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Background: Although numerous studies have investigated the clinicopathologic and prognostic relevance of mucinous adenocarcinoma (MAC) and signet-ring cell carcinoma (SRCC) compared with classic adenocarcinoma (CA), little is known about the prognosis of adenocarcinoma with mixed subtypes (AM) and the differences among these four subtypes.Methods: The statistics of colorectal cancer registered in the Surveillance, Epidemiology and End Results (SEER) database were retrieved and analyzed. We also compared the clinicopathologic and prognostic relevance between CA, SRCC, MAC, and AM.Results: The frequencies of these four subtypes were 69.9% (CA, n = 15,812), 25.1% (MAC, n = 5689), 3.6% (SRCC, n = 814) and 1.4% (AM, n = 321), respectively. All of MAC, SRCC, and AM were significantly related with aggressive features. Only SRCC and AM were identified as independent poor prognostic markers for overall survival by multivariate analysis. The aggressiveness of AM was between MAC and SRCC according to the clinicopathologic associations. The prognosis of AM was significantly worse than MAC but comparable with SRCC.Conclusions: We confirmed the clinicopathologic relevance with aggressive features of MAC and SRCC, as well as poor prognostic relevance of SRCC by analyzing a large study population data set. Furthermore, we identified AM as a rare but aggressive histologic subtype in colorectal cancer, to which particular attention should be given in clinical practice. [ABSTRACT FROM AUTHOR]

Background. Colorectal cancer (CRC) is the third most common malignancies worldwide. Ferroptosis is a programmed, iron-dependent cell death observed in cancer cells. However, the prognostic potential and immunotherapy biomarker potential of ferroptosis-related genes (FRGs) in CRC patients remains to be clarified. Methods. At first, we comprehensively analysed the different expression and prognosis of related FRGs in CRC patients based on TCGA cohort. The relationship between functional enrichment of these genes and immune microenvironment in CRC was investigated using the TCGA database. Prognostic model was constructed to determine the association between FRGs and the prognosis of CRC. Relative verification was done based on the GEO database. Meanwhile, the ceRNA network of FRGs in the model was also performed to explore the regulatory mechanisms. Results. Eight differentially expressed FRGs were associated with the prognosis of CRC patients. Patients from the TCGA database were classified into the A, B, and C FRG clusters with different features. And FRG scores were constructed to quantify the FRG pattern of individual patients with colorectal cancer. The CRC patients with higher FRG score showed worse survival outcomes, higher immune dysfunction, and lower response to immunotherapy. The prognostic model showed a high accuracy for predicting the OS of CRC. Finally, a ceRNA network was analysed to show the concrete regulation mechanisms of critical FRGs in CRC. Conclusions. The FRG risk score prognostic model based on 8 FRGs exhibit superior predictive performance, providing a novel prognostic model with a high accuracy for CRC patients. Moreover, FRG score can be the potential biomarker of the response of immunotherapy for CRC. [ABSTRACT FROM AUTHOR]

Background: The outcomes of immune checkpoint inhibitors in cancer patients with liver metastases are poor, which may be related to a different tumor microenvironment in liver metastases from primary tumors. This study was aimed to analyze PD-L1 expression and the immune microenvironment status in liver metastases and compare the differences of PD-L1 expression between primary tumors and liver metastases of colorectal cancer.Methods: 74 cases of pathologically confirmed colorectal cancer with liver metastasis underwent resection from our hospital were included. Tissue microarrays were used for the interpretation of PD-L1 expression, cluster of differentiation 4 (CD4) and CD8 density by immunohistochemistry. We evaluated the disparity between primary tumor and liver metastasis in PD-L1 expression, CD4 and CD8 density and analyzed the factors associated with obvious PD-L1 disparity.Results: The expression of PD-L1 was positively related to the density of CD4 and CD8 in liver metastases. The expression of PD-L1 in liver metastases was higher than in primary tumors in certain subgroups, including patients with concurrent liver metastases (n = 63, p = 0.05), patients receiving concurrent resection of primary and metastatic tumors (n = 56, p = 0.04). The two subgroups generally reflected those without inconsistent external influences, such as treatment and temporal factors, between primary tumors and liver metastases. In these subgroups, the intrinsic differences of microenvironment between primary tumors and liver metastases could be identified. Furthermore, tumor differentiation [moderate vs. poor: OR = 0.23, 95% CI: 0.03-0.99, p = 0.05)] were demonstrated to be associated with obvious discordance of PD-L1 expression between primary tumors and liver metastases.Conclusions: The expression of PD-L1 in liver metastases was higher than in primary tumors in subgroups, reflecting intrinsic microenvironment differences between primary and metastatic tumors. Obvious discordance of PD-L1 expression between primary tumor and liver metastasis was significantly related to the tumor differentiation. [ABSTRACT FROM AUTHOR]

