occurrence, development, recurrence, and metastasis of CRC. The molecular mechanism regulating the development of colorectal CSCs remains unclear. The discovery of human induced pluripotent stem cells (hiPSCs) through somatic cell reprogramming has revolutionized the fields of stem cell biology and translational medicine. In the present study, we converted hiPSCs into cancer stem-like cells by culture with conditioned medium (CM) from CRC cells. These transformed cells, termed hiPSC-CSCs, displayed cancer stem-like properties, including a spheroid morphology and the expression of both pluripotency and CSC markers. HiPSC-CSCs showed tumorigenic and metastatic abilities in mouse models. The epithelial-mesenchymal transition phenotype was observed in hiPSC-CSCs, which promoted their migration and angiogenesis. Interestingly, upregulation of C-MYC was observed during the differentiation of hiPSC-CSCs. Mechanistically, CREB binding protein (CBP) bound to the C-MYC promoter, while histone deacetylase 1 and 3 (HDAC1/3) dissociated from the promoter, ultimately leading to an increase in histone acetylation and C-MYC transcriptional activation during the differentiation of hiPSC-CSCs. Pharmacological treatment with a CBP inhibitor or abrogation of CBP expression with a CRISPR/Cas9-based strategy reduced the stemness of hiPSC-CSCs. This study demonstrates for the first time that colorectal CSCs can be generated from hiPSCs. The upregulation of C-MYC via histone acetylation plays a crucial role during the conversion process. Inhibition of CBP is a potential strategy for attenuating the stemness of colorectal CSCs.

Loss of EMI1 compromises chromosome stability and is associated with cellular transformation in colonic epithelial cell contexts.

Colorectal cancer (CRC) is still a leading cause of cancer deaths worldwide. Thus, identifying the aberrant genes and proteins underlying disease pathogenesis is critical to improve early detection methods and develop novel therapeutic strategies. Chromosome instability (CIN), or ongoing changes in chromosome complements, is a predominant form of genome instability. It is a driver of genetic heterogeneity found in ~85% of CRCs. Although CIN contributes to CRC pathogenesis, the molecular determinants underlying CIN remain poorly understood. Recently, EMI1, an F-box protein, was identified as a candidate CIN gene. In this study, we sought to determine the impact reduced EMI1 expression has on CIN and cellular transformation. Coupling siRNA-based silencing and CRISPR/Cas9 knockout clones with quantitative imaging microscopy we evaluated the impact reduced EMI1 expression has on CIN and cellular transformation in four colonic epithelial cell contexts. Quantitative imaging microscopy data revealed that reduced EMI1 expression induces increases in CIN phenotypes in both transient (siRNA) and constitutive (CRISPR/Cas9) cell models that are associated with increases in DNA damage and cellular transformation phenotypes in long-term studies. This study determined that reduced EMI1 expression induces CIN and promotes cellular transformation, which is consistent with a role in early CRC development.

Histone MARylation regulates lipid metabolism in colorectal cancer by promoting IGFBP1 methylation

In the global health community, colorectal cancer (CRC) is a major concern, with a high rate of incidence. Mono-ADP-ribosylation (MARylation) is a type of epigenetics and recognized as one of the causes of CRC development and progression. Although the modification level and target proteins in CRC remain unclear, it has been found that MARylation of arginine-117 of histone 3 (H3R117) promotes the proliferation, upregulates methylation of tumor suppressor gene, and is tightly associated with the metabolic processes in LoVo cells. Lipid metabolism disorder is involved in the development of CRC at the early stage. Our study revealed that MARylation of H3R117 of the LoVo cells modulated lipid metabolism, increased cholesterol synthesis, promoted lipid raft (LR) protein IGF-1R distribution, and inhibited cell apoptosis through IGFBP1. In addition, bioinformatics analyses revealed that IGFBP1 promoter was hypermethylated in CRC when compared to that in normal tissues. Moreover, H3R117 MARylation upregulated the methylation of IGFBP1 promoter through histone H3 citrullination (H3cit) by increasing the H3K9me2, heterochromatin protein1 (HP1), and DNA methyltransferase 1 (DNMT1) enrichment of IGFBP1 promoter. Accordingly, IGFBP1 may function as a tumor suppressor gene, while H3R117 MARylation may promote CRC development. Our study findings enrich the available data on epigenetics of CRC and provide a new idea and experimental basis for H3R117 MARylation as a target in CRC treatment.

