Cellular senescence gene TACC3 associated with colorectal cancer risk via genetic and DNA methylated alteration.

Cell senescence genes play a vital role in the pathogenesis of colorectal cancer, a process that may involve the triggering of genetic variations and reversible phenotypes caused by epigenetic modifications. However, the specific regulatory mechanisms remain unclear. Using CellAge and The Cancer Genome Atlas databases and in-house RNA-seq data, DNA methylation-modified cellular senescence genes (DMCSGs) were validated by Support Vector Machine and correlation analyses. In 1150 cases and 1342 controls, we identified colorectal cancer risk variants in DMCSGs. The regulatory effects of gene, variant, and DNA methylation were explored through dual-luciferase and 5-azacytidine treatment experiments, complemented by multiple database analyses. Biological functions of key gene were evaluated via cell proliferation assays, SA-ß-gal staining, senescence marker detection, and immune infiltration analyses. The genetic variant rs4558926 in the downstream of TACC3 was significantly associated with colorectal cancer risk (OR = 1.35, P = 3.22 × 10-4). TACC3 mRNA expression increased due to rs4558926 C > G and decreased DNA methylation levels. The CpG sites in the TACC3 promoter region were regulated by rs4558926. TACC3 knockdown decreased proliferation and senescence in colorectal cancer cells. In addition, subjects with high-TACC3 expression presented an immunosuppressive microenvironment. These findings provide insights into the involvement of genetic variants of cellular senescence genes in the development and progression of colorectal cancer.

Correction: Bioinformatics analysis-based screening of circRNA gene with mainstream expression trend in colorectal cancer and construction of a coexpression regulatory network.

[This corrects the article DOI: 10.1371/journal.pone.0295126.].

Bioinformatics analysis-based screening of circRNA gene with mainstream expression trend in colorectal cancer and construction of a coexpression regulatory network.

OBJECTIVE: Since circRNA can be utilized as a potential diagnostic marker for cancer, to explore the regulatory mechanism of colorectal cancer (CRC) using bioinformatics, the public database of circRNA was mined. METHODS: CRC differentially expressed miRNAs were screened in the Cancer Genome Atlas (TCGA) database, CRC differentially expressed circRNAs were searched in the Gene Expression Omnibus (GEO) database, the two databases were combined to identify CRC differentially expressed mRNAs, and a circRNA-miRNA‒mRNA regulatory network was constructed by combining a plurality of target prediction databases to identify key genes. The upstream circRNA and regulatory axis of the key genes were identified for gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis to explore the biological functions of circRNA in CRC using the regulatory axis. RESULTS: After the screening of the GSE21815 dataset, a total of 22 differentially expressed circRNAs were obtained, with 12 upregulated and 10 downregulated genes. Similarly, the GSE126094 dataset yielded 104 differentially expressed circRNAs, comprising 56 upregulated and 48 downregulated genes. Among the differentially expressed circRNAs, five were identified, with VDAC3 and SETD2 showing downregulated expression, while RAD23B, RPPH1, and MYBL2 exhibited upregulated expression. Following the selection process, five DEcircRNAs, eight target miRNAs, and 105 target DEmRNAs were identified. The protein-protein interaction (PPI) network revealed close relationships among the mRNAs, with E2F2, E2F3, CCND1, TNRC6A, and KAT2B identified as key genes. Notably, CCND1 emerged as a critical gene in the PPI network. Through the upregulation of has-circ-0087862, which binds to miR-892b, the translation inhibition of CCND1 by miR-892b was attenuated, leading to enhanced CCND1 expression. Functional enrichment analysis indicated that CCND1 was involved in protein binding and positive regulation of cellular processes, among other functions. CONCLUSION: The differentially expressed genes (DEGs) in CRC markedly affected the survival time of patients. CircRNAs could be utilized as diagnostic markers of CRC, and the key genes in CRC could be screened out by bioinformatics, which would be helpful to understand the drug targets for the treatment of human immunodeficiency virus (HIV)-related CRC patients.

Unveiling immunogenic cell death-related genes in colorectal cancer: an integrated study incorporating transcriptome and Mendelian randomization analyses.

