Role In Pathogenesis Of Colorectal Cancer Research Articles

Advancements and Challenges in Biomarkers for Colorectal Cancer Detection: A Comprehensive Review

This study provides an overview of the current landscape of biomarkers for colorectal cancer (CRC) detection, focusing on genetic, proteomic, circulating microRNA (miRNA), and metabolomic biomarkers. CRC remains a significant global health challenge, ranking among the most prevalent cancers worldwide and being a leading cause of cancer-related deaths. Despite advancements in screening methods such as colonoscopy, sigmoidoscopy, and fecal occult blood tests (FOBT), the asymptomatic nature of early-stage CRC often results in late diagnoses, negatively impacting patient outcomes. Genetic biomarkers like APC, KRAS, TP53, and microsatellite instability (MSI) play critical roles in CRC pathogenesis and progression. These biomarkers, detectable through polymerase chain reaction, next-generation sequencing, and other advanced techniques, guide early detection and personalized treatment decisions. Proteomic biomarkers such as CEA, CA 19-9, and novel signatures offer insights into CRC’s physiological changes and disease status, aiding prognosis and treatment response assessments through enzyme-linked immunosorbent assay and mass spectrometry. Circulating miRNAs, including miR-21 and miR-92a, present promising non-invasive biomarkers that can be detected in blood and stool samples, reflecting CRC presence, progression, and therapeutic response. Metabolomic biomarkers, encompassing amino acids, lipids, and TCA cycle intermediates, provide further insights into CRC-associated metabolic alterations, which are crucial for early detection and treatment monitoring using mass spectrometry and nuclear magnetic resonance. Despite these advancements, challenges such as biomarker validation, standardization, and clinical utility remain. Future research directions include integrating multi-omics approaches and leveraging technologies like liquid biopsies and AI for enhanced biomarker discovery and clinical application. By addressing these challenges and advancing research in biomarker development, CRC screening and management could potentially be revolutionized, improving patient outcomes and reducing the global burden of this disease.

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

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

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

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

TGF-β Modulated Pathways in Colorectal Cancer: New Potential Therapeutic Opportunities.

Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide, with 20% of patients presenting with metastatic disease at diagnosis. TGF-β signaling plays a crucial role in various cellular processes, including growth, differentiation, apoptosis, epithelial-mesenchymal transition (EMT), regulation of the extracellular matrix, angiogenesis, and immune responses. TGF-β signals through SMAD proteins, which are intracellular molecules that transmit TGF-β signals from the cell membrane to the nucleus. Alterations in the TGF-β pathway and mutations in SMAD proteins are common in metastatic CRC (mCRC), making them critical factors in CRC tumorigenesis. This review first analyzes normal TGF-β signaling and then investigates its role in CRC pathogenesis, highlighting the mechanisms through which TGF-β influences metastasis development. TGF-β promotes neoangiogenesis via VEGF overexpression, pericyte differentiation, and other mechanisms. Additionally, TGF-β affects various elements of the tumor microenvironment, including T cells, fibroblasts, and macrophages, promoting immunosuppression and metastasis. Given its strategic role in multiple processes, we explored different strategies to target TGF-β in mCRC patients, aiming to identify new therapeutic options.

Associations Between Fusobacterium nucleatum and msh2, mlh1, and msh6 Gene Expression in Colorectal Cancer

Background: Colorectal cancer (CRC) is a major global health concern, and the link with Fusobacterium nucleatum has received considerable attention. Objectives: This study aimed to explore the prevalence of F. nucleatum and to assess the expression of the msh2, mlh1, and msh6 genes in CRC patients compared to a control group using real-time PCR. Methods: Forty CRC patients and twenty individuals from a control group participated in this study. Gastroenterologists collected biopsy specimens from which DNA and RNA were extracted using a specialized tissue extraction kit. Complementary DNA (cDNA) was then synthesized. Real-time PCR was employed to evaluate the expression levels of the msh2, mlh1, and msh6 genes and the presence of the F. nucleatum-specific 16srRNA gene to determine the relative prevalence of this bacterium in each group. Results: Results indicated a higher prevalence of the F. nucleatum-specific 16srRNA gene in CRC patients than in the control group. Additionally, expression levels of the msh2, mlh1, and msh6 genes were significantly higher in the cancer group, suggesting their role in CRC pathogenesis. The distribution of F. nucleatum was particularly high in the sigmoid and rectum areas of the colon. Conclusions: This study underscores the significance of F. nucleatum in CRC and provides insights into its association with altered gene expression patterns. Understanding the prevalence of F. nucleatum and its impact on msh2, mlh1, and msh6 genes may aid in developing improved diagnostic and therapeutic strategies for CRC. Further research is necessary to elucidate these relationships more comprehensively.