Application of Mendelian randomization analysis in investigating the genetic background of blood biomarkers for colorectal cancer.

Colorectal cancer (CRC), a malignancy affecting the colon and rectum, ranks as the third most common cancer worldwide and the second leading cause of cancer-related deaths. Early detection of CRC is crucial for preventing metastasis, reducing mortality, improving prognosis, and enhancing patients' quality of life. Genetic factors play a significant role in CRC development, accounting for up to 35% of the disease risk. Genome-wide association studies have identified several genetic loci associated with CRC risk. However, these studies often lack direct evidence of causality. While traditional blood biomarkers such as carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) are widely used for CRC diagnosis and monitoring, their sensitivity and accuracy in early diagnosis are limited. Thus, there is a pressing need to develop new biomarkers that reflect the genetic background of CRC to improve early detection and diagnostic accuracy. In addition, understanding the genetic mechanisms underlying these biomarkers is essential for elucidating CRC pathogenesis and developing precise personalized treatment strategies. Mendelian randomization (MR) analysis, as an emerging epidemiological tool, can accurately assess the causal relationship between genetic variations and diseases by reducing confounding biases in observational studies. MR analysis has been applied in evaluating the causal impact of various blood biomarkers on CRC risk, shedding lights on the potential causal relationships between these biomarkers and CRC pathogenesis in the context of genetic background. In this review, we summarize the applications of MR analysis in studies of blood biomarkers for CRC, aiming to enhance the early diagnosis and personalized treatment of CRC.

S354 Impact of Liver Transplantation on Colorectal Cancer Development in PSC-IBD Patients

S354 Impact of Liver Transplantation on Colorectal Cancer Development in PSC-IBD Patients

MiR-4486 inhibits colorectal cancer proliferation via targeting MAP2K4 to inhibit the activation of the p38MAPK/JNK signaling

ObjectiveSince MAP2K4 was reportedly involved in colorectal cancer development and the p38MAPK/JNK signaling transcription, this study aimed to investigate the mechanism by which the microRNA (miR)-4486 acts on colorectal cell proliferation. MethodsRT-PCR was conducted to measure the expression levels of the MAP2K4 and miR-4486 in NCM460, SW1116, and HCT116 cells. TargetScanHuman site anticipated that MAP2K4 may be a target of miR-4486. The dual-luciferase reporter assay confirmed their relationship. After plasmids of miR-4486 mimic and si-MAP2K4 transfection, MAP2K4 was quantified again, The CCK-8 assay was carried out to assess cell proliferation, while Scratch and Transwell assays were used to evaluate cell migration and invasion. Finally, miR-4486 mimic and SB203580 were applied in HCT116 and SW1116 cells separately or in combination. CCK-8, Scratch and Transwell assay were performed again. In addition, the proteins including c-capase3, Bax, Bcl2, MAP2K4, and the p38MAPK/JNK signaling-related proteins expression levels were quantified by Western blot (WB). ResultsCompared with the NCM460 cells, the expression level of MAP2K4 was elevated, while the expression level of miR-4486 was reduced in SW1116 and HCT116 cells. The results showed that elevated levels of miR-4486 suppressed cell proliferation, migration, and invasion in colorectal cells by downregulating MAP2K4 expression. miR-4486 mimic showed similar effects to SB203580, which promoted colorectal cell apoptosis and inhibited the p38 MAPK/JNK signaling transcription. ConclusionmiR-4486 may target MAP2K4 to inhibit colorectal cell proliferation by inhibiting the activation of the p38/JNK signaling pathway.

Long non‑coding RNAs as diagnostic and prognostic biomarkers for colorectal cancer (Review).