Immunogenic cell death (ICD), a type of cell death that activates the tumor-specific immune response and thus exerts anti-tumor effects, is an emerging target in tumor therapy, but research on ICD-related genes (ICDGs) in colorectal cancer (CRC) remains limited. This study aimed to identify the CRC-specific ICDGs and explore their potential roles. Through RNA sequencing for tissue samples from CRC patients and integration with The Cancer Genome Atlas (TCGA) data, we identified 33 differentially expressed ICDGs in CRC. We defined the ICD score based on these genes in single-cell data, where a high score indicated an immune-active microenvironment. Additionally, molecular subtypes identified in bulk RNA data showed distinct immune landscapes. The ICD-related signature constructed with machine learning effectively distinguished patients' prognosis. The summary data-based Mendelian randomization (SMR) and colocalization analysis prioritized CFLAR for its positive association with CRC risk. Molecular docking revealed its stable binding with chemotherapeutic drugs like irinotecan. Furthermore, experimental validation confirmed CFLAR overexpression in CRC samples, and its knockdown inhibited tumor cell proliferation. Overall, this study expands the understanding of the potential roles and mechanisms of ICDGs in CRC and highlights CFLAR as a promising target for CRC.

The effect of reinforcing sutures and trans-anal drainage tube on the outcome of laparoscopic resection for rectal cancer: propensity score­matched analysis.

OBJECTIVES: Laparoscopic resection for rectal cancer is currently the predominant treatment modality for rectal tumors, with an ongoing focus on reducing the incidence of postoperative complications. In an effort to decrease the occurrence of anastomotic leakage, two additional steps worth considering are reinforcing the anastomosis with a barbed suture and retaining an anal drain as part of the procedure. The results of the operation were analyzed by comparing them to cases where the anastomosis was performed with a stapler alone. METHODS: This study retrospectively analyzed patients who underwent laparoscopic radical rectal cancer surgery between July 2020 and March 2023. The patients were categorized into three cohorts based on the postoperative management following instrumented anastomosis: cohort A, the instrumented anastomosis alone group; cohort B, the reinforced suture group; and cohort C, the reinforced suture and indwelling transanal drainage tube group. Propensity score matching was performed twice in a 1:1 ratio, comparing cohort B to cohort A and cohort C to cohort B. The objective was to compare the benefits and drawbacks among the different groups in terms of operative time, postoperative outcomes and operative costs. RESULTS: 529 patients with laparoscopic resection for rectal cancer were eligible for inclusion. the instrumented anastomosis alone group, reinforced suture group and the reinforced suture and indwelling transanal drainage tube group were performed in 205 patients, 198 patients and 126 patients, respectively. Cohort A and Cohort B differed in three variables after PSM: total operative time (p = 0.018), postoperative hospital stay (p < 0.001) and incidence of anastomotic leakage (p = 0.038). Cohort B had a longer total operative time, shorter postoperative hospital stay and a lower incidence of anastomotic leakage. Similarly, cohort C had less postoperative drainage (P = 0.01) and a longer postoperative hospital stay (P = 0.003) when cohort B and cohort C were matched for propensity scores. There was no significant difference in the cost of surgery between the three cohorts. CONCLUSIONS: The incorporation of barbed suture reinforcement significantly reduces the occurrence of postoperative anastomotic leakage in rectal cancer surgeries. On the other hand, although trans-anal drainage was used as an additional measure to the reinforcement suture of the anastomosis, the utilization of trans-anal drainage tubes does not demonstrate a significant improvement in surgical outcomes.

Subtypes analysis and prognostic model construction based on lysosome-related genes in colon adenocarcinoma.