Holistic exploration of CHGA and hsa-miR-137 in colorectal cancer via multi-omic data Integration

Colorectal cancer (CRC) ranks among the most widespread malignancies globally, with early detection significantly influencing prognosis. Employing a systems biology approach, we aimed to unravel the intricate mRNA-miRNA network linked to CRC pathogenesis, potentially yielding diagnostic biomarkers. Through an integrative analysis of microarray, Bulk RNA-seq, and single-cell RNA-seq data, we explored CRC-related transcriptomes comprehensively. Differential gene expression analysis uncovered crucial genes, while Weighted Gene Co-expression Network Analysis (WGCNA) identified key modules closely linked to CRC. Remarkably, CRC manifested its strongest correlation with the turquoise module, signifying its pivotal role. From the cohort of genes showing high Gene Significance (GS) and Module Membership (MM), and Differential Expression Genes (DEGs), we highlighted the downregulated Chromogranin A (CHGA) as a notable hub gene in CRC. This finding was corroborated by the Human Protein Atlas database, which illustrated decreased CHGA expression in CRC tissues. Additionally, CHGA displayed elevated expression in primary versus metastatic cell lines, as evidenced by the CCLE database. Subsequent RT-qPCR validation substantiated the marked downregulation of CHGA in CRC tissues, reinforcing the significance of our differential expression analysis. Analyzing the Space-Time Gut Cell Atlas dataset underscored specific CHGA expression in epithelial cell subclusters, a trend persisting across developmental stages. Furthermore, our scrutiny of colon and small intestine Enteroendocrine cells uncovered distinct CHGA expression patterns, accentuating its role in CRC pathogenesis. Utilizing the WGCNA algorithm and TargetScan database, we validated the downregulation of hsa-miR-137 in CRC, and integrated assessment highlighted its interplay with CHGA. Our findings advocate hsa-miR-137 and CHGA as promising CRC biomarkers, offering valuable insights into diagnosis and prognosis. Despite proteomic analysis yielding no direct correlation, our multifaceted approach contributes comprehensive understanding of CRC's intricate regulatory mechanisms. In conclusion, this study advances hsa-miR-137 and CHGA as promising CRC biomarkers through an integrated analysis of diverse datasets and network interactions.

5'-Isoforms of miR-1246 Have Distinct Targets and Stronger Functional Impact Compared with Canonical miR-1246 in Colorectal Cancer Cells In Vitro.

Colorectal cancer (CRC) is a multifactorial disease involving genetic and epigenetic factors, such as miRNAs. Sequencing-based studies have revealed that miRNAs have many isoforms (isomiRs) with modifications at the 3'- and 5'-ends or in the middle, resulting in distinct targetomes and, consequently, functions. In the present study, we aimed to evaluate the putative targets and functional role of miR-1246 and its two 5'-isoforms (ISO-miR-1246_a and ISO-miR-1246_G) in vitro. Commercial Caco-2 cells of CRC origin were analyzed for the expression of WT-miR-1246 and its 5'-isoforms using small RNA sequencing data, and the overabundance of the two miR-1246 isoforms was determined in cells. The transcriptome analysis of Caco-2 cells transfected with WT-miR-1246, ISO-miR-1246_G, and ISO-miR-1246_a indicated the minor overlap of the targetomes between the studied miRNA isoforms. Consequently, an enrichment analysis showed the involvement of the potential targets of the miR-1246 isoforms in distinct signaling pathways. Cancer-related pathways were predominantly more enriched in dysregulated genes in ISO-miR-1246_G and ISO-miR-1246_a, whereas cell cycle pathways were more enriched in WT-miR-1246. The functional analysis of WT-miR-1246 and its two 5'-isoforms revealed that the inhibition of any of these molecules had a tumor-suppressive role (reduced cell viability and migration and promotion of early cell apoptosis) in CRC cells. However, the 5'-isoforms had a stronger effect on viability compared with WT-miR-1246. To conclude, this research shows that WT-miR-1246 and its two 5'-isoforms have different targetomes and are involved in distinct signaling pathways but collectively play an important role in CRC pathogenesis.

Cholesterol in colorectal cancer: an essential but tumorigenic precursor?