Colorectal cancer (CRC) ranks as the 3rd most common cancer globally and is the 2nd leading cause of cancer-related death. Owing to the lack of specific early symptoms and the limitations of existing early diagnostic methods, most patients with CRC are diagnosed at advanced stages. To overcome these challenges, researchers have increasingly focused on molecular biomarkers, with particular interest in long non-coding RNAs (lncRNAs). These non-protein-coding RNAs, which exceed 200 nucleotides in length, play critical roles in the development and progression of CRC. The stability and detectability of lncRNAs in the circulatory system make them promising candidate biomarkers. The analysis of circulating lncRNAs in peripheral blood represents a potential option for minimally invasive diagnostic tests based on liquid biopsy samples. The present review aimed to evaluate the efficacy of lncRNAs with altered expression levels in peripheral blood as diagnostic markers for CRC. Additionally, the clinical significance of lncRNAs as prognostic markers for this disease were summarized.

Gardner syndrome in a Tunisian family: Identification of a rare APC mutation through targeted NGS

Gardner syndrome (GS) is a subtype of familial adenomatous polyposis (FAP) characterized by colorectal polyps, multiple osteomas, soft tissue tumors, and specific oral manifestations, such as jaw osteomas. GS is caused by mutations in the APC gene, resulting in a nonfunctional protein. This study reports a comprehensive clinical evaluation and genetic analysis of a Tunisian family affected by GS. Targeted exome sequencing and Sanger sequencing techniques were employed to identify and validate mutations in the APC gene. Clinical observations of the patient revealed multiple sebaceous cysts, frontal and maxillary osteomas, and several gastrointestinal polyps. Genetic analysis revealed a pathogenic variant (c.4652-4655del) in the APC gene, leading to a truncated protein. Additionally, genetic testing of the patient’s child indicated that the child does not carry the APC pathogenic variant.In conclusion, our study highlights the importance of genetic testing in raising awareness of GS among clinicians to ensure early diagnosis and effective management, thereby reducing the risk of development and progression of colorectal cancer.

Circ_0060927 promotes colorectal cancer development by sponging miR-331-3p and upregulating TBX2

BackgroundThe dysregulation of circular RNAs (circRNAs) is closely associated with the pathogenesis of colorectal cancer (CRC). The present study aimed to elucidate the biological function and mechanism of circ_0060927 in CRC. Methods5-ethynyl-2’-deoxyuridine, Cell Counting Kit-8 (CCK-8), flow cytometry and transwell assays, as well as Xenograft tumor models were adopted for in vitro and in vivo analyses. The interaction between microRNA-331-3p (miR-331-3p) and circ_0060927 or T-box transcription factor 2 (TBX2) was verified by the dual-luciferase reporter and RNA pull-down assays. ResultsCirc_0060927 deficiency inhibited cell proliferation, autophagy, migration, and invasion and increased cell apoptosis and necrosis in CRC cells, as well as inhibited tumor growth in vivo. Circ_0060927 could bind to miR-331-3p, and circ_0060927 regulated CRC cell behaviors via sponging miR-331-3p. TBX2 was targeted by miR-331-3p, and miR-331-3p targeted TBX2 to exert the anti-cancer role in CRC cells. Mechanically, circ_0060927 regulated TBX2 expression by sequestering miR-331-3p in CRC cells. ConclusionCirc_0060927 downregulation inhibited CRC progression by regulating the miR-331-3p/TBX2 axis, which might offer a potential treatment target for CRC.

Risk of Colorectal Cancer among Patients with One or Multiple Metabolic Syndrome Components

Background/Objectives: Dysfunctions of metabolic syndrome (MetS) have been identified as a significant risk factor for colorectal cancer (CRC). However, current colon cancer guidelines do not classify patients with MetS as high risk, thereby leaving these individuals vulnerable. Consequently, we explored the relationship between MetS, its individual components, and the development of CRC in a cohort of patients with MetS to assess the necessity for CRC screening in these individuals. Methods: This study included patients ages 18 and older that received a service from the Marshall-Health (MH) practice plan, Cabell-Huntington Hospital (CHH), MU/JCESOM’s Edwards Comprehensive Cancer Center (ECCC), or the University of Kentucky HealthCare (UKHC) system between 2010 and 2018. We implemented log-binomial regression models to assess the individual and collective effects of MetS components after adjusting other CRC risk factors. Results: Given that CRC prevalence increases in the older population (aged 65 years and above), and that multiple components of MetS are observed within the same population, we analyzed the concurrent impact of all MetS components on CRC. Log-binomial regression models were implemented to assess the risk of CRC due to MetS components after adjusting other risk factors. Conclusions: We identified specific components that markedly increased CRC risk, suggesting that individuals with these components should be prioritized for early screening. These findings could significantly influence early CRC screening protocols, with the ultimate aim to reduce mortality associated with the disease.