Background: Lysosomes are essential for the development and recurrence of cancer. The relationship between a single lysosome-related gene and cancer has previously been studied, but the relationship between the lysosome-related genes (LRGs) and colon adenocarcinoma (COAD) remains unknown. This research examined the role of lysosome-related genes in colon adenocarcinoma. Methods: 28 lysosome-related genes associated with prognosis (PLRGs) were found by fusing the gene set that is differently expressed between tumor and non-tumor in colon adenocarcinoma with the gene set that is related to lysosomes. Using consensus unsupervised clustering of PLRGs, the colon adenocarcinoma cohort was divided into two subtypes. Prognostic and tumor microenvironment (TME) comparisons between the two subtypes were then made. The PLRGs_score was constructed using the least absolute shrinkage and selection operator regression (LASSO) method to quantify each patient's prognosis and provide advice for treatment. Lastly, Western Blot and immunohistochemistry (IHC) were used to identify MOGS expression at the protein level in colon adenocarcinoma tissues. Results: PLRGs had more somatic mutations and changes in genetic level, and the outcomes of the two subtypes differed significantly in terms of prognosis, tumor microenvironment, and enrichment pathways. Then, PLRGs_score was established based on two clusters of differential genes in the cancer genome atlas (TCGA) database, and external verification was performed using the gene expression omnibus (GEO) database. Then, we developed a highly accurate nomogram to enhance the clinical applicability of the PLRGs_score. Finally, a higher PLRGs_score was associated with a poorer overall survival (OS), a lower tumor mutation burden (TMB), a lower cancer stem cell (CSC) index, more microsatellite stability (MSS), and a higher clinical stage. MOGS was substantially elevated at the protein level in colon adenocarcinoma as additional confirmation. Conclusion: Overall, based on PLRGs, we identified two subtypes that varied significantly in terms of prognosis and tumor microenvironment. Then, in order to forecast patient prognosis and make treatment suggestions, we developed a diagnostic model with major significance for prognosis, clinical relevance, and immunotherapy. Moreover, we were the first to demonstrate that MOGS is highly expressed in colon adenocarcinoma.

Machine learning-based glycolysis-associated molecular classification reveals differences in prognosis, TME, and immunotherapy for colorectal cancer patients.

Background: Aerobic glycolysis is a process that metabolizes glucose under aerobic conditions, finally producing pyruvate, lactic acid, and ATP for tumor cells. Nevertheless, the overall significance of glycolysis-related genes in colorectal cancer and how they affect the immune microenvironment have not been investigated. Methods: By combining the transcriptome and single-cell analysis, we summarize the various expression patterns of glycolysis-related genes in colorectal cancer. Three glycolysis-associated clusters (GAC) were identified with distinct clinical, genomic, and tumor microenvironment (TME). By mapping GAC to single-cell RNA sequencing analysis (scRNA-seq), we next discovered that the immune infiltration profile of GACs was similar to that of bulk RNA sequencing analysis (bulk RNA-seq). In order to determine the kind of GAC for each sample, we developed the GAC predictor using markers of single cells and GACs that were most pertinent to clinical prognostic indications. Additionally, potential drugs for each GAC were discovered using different algorithms. Results: GAC1 was comparable to the immune-desert type, with a low mutation probability and a relatively general prognosis; GAC2 was more likely to be immune-inflamed/excluded, with more immunosuppressive cells and stromal components, which also carried the risk of the poorest prognosis; Similar to the immune-activated type, GAC3 had a high mutation rate, more active immune cells, and excellent therapeutic potential. Conclusion: In conclusion, we combined transcriptome and single-cell data to identify new molecular subtypes using glycolysis-related genes in colorectal cancer based on machine-learning methods, which provided therapeutic direction for colorectal patients.

Integrated multi-omics approach to distinct molecular characterization and classification of early-onset colorectal cancer.

Incidence of early-onset colorectal cancer (EOCRC), defined by a diagnosed age under 50 years, is increasing, but its heterogeneous etiologies that differ from general CRC remain undetermined. We initially characterize the genome, epigenome, transcriptome, and proteome of tumors from 79 patients in a Chinese CRC cohort. Data for an additional 126 EOCRC subjects are obtained from the International Cancer Genome Consortium Chinese cohort and The Cancer Genome Atlas European cohort. We observe that early-onset tumors have a high tumor mutation burden; increased DNA repair features by mutational signature 3 and multi-layer pathway enrichments; strong perturbations at effects of DNA methylation and somatic copy-number alteration on gene expression; and upregulated immune infiltration as hot tumors underlying immunophenotypes. Notably, LMTK3 exhibits ancestral mutation disparity, potentially being a functional modulator and biomarker that drives molecular alterations in EOCRC development and immunotherapies. This integrative omics study provides valuable knowledge for precision oncology of CRC.

Matairesinol Nanoparticles Restore Chemosensitivity and Suppress Colorectal Cancer Progression in Preclinical Models: Role of Lipid Metabolism Reprogramming.

