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Recent findings have identified microbiota as crucial participants in many disease conditions, including cancers. Competing endogenous RNA (ceRNA) is regarded as a candidate mechanism involving relevant biological processes. We therefore constructed a ceRNA network using the TCGA and GEO database, to determine the potential mechanisms of microbiota-mediated colorectal carcinogenesis and progression. We found a total of 75 lncRNAs, 8 miRNAs, and 9 mRNAs in the probiotics-mediated ceRNA network and a total of 49 lncRNAs, 4 miRNAs, and 3 mRNA in the pathobiont-mediated ceRNA network, which could induce the microbiota-mediated carcinogenesis and progression. The GO and KEGG analysis indicated that the ceRNA network is mainly enriched in the metabolic process, and two unique pathways (the p53 signaling pathway and microRNA in cancer), respectively. A four-gene signature (FRMD6-AS2, DIRC3, LIFR-AS1, and MRPL23-AS1) was suggested as an independent prognostic factor. Four lncRNAs (LINC00355, KCNQ1OT1, LINC00491, and HOTAIR) were associated with poor survival. Three small molecule candidate anticancer drugs (Pentoxyverine, Rimexolone, and Doxylamine) were identified. A four-gene signature (FAM129A, BCL2, PMAIP1, and RPS6) is significantly correlated with immune infiltration level. This study provides a promising biomarker reservoir to explore the mechanism by which microbiota regulate the ceRNA network involving the immune response, and further participate in colorectal carcinogenesis and progression., Graphical Abstractt

Yes-associated protein (YAP) is a transcriptional coactivator that promotes cell proliferation, migration, and tissue homeostasis in colorectal cancer (CRC). Here, we established 5-Fu resistant CRC cell line (SW620R) and examined the role of YAP in chemotherapy resistance. We showed that YAP promoted cell proliferation, migration, and chemotherapy resistance in CRC. To increase efficacy of CRC treatment, we employed another therapeutic target EGFR which interacts with the upstream signaling molecules of YAP in Hippo pathway. Verteporfin, a YAP specific inhibitor, inhibits YAP activity by blocking the YAP-TEAD complex in the cell nucleus, and AG1478, an inhibitor of EGFR/ErbB1, induces the phosphorylation and degradation of YAP. We found that combinational inhibition of YAP by VP and AG1478 synergistically suppressed the CRC development and reversed chemotherapy resistance in vitro and in vivo. Therefore, our results demonstrated a novel therapeutic strategy, the combination of inhibitors targeting EGFR and YAP, to suppress and reverse chemotherapy resistance in colorectal cancer.

Nuclear insulin-like growth factor 1 receptor (nIGF1R) has been associated with poor overall survival and chemotherapy resistance in various types of cancer; however, the underlying mechanism remains unclear. In the present study, immunoprecipitation-coupled mass spectrometry was performed in an IGF1R-overexpressing SW480-OE colorectal cancer cell line to identify the nIGF1R interactome. Network analysis revealed 197 proteins of interest which were involved in several biological pathways, including RNA processing, DNA double-strand break (DSB) repair and SUMOylation pathways. Nuclear mitotic apparatus protein (NuMA) was identified as one of nIGF1R's colocalizing partners. Proximity ligation assay (PLA) revealed different levels of p53-binding protein 1 (53BP1)-NuMA colocalization between IGF1R-positive (R+) and IGF1R-negative (R−) mouse embryonic fibroblasts following exposure to ionizing radiation (IR). 53BP1 was retained by NuMA in the R− cells during IR-induced DNA damage. By contrast, the level of NuMA-53BP1 was markedly lower in R+ cells compared with R− cells. The present data suggested a regulatory role of nIGF1R in 53BP1-dependent DSB repair through its interaction with NuMA. Bright-field PLA analysis on a paraffin-embedded tissue microarray from patients with colorectal cancer revealed a significant association between increased nuclear colocalizing signals of NuMA-53BP1 and a shorter overall survival. These results indicate that nIGF1R plays a role in facilitating 53BP1-dependent DDR by regulating the NuMA-53BP1 interaction, which in turn might affect the clinical outcome of patients with colorectal cancer.

Background: B3GNT6 encodes the core 3 synthase in O-glycan biosynthesis. It is commonly expressed in the GI tract, while its clinical significance in colorectal cancer remains largely unknown.Methods: We gathered mRNA transcriptomic sequencing data from 3 Gene Expression Omnibus (GEO) datasets (GSE37182, GSE39582, GSE103512) and The Cancer Genome Atlas (TCGA) to compare the B3GNT6 mRNA level between colorectal cancer tissues and normal tissues and to evaluate its value as a prognostic marker. We further validated this in protein level using online database Human Protein Atlas and with immunohistochemical staining of B3GNT6 with our own cohort. Results: B3GNT6 expression was downregulated in colorectal cancer tissue compared with that in normal tissue in both mRNA and in protein level. Downregulation of B3GNT6 was associated with poor overall survival of colorectal cancer in GSE39582 and in TCGA database. Low B3GNT6 mRNA level was significantly associated with chromosome stable (CIN negative) and KRAS mutated group colorectal cancer patient. GSEA revealed that low B3GNT6 level in colorectal cancer is associated with upregulated proteasome activity.Conclusions: Downregulated B3GNT6 was correlated with poor overall survival of colorectal cancer patients. B3GNT6 could be used as a good prognostic marker in colorectal cancer.

We conducted this meta-analysis to explore the association between passive smoking and the risk of colorectal cancer. A literature search of online databases, including MEDLINE, EMBASE, the Cochrane Library, and Web of Science was performed up to June 30, 2015. A fixed-effects meta-analysis using Stata 12.0 was carried out to estimate the relative risks (RRs) and 95% confidence intervals (CIs) for the associations. Eleven articles, including 6 case-control studies and 6 cohort studies, were included in our analysis according to inclusion and exclusion criteria. The pooled RR of all studies showed a statistically significant association between passive smoking and colorectal cancer (RR = 1.14; 95% CI = 1.05-1.24). Results of subgroup analysis showed a positive association between passive smoking and rectal cancer ((RR = 1.33; 95% CI = 1.15-1.53) and that male passive smokers were at greater risks of colorectal cancer (RR = 1.73; 95% CI = 1.37-2.19) than females. Results suggested that passive smoking is associated with an increased risk of colorectal cancer.