BackgroundWith more than 600,000 mortalities each year, colorectal cancer (CRC) is the third most commonly diagnosed type of cancer worldwide. Recently, mechanisms involving noncoding RNAs have been implicated in the development of CRC.MethodsWe examined expression levels of lncRNA CRNDE and miR-181a-5p in 64 cases of CRC tissues and cell lines by qRT-PCR. Gain-of-function and loss-of-function assays were performed to examine the effect of CRNDE and miR-181a-5p on proliferation and chemoresistance of CRC cells. Using fluorescence reporter and western blot assays, we also explored the possible mechanisms of CRNDE in CRC cells.ResultsIn this study, we found that the expression levels of the CRNDE were upregulated in CRC clinical tissue samples. We identified microRNA miR-181a-5p as an inhibitory target of CRNDE. Both CRNDE knockdown and miR-181a-5p overexpression in CRC cell lines led to inhibited cell proliferation and reduced chemoresistance. We also determined that β-catenin and TCF4 were inhibitory targets of miR-181a-5p, and that Wnt/β-catenin signaling was inhibited by both CRNDE knockdown and miR-181a-5p overexpression. Significantly, we found that the repression of cell proliferation, the reduction of chemoresistance, and the inhibition of Wnt/β-catenin signaling induced by CRNDE knockdown would require the increased expression of miR-181a-5p.ConclusionsOur study demonstrated that the lncRNA CRNDE could regulate the progression and chemoresistance of CRC via modulating the expression levels of miR-181a-5p and the activity of Wnt/β-catenin signaling.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-017-0583-1) contains supplementary material, which is available to authorized users.

Super-enhancers are important for controlling and defining the expression of cell-specific genes. With research on human disease and biological processes, human H3K27ac ChIP-seq datasets are accumulating rapidly, creating the urgent need to collect and process these data comprehensively and efficiently. More importantly, many studies showed that super-enhancer-associated single nucleotide polymorphisms (SNPs) and transcription factors (TFs) strongly influence human disease and biological processes. Here, we developed a comprehensive human super-enhancer database (SEdb, http://www.licpathway.net/sedb) that aimed to provide a large number of available resources on human super-enhancers. The database was annotated with potential functions of super-enhancers in the gene regulation. The current version of SEdb documented a total of 331 601 super-enhancers from 542 samples. Especially, unlike existing super-enhancer databases, we manually curated and classified 410 available H3K27ac samples from >2000 ChIP-seq samples from NCBI GEO/SRA. Furthermore, SEdb provides detailed genetic and epigenetic annotation information on super-enhancers. Information includes common SNPs, motif changes, expression quantitative trait locus (eQTL), risk SNPs, transcription factor binding sites (TFBSs), CRISPR/Cas9 target sites and Dnase I hypersensitivity sites (DHSs) for in-depth analyses of super-enhancers. SEdb will help elucidate super-enhancer-related functions and find potential biological effects.

Esophageal cancer (EC) is a type of aggressive cancer without clinically relevant molecular subtypes, hindering the development of effective strategies for treatment. To define molecular subtypes of EC, we perform mass spectrometry-based proteomic and phosphoproteomics profiling of EC tumors and adjacent non-tumor tissues, revealing a catalog of proteins and phosphosites that are dysregulated in ECs. The EC cohort is stratified into two molecular subtypes—S1 and S2—based on proteomic analysis, with the S2 subtype characterized by the upregulation of spliceosomal and ribosomal proteins, and being more aggressive. Moreover, we identify a subtype signature composed of ELOA and SCAF4, and construct a subtype diagnostic and prognostic model. Potential drugs are predicted for treating patients of S2 subtype, and three candidate drugs are validated to inhibit EC. Taken together, our proteomic analysis define molecular subtypes of EC, thus providing a potential therapeutic outlook for improving disease outcomes in patients with EC.

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BackgroundThe importance of individual microRNAs (miRNAs) in tumor has been established in different cancers. However, their association with tumor chemoresistance has not been fully understood. Previously, we found two novel MDR-associated microRNAs (miRNAs). In this report, we investigated the combined effects of miRNA gene cluster in chemoresistance of breast cancer.MethodsThis study was performed in two different breast cancer cell lines (MCF-7 and MCF-7/ADR). The levels of miRNAs and mRNA expression were determined by using Quantitative Real-Time PCR. Western blotting was used to detect the levels of protein molecules. Cell viability was assessed by MTS assay. Bioinformatics and Luciferase reporter assay was performed to examine miRNA binding to the 3′-UTR of target genes.ResultsThe miR-302S family including miR-302a, miR-302b, miR-302c, and miR-302d was significantly down-regulated in P-glycoprotein (P-gp)-overexpressing MCF-7/ADR cells. Overexpression of miR-302 increased intracellular accumulation of ADR and sensitized breast cancer cells to ADR. Most importantly, miR-302S produced stronger effects than each individual member alone. The four miRNAs cooperatively downregulate P-gp expression in regulating drug sensitivity. However, our results showed that the suppression of P-gp expression by miR-302 is not through typical miRNA-mediated mRNA degradation but at the level of protein and transcription. Further studies identified MAP/ERK kinase kinase 1 (MEKK1) as a direct and functional target of miR-302. miR-302 showed combinatorial effects on MKEE1 repression and MEKK1-mediated ERK pathway. The suppression of P-gp by miR-302 was reversed by MEKK1 overexpression.ConclusionOur results indicate that miR-302 cooperatively sensitizes breast cancer cells to adriamycin via suppressing P-glycoprotein by targeting MEKK1 of ERK pathway. miR-302 gene cluster may be a potential target for reversing P-gp-mediated chemoresistance in breast cancer.