Oncogenic-driven lipogenic metabolism is a common hallmark of colorectal cancer (CRC) progression. Therefore, there is an urgent need to develop novel therapeutic strategies for metabolic reprogramming. Herein, the metabolic profiles in the plasma between CRC patients and paired healthy controls were compared using metabolomics assays. Matairesinol downregulation was evident in CRC patients, and matairesinol supplementation significantly represses CRC tumorigenesis in azoxymethane/dextran sulfate sodium (AOM/DSS) colitis-associated CRC mice. Matairesinol rewired lipid metabolism to improve the therapeutic efficacy in CRC by inducing mitochondrial damage and oxidative damage and blunting ATP production. Finally, matairesinol-loaded liposomes significantly promoted the enhanced antitumor activity of 5-Fu/leucovorin combined with oxaliplatin (FOLFOX) in CDX and PDX mouse models by restoring chemosensitivity to the FOLFOX regimen. Collectively our findings highlight matairesinol-mediated lipid metabolism reprogramming as a novel druggable strategy to restore CRC chemosensitivity, and this nanoenabled approach for matairesinol will improve the chemotherapeutic efficacy with good biosafety.

Serum Calcium Concentrations and Risk of All-Cause and Cause-Specific Mortality: Results From 2 Prospective Cohorts.

CONTEXT: Calcium plays a critical role in various physiological activities. However, the association between circulating calcium concentrations and mortality in a general healthy population remains undetermined. OBJECTIVE: To examine the association of serum calcium concentrations with all-cause and cause-specific mortality. METHODS: Leveraging data from the UK Biobank (n = 361 662) and the US National Health and Nutrition Examination Survey (NHANES, n = 36 985), we prospectively examined the association of serum calcium concentrations with all-cause and cause-specific mortality using Cox proportional hazard and restricted cubic spline models. RESULTS: During a median follow-up of 12.0 years, UK Biobank documented 18 327 deaths, including 3119 (17.0%) from cardiovascular disease (CVD) and 9599 (52.4%) from cancer. We found a U-shaped relationship of albumin-adjusted calcium concentrations with all-cause and CVD mortality. Compared with participants with moderate calcium levels (the third quintile, Q3), those with low and high levels had an increased risk of all-cause (hazard ratio [HR] 1.02 for Q1 vs Q3; 1.10 for Q5 vs Q3) and CVD mortality (HR 1.11 for Q1 vs Q3; 1.25 for Q5 vs Q3). In contrast, there was a linear positive relationship with cancer mortality (HR 1.09 for Q5 vs Q1). Similar results for all-cause, CVD, and cancer mortality were observed in US NHANES. CONCLUSION: Our findings provide novel insights into the association between serum calcium concentrations and mortality in the general healthy population.

Genetic variants in the calcium signaling pathway participate in the pathogenesis of colorectal cancer through the tumor microenvironment.

Background: Cancer risk is influenced by calcium signaling in intracellular and intercellular signaling pathways. However, the relationship between the calcium signaling pathway and colorectal cancer risk remains unknown. We aim to evaluate the role of genetic variants in calcium signaling pathway genes in colorectal cancer risk through the tumor microenvironment. Methods: An analysis of genetic variants in the calcium signaling pathway was conducted using a case-control study that included 1150 colorectal cancer patients and 1342 non-cancer patients. Using the regression model, we assessed whether single-nucleotide polymorphisms (SNPs) increase the risk of colorectal cancer. We also performed a dual luciferase reporter gene assay using HCT116 cell lines and DLD1 cell lines to demonstrate the regulatory relationship between SNP and candidate risk gene. We evaluated the expression of candidate risk gene in different populations. In addition, we also evaluated candidate risk gene and 22 immune cells correlation studies. Results: There was a significant association between the PDE1C rs12538364 T allele and colorectal cancer risk [odds ratio (OR) = 1.57, 95% confidence interval (CI) = 1.30 - 1.90, P = 3.07 × 10-6, P FDR = 0.004]. Mutation of intron region rs1538364 C to T locus reduces promoter activity of PDE1C in DLD1 and HCT116 cell lines (P < 0.05). We identified that PDE1C is significantly down-regulated in colorectal cancer, closely associated with 22 immune cells. Finally, we found that PDE1C could be the biomarker for individual immunotherapy of colorectal cancer. Conclusion: According to our findings, PDE1C may be a key factor contributing to colorectal cancer, thus improving individual immunotherapy for the disease. The potential mechanism by which polymorphisms in the calcium signaling pathway genes may participate in the pathogenesis of colorectal cancer through the tumor microenvironment.

N7-methylguanosine-related lncRNAs: Predicting the prognosis and diagnosis of colorectal cancer in the cold and hot tumors.