Men demonstrate higher incidence and mortality rates of colorectal cancer (CRC) than women. This study aims to explain the potential causes of such sexual dimorphism in CRC from the perspective of sex‐biased gut microbiota and metabolites. The results show that sexual dimorphism in colorectal tumorigenesis is observed in both ApcMin/+ mice and azoxymethane (AOM)/dextran sulfate sodium (DSS)‐treated mice with male mice have significantly larger and more tumors, accompanied by more impaired gut barrier function. Moreover, pseudo‐germ mice receiving fecal samples from male mice or patients show more severe intestinal barrier damage and higher level of inflammation. A significant change in gut microbiota composition is found with increased pathogenic bacteria Akkermansia muciniphila and deplets probiotic Parabacteroides goldsteinii in both male mice and pseudo‐germ mice receiving fecal sample from male mice. Sex‐biased gut metabolites in pseudo‐germ mice receiving fecal sample from CRC patients or CRC mice contribute to sex dimorphism in CRC tumorigenesis through glycerophospholipids metabolism pathway. Sexual dimorphism in tumorigenesis of CRC mouse models. In conclusion, the sex‐biased gut microbiome and metabolites contribute to sexual dimorphism in CRC. Modulating sex‐biased gut microbiota and metabolites could be a potential sex‐targeting therapeutic strategy of CRC. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is the third most common cause of cancer mortality worldwide. Approximately 40% of CRC patients are KRAS sequence variation, including KRAS G13D mutation (KRASG13D) CRC patients, accounting for approximately 8% of all KRAS mutations in CRC patients and showing little benefit from anti-EGFR therapy. Therefore, there is an urgent need for new and effective anticancer agents in patients with KRASG13D CRC. Here, we identified a natural product, erianin, that directly interacted with purified recombinant human KRASG13D with a Kd of 1.1163 μM, which also significantly improve the thermal stability of KRASG13D. The cell viability assay showed that KRASG13D cells were more sensitive to erianin than KRASWT or KRASG12V cells. In vitro , results showed that erianin suppressed the migration, invasion and epithelial-mesenchymal transition (EMT) of KRASG13D CRC cells. Furthermore, erianin induced ferroptosis, as evidenced by the accumulation of Fe2+ and reactive oxygen species (ROS), lipid peroxidation, and changes in the mitochondrial morphology of KRASG13D CRC cells. Interestingly, we also found that erianin-induced ferroptosis was accompanied by autophagy. Moreover, the occurrence of erianin-induced ferroptosis is reversed by autophagy inhibitors (NH4Cl and Bafilomycin A1) and ATG5 knockdown, suggesting that erianin-induced ferroptosis is autophagy-dependent. In addition, we evaluated the inhibition of tumor growth and metastasis by erianin in vivo using a subcutaneous tumor model and a spleen-liver metastasis model, respectively. Collectively, these data provide novel insights into the anticancer activity of erianin, which is valuable for the further discussion and investigation of the use of erianin in clinical anticancer chemotherapy for KRASG13D CRC. [Display omitted] • Erianin directly interacted with KRASG13D and markedly improve the thermal stability of KRASG13D protein in cells. • Erianin suppressed malignant behaviors and EMT through autophagy-dependent ferroptosis in KRASG13D CRC cells. • Erianin suppresses KRASG13D CRC tumor growth and metastasis in vivo. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) is one of the most common cancers. In recent studies, the gut microbiota has been reported to be potentially involved in aggravating or favoring CRC development. However, little is known about the microbiota composition in CRC patients after treatment. In this study, we explored the fecal microbiota composition to obtain a periscopic view of gut microbial communities. We analyzed microbial 16S rRNA genes from 107 fecal samples of Chinese individuals from three groups, including 33 normal controls (NC), 38 CRC patients (Fa), and 36 CRC post-surgery patients (Fb). Results: Species richness and diversity were decreased in the Fa and Fb groups compared with that of the NC group. Partial least squares discrimination analysis showed clustering of samples according to disease with an obvious separation between the Fa and NC, and Fb and NC groups, as well as a partial separation between the Fa and Fb groups. Based on linear discriminant analysis effect size analysis and a receiver operating characteristic model, Fusobacterium was suggested as a potential biomarker for CRC screening. Additionally, we found that surgery greatly reduced the bacterial diversity of microbiota in CRC patients. Some commensal beneficial bacteria of the intestinal canal, such as Faecalibacterium and Prevotella, were decreased, whereas the drug-resistant Enterococcus was visibly increased in CRC post-surgery group. Meanwhile, we observed a declining tendency of Fusobacterium in the majority of follow-up CRC patients who were still alive approximately 3 y after surgery. We also observed that beneficial bacteria dramatically decreased in CRC patients that recidivated or died after surgery. This revealed that important bacteria might be associated with prognosis. Conclusions: The fecal bacterial diversity was diminished in CRC patients compared with that in NC. Enrichment and depletion of several bacterial strains associated with carcinomas and inflammation were detected in CRC samples. Fusobacterium might be a potential biomarker for early screening of CRC in Chinese or Asian populations. In summary, this study indicated that fecal microbiome-based approaches could be a feasible method for detecting CRC and monitoring prognosis post-surgery. [ABSTRACT FROM AUTHOR]