Colorectal cancer cell-derived exosomal miRNA-372-5p induces immune escape from colorectal cancer via PTEN/AKT/NF-κB/PD-L1 pathway

Tumor cells can escape immune surveillance by changing their own escape or expressing abnormal genes and proteins, resulting in unlimited proliferation and invasive growth of cells. These changes are related to microRNAs (miRNAs), which reduce the killing effect of immune cells, devastate the immune response, and interfere with apoptosis through the aberrant expression of relevant miRNAs. In the preliminary phase of this study, miRNAs in clinical plasma exosomes of colorectal cancer patients were differentially analyzed by RNA sequencing technology, and miR-372-5p derived from extracellular vesicles (sEVs) was found to be a key signaling molecule mediating the regulation of macrophages by colorectal cancer (CRC). miRNA-372-5p is upregulated in colorectal cancer patient tissues and serum, as well as colorectal cancer cell lines and their exosomes. Subsequently, we found that macrophages could take up sEV secreted by colorectal cancer cells HCT116, affecting the expression of the immune checkpoint PD-L1, resulting in the generation of a tumor-immunosuppressive microenvironment and suppression of T cell activation in CRC. Gene enrichment mapping and database revealed that miR-372-5p regulates PD-L1 expression in colorectal cancer through the homologous phosphatase-tensin (PTEN)-phosphatidylinositol 3-kinase-protein kinase B (AKT)-nuclear factor-κB (NF-κB) pathway. Further studies confirmed that miRNA-372-5p-treated macrophages co-cultured with T cells affected the regulation of PD-L1 expression through the PTEN/AKT/NF-κB signaling pathway, resulting in decreased CD3+CD8+ T cell activity, decreased cytokine IL-2 and increased IFN-γ. And miRNA-372-5p could down-regulate the expression of PD-L1 in HCT116 through the PTEN/AKT/NF-κB pathway, inhibit tumor cell proliferation and promote apoptosis. Conclusion: Colorectal cancer cell-derived exosome miR-372-5p can be phagocytosed by colorectal cancer and macrophage cells, regulate the expression of PD-L1 in colorectal cancer cells and macrophages by targeting the PTEN/AKT/NF-κB pathway, and induce the immunosuppressive microenvironment of CRC to promote CRC development. This suggests that inhibiting the secretion of HCT116-specific sEV-miR-372-5p or targeting PD-L1 in tumor-associated macrophages could be a novel approach for CRC treatment and possibly a sensitizing approach for CRC anti-PD-L1 therapy.

Phytochemicals and colorectal cancer: About polyphenols

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

USP36 promotes colorectal cancer progression through inhibition of p53 signaling pathway via stabilizing RBM28.

Colorectal cancer (CRC) stands as the second most common cause of cancer-related mortality globally and p53, a widely recognized tumor suppressor, contributes to the development of CRC. Ubiquitin-specific protease 36 (USP36), belonging to the deubiquitinating enzyme family, is involved in tumor progression across multiple cancers. However, the underlying molecular mechanism in which USP36 regulates p53 signaling pathway in CRC is unclear. Here, our study revealed that USP36 was increased in CRC tissues and associated with unfavorable prognosis. Functionally, elevated USP36 could promote proliferation, migration, and invasion of CRC cells in vitro and in vivo. Mechanistically, USP36 could interact with and stabilize RBM28 via deubiquitination at K162 residue. Further, upregulated RBM28 could bind with p53 to suppress its transcriptional activity and therefore inactivate p53 signaling pathway. Collectively, our investigation identified the novel USP36/RBM28/p53 axis and its involvement in promoting cell proliferation and metastasis in CRC, which presents a promising therapeutic strategy for CRC treatment.