Background: 7-Methylguanosine(m7G) contributes greatly to its pathogenesis and progression in colorectal cancer. We proposed building a prognostic model of m7G-related LncRNAs. Our prognostic model was used to identify differences between hot and cold tumors. Methods: The study included 647 colorectal cancer patients (51 cancer-free patients and 647 cancer patients) from The Cancer Genome Atlas (TCGA). We identified m7G-related prognostic lncRNAs by employing the univariate Cox regression method. Assessments were conducted using univariate Cox regression, multivariate Cox regression, receiver operating characteristics (ROC), nomogram, calibration curves, and Kaplan-Meier analysis. All of these procedures were used with the aim of confirming the validity and stability of the model. Besides these two analyses, we also conducted half-maximal inhibitory concentration (IC50), immune analysis, principal component analysis (PCA), and gene set enrichment analysis (GSEA). The entire set of m7G-related (lncRNAs) with respect to cold and hot tumors has been divided into two clusters for further discussion of immunotherapy. Results: The risk model was constructed with 17 m7G-related lncRNAs. A good correlation was found between the calibration plots and the prognosis prediction in the model. By assessing IC50 in a significant way across risk groups, systemic treatment can be guided. By using clusters, it may be possible to distinguish hot and cold tumors effectively and to aid in specific therapeutic interventions. Cluster 1 was identified as having the highest response to immunotherapy drugs and thus was identified as the hot tumor. Conclusion: This study shows that 17 m7G-related lncRNA can be used in clinical settings to predict prognosis and use them to determine whether a tumor is cold or hot in colorectal cancer and improve the individualization of treatment.

Analysis of the Prognostic Significance and Immune Infiltration of the Amino Acid Metabolism-Related Genes in Colon Adenocarcinoma.

Amino acid metabolization is verified to be a part in the progression of cancer. However, genes related to the amino acid metabolism have not been identified in colon adenocarcinoma (COAD). A systematic prognostic model of COAD becomes a pressing need. Among genes related to the amino acid metabolism, RIMKLB, ASPG, TH, MTAP, AZIN2, PSMB2, HDC, ACMSD, and PSMA8 were identified to construct a risk model. Kaplan-Meier (K-M) analyses demonstrated that the high-risk group achieved a poor prognosis. Area under the respective ROC (AUC) values indicated the robustness of the model. To highlight its clinical value, multivariate Cox was used to obtain the optimal variables to construct a nomogram. A higher tumor mutation burden was observed in the high-risk group. However, the low-risk group had a stronger immune infiltration. Seven molecular subtypes were found by consensus cluster. Twenty-two hub genes were identified related to the ESTIMATE score using WGCNA. In brief, our research constructed a stable prognostic model related to the amino acid metabolism in COAD, revealing its connection to the immune microenvironment. The model guided the outcome of COAD and the direction of immunotherapy.

PD-1 inhibitor in combination with fruquintinib therapy for initial unresectable colorectal cancer: A case report.

BACKGROUND: PD-1 inhibitors in combination with fruquintinib have not previously been reported as neoadjuvant therapy for patients with colorectal cancer. In this case report, the combination of a PD-1 inhibitor and fruquintinib demonstrated good efficacy in patients with MSI-H colorectal cancer. CASE SUMMARY: The patient was a young man in his 30s who had MSI-H type colon cancer. The patient underwent four cycles of neoadjuvant therapy with a PD-1 inhibitor combined with fruquintinib before surgery, resulting in regression of the mass and a successful surgery. CONCLUSION: Some patients with colorectal cancer have the MSI-H type, and the first-line chemotherapy regimen is not effective. However, PD-1 monoclonal antibody immunotherapy has a good therapeutic effect, which can be improved by combination therapy with fruquintinib. We recommend that patients with a history of colon or rectal cancer receive universal MSI testing; then, neoadjuvant therapy should be used.

HIST2H2BF Potentiates the Propagation of Cancer Stem Cells via Notch Signaling to Promote Malignancy and Liver Metastasis in Colorectal Carcinoma.