Colorectal cancer (CRC) is one of the most lethal human malignancies, and with the growth of societies and lifestyle changes, the rate of people suffering from it increases yearly. Important factors such as genetics, family history, nutrition, lifestyle, smoking, and alcohol can play a significant role in increasing susceptibility to this cancer. On the other hand, the metabolism of several macromolecules is also involved in the fate of tumors and immune cells. The evidence discloses that cholesterol and its metabolism can play a role in the pathogenesis of several cancers because there appears to be an association between cholesterol levels and CRC, and cholesterol-lowering drugs may reduce the risk. Furthermore, changes or mutations of some involved genes in cholesterol metabolism, such as CYP7A1 as well as signaling pathways, such as mitogen-activated protein kinase (MAPK), can play a role in CRC pathogenesis. This review summarized and discussed the role of cholesterol in the pathogenesis of CRC as well as available cholesterol-related therapeutic approaches in CRC.

Transcriptomic Changes Associated with ERBB2 Overexpression in Colorectal Cancer Implicate a Potential Role of the Wnt Signaling Pathway in Tumorigenesis

Colorectal cancer (CRC) remains the third most common cause of cancer mortality worldwide. Precision medicine using OMICs guided by transcriptomic profiling has improved disease diagnosis and prognosis by identifying many CRC targets. One such target that has been actively pursued is an erbb2 receptor tyrosine kinase 2 (ERBB2) (Human Epidermal Growth Factor Receptor 2 (HER2)), which is overexpressed in around 3-5% of patients with CRC worldwide. Despite targeted therapies against HER2 showing significant improvement in disease outcomes in multiple clinical trials, to date, no HER2-based treatment has been clinically approved for CRC. In this study we performed whole transcriptome ribonucleic acid (RNA) sequencing on 11 HER2+ and 3 HER2- CRC patients with advanced stages II, III and IV of the disease. In addition, transcriptomic profiling was carried out on CRC cell lines (HCT116 and HT29) and normal colon cell lines (CCD841 and CCD33), ectopically overexpressing ERBB2. Our analysis revealed transcriptomic changes involving many genes in both CRC cell lines overexpressing ERBB2 and in HER2+ patients, compared to normal colon cell lines and HER2- patients, respectively. Gene Set Enrichment Analysis indicated a role for HER2 in regulating CRC pathogenesis, with Wnt/β-catenin signaling being mediated via a HER2-dependent regulatory pathway impacting expression of the homeobox gene NK2 homeobox 5 (NKX2-5). Results from this study thus identified putative targets that are co-expressed with HER2 in CRC warranting further investigation into their role in CRC pathogenesis.

Predicting lymph node metastasis and recurrence in patients with early stage colorectal cancer.

Tumor budding (TB), a powerful, independent predictor of colorectal cancer (CRC), is important for making appropriate treatment decisions. Currently, TB is assessed only using the tumor bud count (TBC). In this study, we aimed to develop a novel prediction model, which includes different TB features, for lymph node metastasis (LNM) and local recurrence in patients with pT1 CRC. Enrolled patients (n = 354) were stratified into training and validation cohorts. Independent predictors of LNM and recurrence were identified to generate predictive nomograms that were assessed using the area under the receiver operating characteristic (AUROC) and decision curve analysis (DCA). Seven LNM predictors [gross type, histological grade, lymphovascular invasion (LVI), stroma type, TBC, TB mitosis, and TB CDX2 expression] were identified in the training cohort. LNM, histology grade, LVI, TBC, stroma type, and TB mitosis were independent predictors of recurrence. We constructed an LNM predictive nomogram with a high clinical application value using the DCA. Additionally, a nomogram predicting recurrence-free survival (RFS) was constructed. It presented an AUROC value of 0.944 for the training cohort. These models may assist surgeons in making treatment decisions. In the high-risk group, radical surgery with a postoperative adjuvant chemotherapy was associated with RFS. Postoperative chemotherapy can be better for high-risk patients with pT1 CRC. We showed that TB features besides TBC play important roles in CRC pathogenesis, and our study provides prognostic information to guide the clinical management of patients with early stage CRC.

Involvement of the oncogenic small nucleolar RNA SNORA24 in regulation of p53 stability in colorectal cancer.