Functional links between the microbiome and the molecular pathways of colorectal carcinogenesis.

Colorectal cancer (CRC) is a common cancer, with a concerning rise in early-onset CRC cases, signalling a shift in disease epidemiology. Whilst our understanding of the molecular underpinnings of CRC has expanded, the complexities underlying its initiation remain elusive, with emerging evidence implicating the microbiome in CRC pathogenesis. This review synthesizes current knowledge on the intricate interplay between the microbiome, tumour microenvironment (TME), and molecular pathways driving CRC carcinogenesis. Recent studies have reported how the microbiome may modulate the TME and tumour immune responses, consequently influencing cancer progression, and whilst specific bacteria have been linked with CRC, the underlying mechanisms remains poorly understood. By elucidating the functional links between microbial landscapes and carcinogenesis pathways, this review offers insights into how bacteria orchestrate diverse pathways of CRC development, shedding light on potential therapeutic targets and personalized intervention strategies.

Gut commensal Alistipes as a potential pathogenic factor in colorectal cancer

Although previous research has shown that inflammation is associated with development of colorectal cancer (CRC), questions remain about whether inflammatory factor-secreting bacteria play a crucial role in CRC development. The potential role of gut microbiota in secreting inflammatory factors involved in the carcinogenesis of CRC among Chinese patients was explored in this study. 16S rRNA sequencing was utilized to evaluate the distinct microbial characteristics between patients with CRC and colorectal adenoma. The serum levels of TNF-α, IL-6 and IL-10 were measured using Enzyme-linked immunosorbent assay (ELISA), while the expression of LRG1 and TGF-β1 in tissues was evaluated by immunohistochemistry. The correlation between gut microbiota and inflammatory factor signaling was analyzed. Compared with the adenoma group, CRC patients exhibit distinct pathologies. Moreover, elevated levels of CEA, erythrocytes and haemoglobin in the blood of CRC patients were found. In addition, CRC patients have significantly higher levels of TNF-α, IL-6, IL-10, LRG1 and TGF-β1. Spearman correlation analysis revealed that LRG1 was positively related to IL-6 and TNF-α, respectively. The correlation analysis results of TGF-β1 were consistent with the above. The abundance of Blautia and Streptococcus was lower in CRC patients, while the relative abundance of Alistipes, Peptostreptococcus and Porphyromonas was significantly elevated. Moreover, positive correlations between Alistipes and inflammatory factor signaling were also found. Our results suggest that gut commensal Alistipes is a key bacterium with pro-inflammatory properties in the CRC carcinogenesis. TNF-α and IL-6 associated with Alistipes might activate LRG1/TGF-β1 signaling which contributed to the carcinogenesis of CRC.

Effect of smoking on the risk of gastrointestinal cancer after cholecystectomy: A national population-based cohort study.

The role of smoking in the incidence of colorectal cancer (CRC) or gastric cancer (GC) in populations undergoing cholecystectomy has not been investigated. To evaluate the effect of smoking on CRC or GC development in cholecystectomy patients. A total of 174874 patients who underwent cholecystectomy between January 1, 2010 and December 31, 2017 were identified using the Korean National Health Insurance Service claims database. These patients were matched 1:1 with members of a healthy population according to age and sex. CRC or GC risk after cholecystectomy and the association between smoking and CRC or GC risk in cholecystectomy patients were evaluated using adjusted hazard ratios (HRs) and 95%CIs. The risks of CRC (adjusted HR: 1.15; 95%CI: 1.06-1.25; P = 0.0013) and GC (adjusted HR: 1.11; 95%CI: 1.01-1.22; P = 0.0027) were significantly higher in cholecystectomy patients. In the population who underwent cholecystectomy, both CRC and GC risk were higher in those who had smoked compared to those who had never smoked. For both cancers, the risk tended to increase in the order of non-smokers, ex-smokers, and current smokers. In addition, a positive correlation was observed between the amount of smoking and the risks of both CRC and GC. Careful follow-up and screening should be performed, focusing on the increased risk of gastrointestinal cancer in the cholecystectomy group, particularly considering the individual smoking habits.