BACKGROUND: Growing evidence demonstrates that the initiation and progression of colorectal carcinoma (CRC) is related to the presence of cancer stem cells (CSCs). However, the mechanism through which the stem cell features of CRC cells are maintained is poorly understood. In this study, we identified the oncogenic histone cluster 2 H2B family member F (HIST2H2BF) and aimed to investigate the function of upregulated HIST2H2BF expression in maintaining the stem cell features of CRC cells, which accelerate the progression of CRC. METHODS: HIST2H2BF expression was quantified using real-time polymerase chain reaction, immunohistochemistry, and western blotting. The correlation between CpG island methylation status and HIST2H2BF re-expression was assessed through bisulfite sequencing polymerase chain reaction, methylation-specific polymerase chain reaction, and 5-Aza-dC treatment. Functional assays were performed on CRC cells and mice to investigate the HIST2H2BF-induced stem cell-like and cancer properties of CRC. Using the Notch pathway inhibitor FLI-06, the regulatory effect of HIST2H2BF on downstream Notch signaling was confirmed. RESULTS: HIST2H2BF was highly expressed in CRC tissues and cell lines. The reactivation of HIST2H2BF in CRC stems at least in part from the hypomethylated CpG islands. CRC patients with high HIST2H2BF expression have poor survival outcomes. Functional studies have shown that HIST2H2BF promotes CSC phenotype, malignancy, and liver metastasis through the activation of Notch signaling in CRC. Blockage of the Notch pathway reduced the stem cell-like and cancer properties. CONCLUSION: Our study suggests that HIST2H2BF upregulation enhances the CSC phenotype, malignancy, and liver metastasis through the activation of Notch signaling in CRC. These results identified a new perspective on the mechanism by which the stem cell features of CRC cells are maintained and highlighted the potential novel therapeutic targets for CRC.

Association between circulating insulin-like growth factor 1 and risk of all-cause and cause-specific mortality.

BACKGROUND: Insulin-like growth factor 1 (IGF1) is an important growth factor modulating development, homeostasis, and aging. However, whether and how circulating IGF1 concentrations influence early death risk in the general population remains largely unknown. METHODS: We included 380 997 participants who had serum IGF1 measurement and no history of cancer, cardiovascular disease (CVD), or diabetes at baseline from UK Biobank, a prospective cohort study initiated in 2006-2010. Restricted cubic splines and Cox proportional hazards regression models were used to assess the association between baseline IGF-1 concentrations and all-cause and cause-specific mortality. RESULTS: Over a median follow-up of 8.8 years, 10 753 of the participants died, including 6110 from cancer and 1949 from CVD. Dose-response analysis showed a U-shaped relationship between IGF1 levels and mortality. Compared to the fifth decile of IGF1, the lowest decile was associated with 39% (95% CI: 29-50%), 20% (95% CI: 8-34%), and 39% (95% CI: 14-68%) higher risk of all-cause, cancer, and CVD mortality, respectively, while the highest decile was associated with 17% (95% CI: 7-28%) and 38% (95% CI: 11-71%) higher risk of all-cause and CVD mortality, respectively. The results remained stable in detailed stratified and sensitivity analyses. CONCLUSIONS: Our findings indicate that both low and high concentrations of serum IGF1 are associated with increased risk of mortality in the general population. Our study provides a basis for future interrogation of underlying mechanisms of IGF1 in early death occurrence and possible implications for mitigating the risk.

SCRIB Promotes Proliferation and Metastasis by Targeting Hippo/YAP Signalling in Colorectal Cancer.

The complex in which scribble planar cell polarity protein (SCRIB) is located is one of the three main polar protein complexes that play an important role in maintaining epithelial polarity and affecting tumour growth. However, the role of SCRIB in colorectal cancer (CRC) remains largely unknown. This study used date from The Cancer Genome Atlas (TCGA) and clinical samples to determine the expression of SCRIB in CRC and explored its mechanism through bioinformatics analysis and in vivo and in vitro experiments. In this study, SCRIB was found to be highly expressed in CRC patients, and it was often associated with malignant characteristics, such as proliferation, apoptosis, and epithelial-mesenchymal transition (EMT). Furthermore, we found that SCRIB may interact with the Hippo signalling pathway and affect the phosphorylation of YAP and its distribution inside and outside of the nucleus. We concluded that increased expression of SCRIB is likely to inhibit the Hippo signalling pathway by promoting YAP phosphorylation. This role of SCRIB in the progression of CRC provides an important information for the treatment of CRC.

Genetic variants in Hippo signalling pathway-related genes affect the risk of colorectal cancer.