Colorectal cancer (CRC) is a common malignant cancer worldwide. Although the molecular mechanism of CRC carcinogenesis has been studied extensively, the details remain unclear. Small nucleolar RNAs (snoRNAs) have recently been reported to have essential functions in carcinogenesis, although their roles in CRC pathogenesis are largely unknown. In this study, we found that the H/ACA snoRNA SNORA24 was upregulated in various cancers, including CRC. SNORA24 expression was significantly associated with age and history of colon polyps in CRC patient cohorts, with high expression associated with a decreased 5-year overall survival. Our results indicated that the oncogenic function of SNORA24 is mediated by promoting G1/S phase transformation, cell proliferation, colony formation, and growth of xenograft tumors. Furthermore, SNORA24 knockdown induced massive apoptosis. RNA-sequencing and gene ontology (GO) enrichment analyses were performed to explore its downstream targets. Finally, we confirmed that SNORA24 regulates p53 protein stability in a proteasomal degradation pathway. Our study clarifies the oncogenic role of SNORA24 in CRC and advance the current model of the role of the p53 pathway in this process.

A Bioinformatics Evaluation of the Role of Dual-Specificity Tyrosine-Regulated Kinases in Colorectal Cancer.

Simple SummaryThe dual-specificity tyrosine-regulated kinase (DYRK) family has been implicated in various diseases, including cancer. However, its role in colorectal cancer has not been elucidated. In this research, we used publicly available web-based tools to investigate DYRKs status in colorectal cancer. Our results showed that among DYRKs, only DYRK1A was upregulated significantly in late tumor stages, and it is associated with poor prognosis for colorectal cancer patients. These finding comprehensively characterized DYRK1A as a potential new therapeutic approach in CRC, especially in late tumor stages.Colorectal cancer (CRC) is the third most common cancer worldwide and has an increasing incidence in younger populations. The dual-specificity tyrosine-regulated kinase (DYRK) family has been implicated in various diseases, including cancer. However, the role and contribution of the distinct family members in regulating CRC tumorigenesis has not been addressed yet. Herein, we used publicly available CRC patient datasets (TCGA RNA sequence) and several bioinformatics webtools to perform in silico analysis (GTEx, GENT2, GEPIA2, cBioPortal, GSCALite, TIMER2, and UALCAN). We aimed to investigate the DYRK family member expression pattern, prognostic value, and oncological roles in CRC. This study shed light on the role of distinct DYRK family members in CRC and their potential outcome predictive value. Based on mRNA level, DYRK1A is upregulated in late tumor stages, with lymph node and distant metastasis. All DYRKs were found to be implicated in cancer-associated pathways, indicating their key role in CRC pathogenesis. No significant DYRK mutations were identified, suggesting that DYRK expression variation in normal vs. tumor samples is likely linked to epigenetic regulation. The expression of DYRK1A and DYRK3 expression correlated with immune-infiltrating cells in the tumor microenvironment and was upregulated in MSI subtypes, pointing to their potential role as biomarkers for immunotherapy. This comprehensive bioinformatics analysis will set directions for future biological studies to further exploit the molecular basis of these findings and explore the potential of DYRK1A modulation as a novel targeted therapy for CRC.

The Concentration of CMKLR1 Expression on Clinicopathological Parameters of Colorectal Cancer: A Preliminary Study.

Background and Objectives: Colorectal cancer (CRC) is the second-most common cause of cancer-related deaths worldwide. Angiogenesis is crucial for cancer growth, infiltration of surrounding tissues, and metastasis and plays a key role in the pathogenesis of CRC. Chemerin/chemokine-like receptor 1 (CMKLR1) is one of the biochemical pathways involved in the regulation of angiogenesis in solid tumors. The aim of the study was to assess the CMKLR1 level in tumor and margin tissues of CRC in relation to histopathological parameters: microvessel density (MVD), budding, tumor-infiltrating lymphocytes (TILs), TNM scale, and grading. Materials and Methods: The study involved 43 samples of tumor and margin tissues obtained from CRC patients. To assess the concentration of CMKLR1 a commercially available enzyme-linked immunosorbent assay kit was used. For 35 cases, we performed CD34 immunostaining. The MVD, budding, and TILs were assessed using a light microscope. Results: The levels of CMKLR1 in both tumor and margin were negatively correlated with MVD and budding. CMKLR1 concentration in margin was higher in tissues with lymphocytic infiltration. Conclusions: Low vascularity and low budding are associated with higher CMKLR1 expression. CMKLR1 might play a multifunctional role in CRC pathogenesis by influencing tumor budding and peritumoral lymphocytic infiltration.

Characterization of the consensus mucosal microbiome of colorectal cancer.