Glioblastoma Arising in Lynch-like Syndrome after Repeated Development of Colorectal Cancers: A Case Report.

We herein report a patient with Lynch-like syndrome in whom a brain tumor (glioblastoma) developed after repeated resection of colorectal cancer. The patient had a significant family history of cancer. Immunohistochemical expression of mismatch repair proteins was decreased in both brain and colon tumors, but no pathogenic variant of the related genes was detected. Although brain tumors occasionally develop in Lynch syndrome, they have not been reported in cases of Lynch-like syndrome. This first report of Lynch-like syndrome with the development of glioblastoma suggests the need for further investigation on the surveillance of brain tumors in patients with this syndrome.

Identifying targetable metabolic dependencies across colorectal cancer progression

Colorectal cancer (CRC) is a multi-stage process initiated through the formation of a benign adenoma, progressing to an invasive carcinoma and finally metastatic spread. Tumour cells must adapt their metabolism to support the energetic and biosynthetic demands associated with disease progression. As such, targeting cancer cell metabolism is a promising therapeutic avenue in CRC. However, to identify tractable nodes of metabolic vulnerability specific to CRC stage, we must understand how metabolism changes during CRC development. Here, we use a unique model system – comprising human early adenoma to late adenocarcinoma. We show that adenoma cells transition to elevated glycolysis at the early stages of tumour progression but maintain oxidative metabolism. Progressed adenocarcinoma cells rely more on glutamine-derived carbon to fuel the TCA cycle, whereas glycolysis and TCA cycle activity remain tightly coupled in early adenoma cells. Adenocarcinoma cells are more flexible with respect to fuel source, enabling them to proliferate in nutrient-poor environments. Despite this plasticity, we identify asparagine (ASN) synthesis as a node of metabolic vulnerability in late-stage adenocarcinoma cells. We show that loss of asparagine synthetase (ASNS) blocks their proliferation, whereas early adenoma cells are largely resistant to ASN deprivation. Mechanistically, we show that late-stage adenocarcinoma cells are dependent on ASNS to support mTORC1 signalling and maximal glycolytic and oxidative capacity. Resistance to ASNS loss in early adenoma cells is likely due to a feedback loop, absent in late-stage cells, allowing them to sense and regulate ASN levels and supplement ASN by autophagy. Together, our study defines metabolic changes during CRC development and highlights ASN synthesis as a targetable metabolic vulnerability in later stage disease.

Identification and Validation of Biomarkers to Predict Early Diagnosis of Inflammatory Bowel Disease and Its Progression to Colorectal Cancer.

Inflammatory bowel disease (IBD) has become a common global health problem as prevalence continues to rise. It is often associated with increased risk of colorectal cancer (CRC) development. Limitations in current IBD biomarker-based diagnosis hinder the accuracy of early detection of CRC progression. Therefore, in this study, we proposed the use of transcription factor (TF)-based biomarkers that can potentially detect the transition of IBD to CRC. Various bioinformatic analysis and online database validations, and RT-qPCR validations were performed to identify possible diagnostic TFs. RUNX1 was identified as a promising TF that regulates 106 IBD/CRC-related genes. The incorporation of RUNX1 in combination with currently known IBD biomarkers, FEV + NFKB1 + RELA, achieved a comparable sensitivity and specificity scores of 99% and 87%, respectively, while RUNX1 in combination with known CRC markers, CEA + TIMP1 + CA724 + CA199, achieved a sensitivity and specificity score of 97% and 99%, respectively. Furthermore, a small pilot RT-qPCR-based analysis confirmed a demarcated shift in expression profiles in CA724, CEA, RUNX1 and TIMP1 in IBD patients compared to CRC patients' tissue samples. Specifically, CA724 is noticeably elevated in IBD, while the levels of CEA, RUNX1 with TIMP1 are probable genes that may be employed in discerning IBD progression to CRC. Therefore, these preliminary results once validated in large patient cohorts could potentially have a significant impact on CRC disease stratification, resulting in a more precise prediction for treatment and treatment outcomes, especially in South African patients.