The Hippo signalling pathway plays a crucial role in carcinogenesis. Therefore, we hypothesized that genetic variants in genes related to this pathway are associated with the colorectal cancer risk. A case-control study including 1150 patients and 1342 controls was performed to assess the association of genetic variants of genes involved in the Hippo signalling pathway with the risk of colorectal cancer. The results were corrected for multiple comparisons using the false discovery rate (FDR). We used a regression model to determine the effects of single-nucleotide polymorphisms (SNPs) on the survival of patients with colorectal cancer in The Cancer Genome Atlas (TCGA) datasets. An expression quantitative trait loci (eQTL) analysis was performed using TCGA datasets and the Genotype-Tissue Expression (GTEx) project. Gene Expression Omnibus (GEO) datasets were used to provide additional data on the expression of genes in colorectal cancer. The SCRIB rs13251492 G allele was associated with a significantly decreased risk of colorectal cancer (odds ratio (OR) = 0.79, 95% confidence interval (CI) = 0.70-0.89, P = 7.76 × 10-5, P(FDR) = 6.98 × 10-4). Patients with the rs13251492 AG/GG allele experienced a longer recurrence-free survival (RFS) time (hazard ratio (HR) = 0.64, 95% CI = 0.42-0.99, P = 0.049) than patients with the rs13251492 A allele. The eQTL analysis revealed a significant association between rs13251492 and the expression of the SCRIB mRNA in colorectal tumors. Dual-luciferase reporter assays in DLD-1 and HCT116 cells revealed a lower enhancer activity of the rs13251492 G allele than the A allele. In addition, the SCRIB mRNA was expressed at markedly higher levels in colorectal cancer tissues than in normal tissues. Therefore, we identified the SCRIB rs13251492 variant as a novel colorectal cancer susceptibility locus and provided evidence of its functional relevance.

RFC2, a direct target of miR-744, modulates the cell cycle and promotes the proliferation of CRC cells.

Colorectal cancer (CRC) is a common digestive tract malignancy, which is characterized by high mortality, morbidity, and poor prognosis. Replication factor C subunit 2 (RFC2), one RFC family member, was reported to be related to various malignancies and plays an important role in proliferation, invasion, and metastasis. Nonetheless, the RFC2 biological role within CRC is still unknown. RFC2 expression profiles in CRC tissues were collected based on The Cancer Genome Atlas database, whereas miR-744 and RFC2 expression levels were detected in human CRC tissues. miR-744 and RFC2 effects on the proliferation of CRC were assessed both in vivo and in vitro. RFC2 was recognized to be a direct miR-744 target through luciferase reporter assay. RFC2 upregulation was observed within CRC tissues, and a high RFC2 level showed a correlation with poor clinicopathological symptoms. RFC2 knockdown inhibited CRC cell proliferation through promoting cell cycle arrest at the G1 phase, which was achieved by cyclin E2 (CCNE2) downregulation in vivo and in vitro. miR-744 was identified to be the tumor suppressor microRNA, which targeted RFC2 directly for inhibiting the proliferation of CRC cells both in vivo and in vitro. miR-744 downregulation was detected within CRC tissue, and messenger RNA expression showed a negative correlation with RFC2 expression within CRC tissues. Our study demonstrates that the miR-744/RFC2/CCNE2 axis potentially provides a candidate for a treatment strategy for CRC.

Feasibility of bile duct as venous graft for venous reconstruction in pancreatic surgery: An animal experimental study.

OBJECTIVE: Pancreatic cancer is a kind of high malignant tumor with a poor prognosis. The aim is to determine whether the dilated bile duct can be used to reconstruct the vessels. METHODS: An animal model of jugular vein and portal vein reconstruction was established using the bile duct. A total of 20 landrace pigs were selected to undergo jugular vein reconstruction or portal vein reconstruction using the bile duct as a patch or bridge. The patency was evaluated by color Doppler, the reconstructed segments were removed and examined macroscopically and histologically at specified intervals, and the results were compared with synthetic vessels (IMPRA straight, 10s03-19). RESULTS: The lumen was patent, although a low level thrombosis was observed when jugular or portal vein patching was used. For bridging, stenosis of the lumen was observed, and necrosis appeared when the bile duct was used for bridging, indicating that it is feasible to reconstruct the jugular vein and portal vein with a bile duct patch. However, the bridge was not feasible possibly due to loss of blood supply, and consequent necrosis and fibrosis. CONCLUSION: The bile duct is technically feasible, but the outcomes are unsatisfactory.