Erk and MAPK signaling is essential for intestinal development through Wnt pathway modulation.

Homeostasis of intestinal stem cells (ISCs) is maintained by the orchestration of niche factors and intrinsic signaling networks. Here, we have found that deletion of Erk1 and Erk2 (Erk1/2) in intestinal epithelial cells at embryonic stages resulted in an unexpected increase in cell proliferation and migration, expansion of ISCs, and formation of polyp-like structures, leading to postnatal death. Deficiency of epithelial Erk1/2 results in defects in secretory cell differentiation as well as impaired mesenchymal cell proliferation and maturation. Deletion of Erk1/2 strongly activated Wnt signaling through both cell-autonomous and non-autonomous mechanisms. In epithelial cells, Erk1/2 depletion resulted in loss of feedback regulation, leading to Ras/Raf cascade activation that transactivated Akt activity to stimulate the mTor and Wnt/ß-catenin pathways. Moreover, Erk1/2 deficiency reduced the levels of Indian hedgehog and the expression of downstream pathway components, including mesenchymal Bmp4 - a Wnt suppressor in intestines. Inhibition of mTor signaling by rapamycin partially rescued Erk1/2 depletion-induced intestinal defects and significantly prolonged the lifespan of mutant mice. These data demonstrate that Erk/Mapk signaling functions as a key modulator of Wnt signaling through coordination of epithelial-mesenchymal interactions during intestinal development.

CircASXL1 knockdown represses the progression of colorectal cancer by downregulating GRIK3 expression by sponging miR-1205.

BACKGROUND: Colorectal cancer (CRC) is a common aggressive tumor that poses a heavy burden to human health. An increasing number of studies have reported that circular RNA (circRNA) is involved in the progression of CRC. In this study, the special profiles of circASXL1 (circ_0001136) in CRC progression were revealed. METHODS: The expression of circASXL1, microRNA-1205 (miR-1205), and glutamate ionotropic receptor kainate type subunit 3 (GRIK3) mRNA was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The protein expression was determined by Western blot or immunohistochemistry. Cell colony-forming ability was investigated by colony formation assay. Cell cycle and apoptosis were demonstrated using cell-cycle and cell-apoptosis analysis assays, respectively. Cell migration and invasion were detected by wound-healing and transwell migration and invasion assays, respectively. The binding sites between miR-1205 and circASXL1 or GRIK3 were predicted by circBank or miRDB online database, and identified by dual-luciferase reporter assay. The impact of circASXL1 on tumor formation in vivo was investigated by in vivo tumor formation assay. RESULTS: CircASXL1 and GRIK3 expression were apparently upregulated, and miR-1205 expression was downregulated in CRC tissues and cells relative to control groups. CircASXL1 knockdown inhibited cell colony-forming ability, migration and invasion, whereas induced cell arrest at G0/G1 phase and cell apoptosis in CRC cells; however, these effects were attenuated by miR-1205 inhibitor. Additionally, circASXL1 acted as a sponge for miR-1205, and miR-1205 was associated with GRIK3. Furthermore, circASXL1 silencing hindered tumor formation by upregulating miR-1205 and downregulating GRIK3 expression. CONCLUSION: CircASXL1 acted an oncogenic role in CRC malignant progression via inducing GRIK3 through sponging miR-1205. Our findings provide a theoretical basis for studying circASXL1-directed therapy for CRC.

Clinical and molecular heterogeneity associated with tumor sidedness in colorectal liver metastasis: a multicenter propensity cohort study.

Background: Colorectal liver metastasis (CRLM) exhibits highly heterogeneity, with clinically and molecularly defined subgroups that differ in their prognosis. The aim of this study is to explore whether left-sided tumors is clinically and gnomically distinct from right-sided tumors in CRLM. Methods: This retrospective study included 1,307 patients who underwent primary tumor and metastases resection at three academic centers in China from January 1, 2012, to December 31, 2020. Propensity score matching with 1:1 ratio matching was performed. The prognostic impact of tumor sidedness was determined after stratifying by the KRAS mutational status. Moreover, whole-exome sequencing (WES) of 200 liver tumor tissues were performed to describe the heterogeneity across the analysis of somatic and germline profiles. Results: The median follow-up was 68 months. Matching yielded 481 pairs of patients. Compared to right-sided CRLM, left-sided patients experienced with better 5-year overall survival (OS) in surgery responsiveness, with a 14.6 lower risk of death [hazard ratio (HR), 1.36, 95% confidence interval (CI), 1.10-1.69, P=0.004]. Interaction between tumor sidedness and KRAS status was statistically significant: left-sidedness was associated with better prognosis among KRAS wild-type patients (HR 1.71; 95% CI: 1.20-2.45; P=0.003), but not among KRAS mutated-type patients. Integrated molecular analyses showed that right-sided tumors more frequently harbored TP53, APC, KRAS, and BRAF alterations, and identified a critical role of KRAS mutation in correlation with their survival differences. Higher pathogenic germline variants were identified in the right-sided tumors compared with left-sided tumors (29.3% vs. 15.5%, P=0.03). Conclusions: We demonstrated that the prognostic impacts of tumor sidedness in CRLM is restricted patients with KRAS wild-type tumors. Tumor sidedness displays considerable clinical and molecular heterogeneity that may associate with their therapy benefits and prognosis.

Association between inflammatory bowel disease and interleukins, chemokines: a two-sample bidirectional mendelian randomization study.

