Gut microbial dysbiosis contributes to the development of colorectal cancer (CRC). Here we catalogue the microbial communities in human gut mucosae at different stages of colorectal tumorigenesis. We analyse the gut mucosal microbiome of 47 paired samples of adenoma and adenoma-adjacent mucosae, 52 paired samples of carcinoma and carcinoma-adjacent mucosae and 61 healthy controls. Probabilistic partitioning of relative abundance profiles reveals that a metacommunity predominated by members of the oral microbiome is primarily associated with CRC. Analysis of paired samples shows differences in community configurations between lesions and the adjacent mucosae. Correlations of bacterial taxa indicate early signs of dysbiosis in adenoma, and co-exclusive relationships are subsequently more common in cancer. We validate these alterations in CRC-associated microbiome by comparison with two previously published data sets. Our results suggest that a taxonomically defined microbial consortium is implicated in the development of CRC.

BackgroundThe role of cancer cell FOXP3 in tumorigenesis is conflicting. We aimed to study FOXP3 expression and regulation, function and clinical implication in human non-small cell lung cancer (NSCLC).MethodsOne hundred and six patients with histologically-confirmed NSCLC who underwent surgery were recruited for the study. Tumor samples and NSCLC cell lines were used to examine FOXP3 and its related molecules. Various cell functions related to tumorigenesis were performed. In vivo mouse tumor xenograft was used to confirm the in vitro results.ResultsNSCLC patients with the high level of FOXP3 had a significant decrease in overall survival and recurrence-free survival. FOXP3 overexpression significantly induced cell proliferation, migration, and invasion, whereas its inhibition impaired its oncogenic function. In vivo studies confirmed that FOXP3 promoted tumor growth and metastasis. The ectopic expression of FOXP3 induced epithelial–mesenchymal transition (EMT) with downregulation of E-cadherin and upregulation of N-cadherin, vimentin, snail, slug, and MMP9. The oncogenic effects by FOXP3 could be attributed to FOX3-mediated activation of Wnt/β-catenin signaling, as FOXP3 increased luciferase activity of Topflash reporter and upregulated Wnt signaling target genes including c-Myc and Cyclin D1 in NSCLC cells. Co-immunoprecipitation results further indicated that FOXP3 could physically interacted with β-catenin and TCF4 to enhance the functions of β-catenin and TCF4, inducing transcription of Wnt target genes to promote cell proliferation, invasion and EMT induction.ConclusionsFOXP3 can act as a co-activator to facilitate the Wnt-b-catenin signaling pathway, inducing EMT and tumor growth and metastasis in NSCLC.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-017-0700-1) contains supplementary material, which is available to authorized users.

Using microRNA (miRNA) expression array, we identified that miR-7 was deregulated in colorectal cancer (CRC). We studied the biological role and molecular target of miR-7 in CRC. miR-7 was downregulated in six out of seven colon cancer cell lines. Ectopic expression of miR-7 suppressed colon cancer cell proliferation (Po0.05), induced apoptosis (Po0.05) and caused cell-cycle arrest in G1 phase (Po0.05). The tumor suppressive function of miR-7 was further confirmed in nude mice (Po0.05). The 3 0 -untranslated region (3 0 UTR) of Yin Yang 1 (YY1) mRNA contains an evolutionarily conserved miR-7 binding site using in silico searches, luciferase reporter assay and western blot analysis confirmed that miR-7 directly bound to YY1 3 0 UTR to negatively regulate the protein expression of YY1 in colon cancer cell lines HCT116 and LOVO. Intriguingly, knock-down of YY1 in three colon cancer cell lines (HCT116, LOVO and DLD1) consistently suppressed cell proliferation (Po0.01) and induced apoptosis (Po0.01), indicating the opposite functions of miR-7 and YY1 in CRC. Consistent with these data, ectopic expression of YY1 promoted cell growth by increasing proliferation (Po0.01) and suppressing apoptosis (Po0.001). The tumorigenic ability of YY1 was further confirmed in vivo in xenograft-nude mouse model (Po0.01). In addition, pathway analyses revealed that the oncogenic effect by YY1 was associated with inhibiting p53 and modulating its downstream effectors p15, caspase cascades and C-Jun, and activating Wnt signaling pathway through activating b-catenin, anti-apoptotic survivin and fibroblast growth factor 4. Furthermore, multivariate analysis revealed that patients with YY1 protein high expression had a significant decrease in overall survival, and Kaplan-Meier survival curves showed that these patients had significantly shorter survival than others (Po0.0001). In conclusion, MiR-7 is a novel miRNA with tumor suppressive function in colon cancer by targeting oncogenic YY1. YY1 promotes colon cancer growth through inhibiting p53 and promoting Wnt signaling pathways and serves as an independent prognostic biomarker for CRC patients.

Although surgery remains the mainstay of curative treatment for colorectal cancer (CRC), many patients still have high chance to experience disease relapse. It is therefore imperative to identify prognostic markers that can help predict the clinical outcomes of CRC. Aberrant microRNA expression holds great potential as diagnostic and prognostic biomarker for CRC. Here we aimed to investigate clinical potential of miR-34a-5p as a prognostic marker for CRC recurrence and its functional significance. First, we validated that miR-34a-5p was downregulated in CRC tumour tissues (P<0.05). The expression level of tissue miR-34a-5p was then evaluated in two independent cohorts of 268 CRC patients. miR-34a-5p expression was positively correlated with disease-free survival in two independent cohorts (cohort I: n=205, P<0.001; cohort II: n=63, P=0.006). Moreover, the expression of miR-34a-5p was an independent prognostic factor for CRC recurrence by multivariate analysis (P<0.001 for cohort I, P=0.007 for cohort II). Ectopic expression of miR-34a-5p in p53 wild-type colon cancer cell HCT116 significantly inhibited cell growth, migration, invasion and metastasis. miR-34a-5p induced cell apoptosis, cell cycle arrest at G1 phase and p53 transcription activity in HCT116 cells, but not in the HCT116 p53 knockout (p53(-/-)) cells. miR-34a-5p significantly suppressed the HCT116 growth in vivo, whereas it showed no effect on the HCT116 p53(-/-) xenograft, indicating that the growth-inhibiting effect by miR-34a-5p was dependent on p53. In addition, the expression level of miR-34a-5p in patients with p53-positive expression was higher than that in patients with p53-negative expression (P<0.01). In conclusion, miR-34a-5p inhibits recurrence of CRC through inhibiting cell growth, migration and invasion, inducing cell apoptosis and cell cycle arrest in a p53-dependent manner.