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Objective·To investigate the potential causal relationship between type 1 diabetes and colorectal cancer by using Mendelian randomization (MR).Methods·Two-sample bidirectional MR was used to investigate the causal relationship between type 1 diabetes and colorectal cancer. All research data were collected from the IEU Open GWAS Project database. The dataset of type 1 diabetes included 9 266 cases and 15 574 controls, with correlation analysis in 12 783 129 single nucleotide polymorphisms (SNPs); the dataset of colorectal cancer included 5 657 cases and 372 016 controls, with correlation analysis in 29 999 696 SNPs. The instrumental variables SNPs were screened. The results derived from the inverse-variance weighted (IVW) method were used as the main indicator of effect. The results derived from other four methods, namely MR-Egger regression, weighted median, simple mode, and weighted mode, were used as reference. Sensitivity was analyzed with the leave-one-out method. Heterogeneity was analyzed with Cochran's Q test by using both IVW and MR-Egger methods. Pleiotropy was analyzed with MR-pleiotropy function, and Steiger test was used for directional research. The colocation analysis was used to find out whether the causal relationship between type 1 diabetes and colorectal cancer was caused by the same SNP. The genetic correlation between 2 diseases was analyzed by using the linkage disequilibrium score regression (LDSC). All tests were analyzed by using R language software (version 4.3.1).Results·After being screened, a total of 33 instrumental variables (SNPs) were used. The heterogeneity test results showed that there was heterogeneity among the SNPs (IVW and MR-Egger: P0.05). Steiger test showed that the effect of type 1 diabetes on colorectal cancer was not interfered with by the reverse effect. Reverse MR analysis showed no causal effect of colorectal cancer on type 1 diabetes (P>0.05). The results of colocalization analysis showed that the probability of H4 hypothesis was 45.7%, and the causal relationship between the 2 diseases was not caused by the same SNP in the gene sequences. LDSC analysis demonstrated that there was no genetic correlation between the two diseases.Conclusion·Type 1 diabetes may promote colorectal cancer, but colorectal cancer has no effect on type 1 diabetes.

Evidence suggests that Weichang'an (WCA) inhibited the metastasis of colorectal cancer (CRC) in vitro and downregulates oncogenic β‐catenin; more intriguingly, we also found an upregulation of ARHGAP25 in this process. This study aimed to investigate the mechanisms by which WCA regulated CRC metastasis in vitro. Here, HCT116 cells were transfected with siRNAs to interfere ARHGAP25 expression. WCA decoction, XAV939 (a specific Wnt/β‐catenin pathway inhibitor), and LiCl (an activator for Wnt/β‐catenin pathway) were used for treatment. Cell migratory and invasive capacities were determined using Transwell chamber. The activation of Wnt/β‐catenin pathway was assessed by determining the expression of MMP7, MMP9, ZEB1, and β‐catenin. The study suggests that WCA inhibited the migration and invasion of HCT116 cells and suppressed the activation of Wnt/β‐catenin pathway, as evidenced by retarding MMP7, MMP9, ZEB1, and β‐catenin. However, siRNA–ARHGAP25 resulted in the opposite. In siRNA–ARHGAP25‐transfected HCT116 cells, WCA (0.4 mg/mL) induced the antimetastatic effects and the inactivation of Wnt/β‐catenin pathway was remarkably reversed with additional LiCl treatment. Our study concludes that inhibiting Wnt/β‐catenin pathway while promoting ARHGAP25 was the mechanism, whereby WCA retarded migration and invasion of CRC in vitro. [ABSTRACT FROM AUTHOR]

Although progress has been made in the early diagnosis of colorectal cancer (CRC) and in the systemic therapy of patients with CRC, the prognosis for advanced CRC remains poor. Our previous study demonstrated that ARHGAP25 overexpression significantly inhibits CRC cell growth, invasion and migration. However, it was not possible to evaluate and analyze the overall survival (OS) rate of patients with CRC. Thus, the discovery of relevant factors and their expression on the basis of existing research is necessary to predict the OS rate of patients with advanced CRC. Therefore, the aim of the present study was to define the value of Rho GTPase-activating protein 25 (ARHGAP25) expression in predicting the OS rate in patients with CRC. The clinical data of 153 patients with CRC who underwent colorectal resection were retrospectively analyzed. In order to explore the expression of ARHGAP25, immunohistochemical analysis of the tumor tissues of these patients, was performed. Univariate Cox regression analysis was used to assess the prognostic value of ARHGAP25 expression for OS. Multivariate analysis was used to evaluate the effect of ARHGAP25 expression in the presence of other variables. Confounding factors and interaction were assessed by a stratified analysis using ARHGAP25 expression and other variables associated with survival. The univariate analysis revealed that, ARHGAP25 expression was associated with an improved OS in patients with CRC (P<0.05). The multivariate analysis revealed that ARHGAP25 expression was still correlated with an improved OS after adjusting for sex, age, invasion degree, lymph node metastasis, distant metastasis, TNM stage, tumor location, histological type, histological grade, tumor deposits, and postoperative treatment (P<0.05). The stratified analysis demonstrated that the predictive value of ARHGAP25 for the OS of patients with CRC was stronger in males, elderly patients (>70 years old), patients with T3 stage tumor, lymph node metastasis, TNM stage III, right hemicolon location and patients with a poorly differentiated tumor (P<0.05). Overall, our results demonstrated that ARHGAP25 may have an important potential value for improving the prognosis of patients with CRC. [ABSTRACT FROM AUTHOR]

Herein, we found ARHGAP25 was down-regulated in colon biopsies of patients with colorectal cancer (CRC). Gene set enrichment analysis (GSEA) also showed that ARHGAP25 was negatively correlated with Wnt/β-catenin activation. To study the role of ARHGAP25 in CRC and its possible mechanism, we established lentiviral-mediated ARHGAP25 overexpression in HCT116 and RKO cells along with siRNA-mediated ARHGAP25 knockdown in SW620 cells. The metastatic capacity of the CRC cell lines in vitro was assessed by measuring cell proliferation, migration and invasion. Additionally, expression of matrix metalloproteinases (MMP2, MMP7 and MMP9), EMT-associated factors (E-cadherin, ZEB1, Snail and Twist1) and β-catenin (a core part of Wnt/β-catenin signaling) was determined. XAV939, a Wnt/β-catenin inhibitor, was used for treatment. Our data suggests that ARHGAP25 overexpression significantly inhibits CRC cell growth, suppresses cell migration and invasion, and reduces expression of MMPs, EMT-associated factors and β-catenin. Our results suggest not only that ARHGAP25 has an anti-metastatic role in CRC cells, but also that the inactivation of the Wnt/β-catenin pathway is important in this process. Accordingly, siRNA-ARHGAP25 resulted in the opposite effect, favoring CRC metastasis in vitro, and activating the Wnt/β-catenin pathway in CRC cells. In addition, the siRNA-ARHGAP25 induced changes on cell proliferation, migration, and invasion were significantly reversed with XAV939 treatment. Importantly, the anti-metastatic effects of ARHGAP25 were further substantiated in a CRC lung metastasis xenograft model. We conclude that ARHGAP25 negatively regulates the metastatic potential of CRC cells via the Wnt/β-catenin pathway. Thus, our findings implicate ARHGAP25 as a potential therapeutic target in CRC metastasis. [ABSTRACT FROM AUTHOR]