Background: Mendelian randomization (MR) was used to evaluate the bidirectional causal relationship between inflammatory bowel disease (IBD) and interleukins (ILs), chemokines. Methods: Genetic instruments and summary data of five ILs and six chemokines were obtained from a genome-wide association study database, and instrumental variables related to IBD were obtained from the FinnGen Consortium. Inverse variance weighting (IVW) was used as the main MR analysis method, and several other MR methods including MR-Egger and weighted median were used to confirm the reliability of the results. Sensitivity analyses such as heterogeneity and pleiotropy were also performed. Results: The IVW method provided evidence to support that genetically predicted IL-16, IL-18, and CXCL10 significantly positively correlated with IBD, while IL-12p70 and CCL23 significantly negatively correlated with IBD. IL-16 and IL-18 had a suggestive association with an increased risk of ulcerative colitis (UC), and CXCL10 had a suggestive association with an increased risk of Crohn's disease (CD). However, there was no evidence to support that IBD and two main subtypes (UC and CD) are associated with changes in the levels of ILs and chemokines. The results of the sensitivity analyses were robust and no evidence of heterogeneity and horizontal pleiotropy was observed. Conclusions: The present study showed that some ILs and chemokines affect IBD, but IBD and its main subtypes (UC and CD) have no effect on the level changes of ILs and chemokines.

Association of Simultaneous vs Delayed Resection of Liver Metastasis With Complications and Survival Among Adults With Colorectal Cancer.

Importance: Simultaneous or delayed resection of synchronous liver metastasis (SLM) with primary colorectal cancer (CRC) remains a controversial topic. Objective: To investigate the outcomes of simultaneous vs delayed resection in patients with resectable SLM. Design, Setting, and Participants: This comparative effectiveness research study included 1569 patients with resectable SLM who underwent curative-intent liver resection at 3 independent centers in China between January 1, 2000, to December 31, 2019. A 1:1 propensity score matching was performed. Follow-up was completed on August 31, 2021, and the data were analyzed from April 1 to 30, 2022. Main Outcomes and Measures: Primary outcome was the percentage of patients with at least 1 major complication within 60 days after surgery. Secondary outcomes were intraoperative and postoperative complications, overall survival (OS), and cancer-specific survival (CSS) rates. Results: Among the 1569 patients included, 1057 (67.4%) underwent delayed resection (719 men [68.0%] with a mean [SD] age of 57.4 [11.2] years), and 512 patients (310 men [60.5%] with a mean [SD] age of 57.1 [10.5] years) underwent simultaneous resection. Matching yielded 495 pairs of patients underwent simultaneous resection. The percentage of major perioperative complications did not differ between the simultaneous and delayed resection groups (34.1% vs 30.0%; P = .89). The OS rates were 65.2% at 3 years, 47.1% at 5 years, and 38.0% at 8 years for the delayed resection group and 78.0% at 3 years, 65.4% at 5 years, and 63.1% at 8 years for the simultaneous resection group (hazard ratio [HR], 1.42; 95% CI, 1.10-1.85, P = .003). The CSS rates were 68.3% at 3 years, 48.5% at 5 years, and 37.1% at 8 years for the delayed resection group and 79.2% at 3 years, 67.2% at 5 years, and 65.9% at 8 years for the simultaneous resection group (HR, 1.45; 95% CI, 1.14-1.98; P = .004). On subgroup analysis comparing the 2 strategies according to the KRAS sequence variation status, the OS rates (HR, 1.61; 95% CI, 1.45-2.18; P < .001) and CSS rates (HR, 1.62; 95 CI, 1.40-1.87; P = .003]) in the simultaneous resection group were significantly better than those in the delayed resection group in patients with KRAS wild-type tumors. Conclusions and Relevance: Results of this study suggest that complication rates did not differ when CRC and SLM were resected simultaneously and that the survival benefits of simultaneous resection were restricted to patients with KRAS wild-type tumors. Integrating molecular features into the treatment decision is a basis for accurate, individualized treatments.

NUP153 overexpression suppresses the proliferation of colorectal cancer by negatively regulating Wnt/ß-catenin signaling pathway and predicts good prognosis.

BACKGROUND: Nucleoporin NUP153 (NUP153) is well known to be involved in the regulating of nuclear transport. Although NUP153 is associated with several cancers, its role in colorectal cancer (CRC) and the underlying mechanism are still unknown. OBJECTIVE: The aim of this study was to access the effect of NUP153 on the prognosis of patients with CRC, and cancer cell proliferation. METHODS: The expression levels of NUP153 in CRC tissues and matched normal colon tissues were examined by real-time quantitative PCR and immunohistochemistry. Then the association between NUP153 levels with clinical variables as well as survival time was investigated. Moreover, overexpression of NUP153 in HCT116 cells was established to study its influence on cell proliferation in vitro, and a xenograft model was performed to explore this effect in vivo. RESULTS: We found that NUP153 was highly expressed in adjacent normal tissues than in cancer tissues, and elevated NUP153 expression was negatively associated with pathological grade (P= 0.015), T stage (P= 0.048) and distant metastasis (P= 0.006). Kaplan-Meier analysis revealed that patients with higher NUP153 expression had a longer overall survival (OS) (P= 0.01) and recurrence free disease (RFS) (P= 0.001). Logistic regression analysis further identified NUP153 as an independent prognostic safe factor for OS and recurrence. Moreover, NUP153 overexpression suppressed CRC cells proliferation and inhibited tumor growth in a xenograft model. Its mechanistic investigations showed that NUP153 overexpression inhibited ß-catenin transcriptional activity and down-regulated the mRNA expression levels of Wnt downstream proteins-Axin2, cyclinD1, c-myc and lef-1. CONCLUSIONS: NUP153 might be a promising prognostic factor, a potential tumor suppressor and therapeutic target in human CRC through an interaction with the Wnt/ß-catenin signaling pathway.