Dysbioisis is an imbalance of an organ's microbiome and plays a role in colorectal cancer pathogenesis. Characterizing the bacteria in the microenvironment of a cancer through genome sequencing has advantages compared to culture-based profiling. However, there are notable technical and analytical challenges in characterizing universal features of tumor microbiomes. Colorectal tumors demonstrate microbiome variation among different studies and across individual patients. To address these issues, we conducted a computational study to determine a consensus microbiome for colorectal cancer, analyzing 924 tumors from eight independent RNA-Seq data sets. A standardized meta-transcriptomic analysis pipeline was established with quality control metrics. Microbiome profiles across different cohorts were compared and recurrently altered microbial shifts specific to colorectal cancer were determined. We identified cancer-specific set of 114 microbial species associated with tumors that were found among all investigated studies. Firmicutes, Bacteroidetes, Proteobacteria and Actinobacteria were among the four most abundant phyla for the colorectal cancer microbiome. Member species of Clostridia were depleted and Fusobacterium nucleatum was one of the most enriched bacterial species in tumors. Associations between the consensus species and specific immune cell types were noted. Our results are available as a web data resource for other researchers to explore (https://crc-microbiome.stanford.edu).

Integrin β7 Inhibits Colorectal Cancer Pathogenesis via Maintaining Antitumor Immunity.

Immune cell infiltration is important for predicting the clinical outcomes of colorectal cancer. Integrin β7 (ITGB7), which is expressed on the surface of leukocytes, plays an essential role in the homing of immune cells to gut-associated lymphoid tissue and facilitating the retention of lymphocytes in gut epithelium; however, its role in colorectal cancer pathogenesis is poorly explored. Here, we found that the number of β7+ cells decreased significantly in tumor tissue compared with adjacent normal tissue. β7 expression decreased in tumor-derived compared with normal tissue-derived CD8+ T cells. With bulk RNA expression data from public platforms, we demonstrated that higher ITGB7 expression correlated with longer patient survival, higher cytotoxic immune cell infiltration, lower somatic copy-number alterations, decreased mutation frequency of APC and TP53, and better response to immunotherapy. The possible cell-cell interactions mediated by ITGB7 and its ligands MAdCAM-1, VCAM-1, and CDH1 were investigated using public single-cell RNA sequencing data. ITGB7 deficiency led to exaggerated tumorigenesis and progression in both Apcmin /+ spontaneous and MC38 orthotopic models of colorectal cancer, which could be due to a reduced infiltration of activated CD8+ T cells, effector memory CD8+ T cells, IFNγ+ CD8+ T cells, IFNγ+ natural killer cells, CD103+ dendritic cells, and other immune cell subsets that are essential players in antitumor immunity. In conclusion, our data revealed that ITGB7 could inhibit the tumorigenesis and progression of colorectal cancer by maintaining antitumor immunity.

The Significance of CXCL1 and CXCL8 as Well as Their Specific Receptors in Colorectal Cancer.

Every year, almost 2 million people develop colorectal cancer (CRC), which makes it the fourth most common malignancy worldwide. It is also estimated that approximately 48% of CRC patients will die from the disease. Thus, noninvasive and accurate methods for early detection and prevention of CRC are sorely needed. It is suggested that C-X-C motif ligand 1 (CXCL1) and C-X-C motif ligand 8 (CXCL8) as well as their cognate receptors can mediate tumor growth, proliferation, survival, neoangiogenesis and metastasis of malignant cells, including CRC. However, little is known about the clinical significance of these proteins as potential biomarkers for CRC. Therefore, in our review, we performed a comprehensive literature search using the PubMed database to identify original articles that investigated whether CXCL1 and CXCL8 and their receptors play a role in CRC pathogenesis. In summary, our review highlighted the potential significance of CXCL1/CXCR2 and CXCL8/CXCR1,-2 in the diagnosis and progression of CRC as well as indicated their potential therapeutic significance. However, given the non-specific nature of analyzed chemokines and a small number of studies concerning the assessment of blood concentration of these proteins in CRC patients, investigations need to be continued in the future before selected chemokines could be established as biomarkers for CRC.

Integrative Analysis of Fecal Metagenomics and Metabolomics in Colorectal Cancer.