Background: Numerous reports on microRNAs have illustrated their role in tumor growth and metastasis. Recently, a new prognostic factor, miR‐125b‐2‐3p, has been identified for predicting chemotherapeutic sensitivity in advanced colorectal cancer (CRC). However, the specific mechanisms and biological functions of miR‐125b‐2‐3p in advanced CRC under chemotherapy have yet to be elucidated. Methods: MiR‐125b‐2‐3p expression was detected by real‐time PCR (RT‐PCR) in CRC tissues. The effects of miR‐125b‐2‐3p on the growth, metastasis, and drug sensitivity of CRC cells were tested in vitro and in vivo. Based on multiple databases, the upstream competitive endogenous RNAs (ceRNAs) and the downstream genes for miR‐125b‐2‐3p were predicted by bioinformatic analysis, followed by the experiments including luciferase reporter assays, western blot assays, and so on. Results: MiR‐125b‐2‐3p was significantly lowly expressed in the tissues and cell lines of CRC. Higher expression of miR‐125b‐2‐3p was associated with relatively lower proliferation rates and fewer metastases. Moreover, overexpressed miR‐125b‐2‐3p remarkably improved chemotherapeutic sensitivity of CRC in vivo and in vitro. Mechanistically, miR‐125b‐2‐3p was absorbed by long noncoding RNA (lncRNA) XIST regulating WEE1 G2 checkpoint kinase (WEE1) expression. The upregulation of miR‐125b‐2‐3p inhibited the proliferation and epithelial‐mesenchymal transition (EMT) of CRC induced by lncRNA XIST. Conclusions: Lower miR‐125b‐2‐3p expression resulted in lower sensitivity of CRC to chemotherapy and was correlated with poorer survival of CRC patients. LncRNA XIST promoted CRC metastasis acting as a ceRNA for miR‐125b‐2‐3p to mediate WEE1 expression. LncRNA XIST‐miR‐125b‐2‐3p‐WEE1 axis not only regulated CRC growth and metastasis but also contributed to chemotherapeutic resistance to CRC. [ABSTRACT FROM AUTHOR]

Gastrointestinal cancer causes countless deaths every year due to therapeutic resistance. However, whether metabolic alterations contribute to chemoresistance is not well understood. In this study, we report that fatty acid (FA) catabolism was activated in gastrointestinal cancer cells treated with oxaliplatin, which exhibited higher expression of the rate-limiting enzymes carnitine palmitoyltransferase 1B (CPT1B) and CPT2. The clinical analysis also showed that high expression of these enzymes was associated with poor oxaliplatin-based chemotherapy outcomes in patients. Furthermore, genetic or pharmacological inhibition of CPT2 with perhexiline disturbed NADPH and redox homeostasis and increased reactive oxygen species (ROS) generation and cell apoptosis in gastrointestinal cancer cells following oxaliplatin treatment. Specifically, the combination of oxaliplatin and perhexiline significantly suppressed the progression of gastrointestinal cancer in cell-based xenograft and patient-derived xenograft (PDX) models. Mechanistically, CPT2 was transcriptionally upregulated by nuclear factor of activated T cells 3 (NFATc3), which translocated to the nucleus in response to oxaliplatin treatment. In summary, our study suggests that the inhibition of CPT-mediated FA catabolism combined with conventional chemotherapy is a promising therapeutic strategy for patients with gastrointestinal cancers. [ABSTRACT FROM AUTHOR]

Nafamostat mesilate is an anti-inflammatory drug that is usually used to treat pancreatitis. Recent studies show that it can suppress pancreatic cancer via inhibition of the nuclear factor κB (NF-κB) pathway. However, whether it has anti-tumor activity in some other cancer, including colorectal cancer (CRC), has not been investigated and remained unclear. Here, our study showed that nafamostat mesilate abrogated the constitutive NF-κB activation in CRC cells, which is mediated through inhibition of phosphorylation of IκBα and nuclear translocation of p65. Also, we found that nafamostat mesilate inhibited phosphorylation of Erk in CRC cells. Consistently, our study demonstrated that nafamostat mesilate inhibited the CRC cell proliferation, invasion and migration and induced mitochondria-dependent apoptosis. Furthermore, nafamostat mesilate could reverse oxaliplatin induced NF-κB and Erk activation in CRC cells, and enhance the sensitivity of CRC cells to oxaliplatin. Nafamostat mesilate combined with oxaliplatin repressed subcutaneous tumor growth and hepatic metastasis in vivo. Overall, our data suggest that nafamostat mesilate, a relatively non-toxic drug that targets NF-κB and Erk, may, in combination with oxaliplatin, represent a novel therapeutic strategy for CRC treatment. [ABSTRACT FROM AUTHOR]