Although colorectal cancer (CRC) is the second leading cause of death in developed countries, current diagnostic tests for early disease stages are suboptimal. We have performed a combination of UHPLC-MS metabolomics and 16S microbiome analyses on 224 feces samples in order to identify early biomarkers for both advanced adenomas (AD) and CRC. We report differences in fecal levels of cholesteryl esters and sphingolipids in CRC. We identified Fusobacterium, Parvimonas and Staphylococcus to be increased in CRC patients and Lachnospiraceae family to be reduced. We finally described Adlercreutzia to be more abundant in AD patients’ feces. Integration of metabolomics and microbiome data revealed tight interactions between bacteria and host and performed better than FOB test for CRC diagnosis. This study identifies potential early biomarkers that outperform current diagnostic tools and frame them into the stablished gut microbiota role in CRC pathogenesis.

CREB1-induced lncRNA LEF1-AS1 contributes to colorectal cancer progression via the miR-489/DIAPH1 axis

Long non-coding RNAs (lncRNAs) have been identified as new regulatory factors in tumor progression. Lymphoid enhancer-binding factor 1 antisense RNA 1 (LEF1-AS1) was a recently identified lncRNA. This research aimed to investigate the roles and mechanisms of LEF1-AS1 in colorectal cancer (CRC). We firstly showed that LEF1-AS1 expression was upregulated in human CRC tissues and cell lines. LEF1-AS1 upregulation was demonstrated to be induced by CREB1. Clinical study revealed that high LEF1-AS1 expression was positively associated with histological grade, lymph nodes metastasis, and decreased survivals of CRC patients. Functionally, down-regulation of LEF1-AS1 using si-LEF1-AS1 decreased cell growth, migration and invasion, as well as increased apoptosis in CRC cells. Mechanically, LEF1-AS1 functioned as competing endogenous RNA (ceRNA) for miR-489 to positively recover DIAPH1, thus playing an oncogenic role in CRC pathogenesis. Overall, our observations identified a novel CRC-related lncRNA LEF1-AS1 and discovered a critical role for this lncRNA as a ceRNA in CRC pathogenesis, suggesting that it may serve as a novel biomarker for prognosis and act as a therapeutic target for CRC treatment.

Caffeine and its main targets of colorectal cancer.

Caffeine is a purine alkaloid and is widely consumed in coffee, soda, tea, chocolate and energy drinks. To date, a growing number of studies have indicated that caffeine is associated with many diseases including colorectal cancer. Caffeine exerts its biological activity through binding to adenosine receptors, inhibiting phosphodiesterases, sensitizing calcium channels, antagonizing gamma-aminobutyric acid receptors and stimulating adrenal hormones. Some studies have indicated that caffeine can interact with signaling pathways such as transforming growth factor β, phosphoinositide-3-kinase/AKT/mammalian target of rapamycin and mitogen-activated protein kinase pathways through which caffeine can play an important role in colorectal cancer pathogenesis, metastasis and prognosis. Moreover, caffeine can act as a general antioxidant that protects cells from oxidative stress and also as a regulatory factor of the cell cycle that modulates the DNA repair system. Additionally, as for intestinal homeostasis, through the interaction with receptors and cytokines, caffeine can modulate the immune system mediating its effects on T lymphocytes, B lymphocytes, natural killer cells and macrophages. Furthermore, caffeine can not only directly inhibit species in the gut microbiome, such as Escherichia coli and Candida albicans but also can indirectly exert inhibition by increasing the effects of other antimicrobial drugs. This review summarizes the association between colorectal cancer and caffeine that is being currently studied.

BCL9 provides multi-cellular communication properties in colorectal cancer by interacting with paraspeckle proteins

Colorectal cancer (CRC) is the third most commonly diagnosed cancer, which despite recent advances in treatment, remains incurable due to molecular heterogeneity of tumor cells. The B-cell lymphoma 9 (BCL9) oncogene functions as a transcriptional co-activator of the Wnt/β-catenin pathway, which plays critical roles in CRC pathogenesis. Here we have identified a β-catenin-independent function of BCL9 in a poor-prognosis subtype of CRC tumors characterized by expression of stromal and neural associated genes. In response to spontaneous calcium transients or cellular stress, BCL9 is recruited adjacent to the interchromosomal regions, where it stabilizes the mRNA of calcium signaling and neural associated genes by interacting with paraspeckle proteins. BCL9 subsequently promotes tumor progression and remodeling of the tumor microenvironment (TME) by sustaining the calcium transients and neurotransmitter-dependent communication among CRC cells. These data provide additional insights into the role of BCL9 in tumor pathogenesis and point towards additional avenues for therapeutic intervention.