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BACKGROUND: Recently, extensive researches have explored the potential biomarker roles of microRNA-210 (miR-210) in non-small cell lung cancer (NSCLC). Inconsistent results, however, have prevented its widespread use in diagnosis. In the present study, we aimed to clarify the biomarker roles of miR-210 in NSCLC through a comprehensive meta-analysis and an integrative bioinformatics analysis. METHODS: Relevant studies were searched from several literature databases and included for qualitative synthesis based on the bivariate random-effects meta-analysis model. At the same time, we combined several bioinformatics analysis methods for exploring the potential mechanism of miR-210 involved in NSCLC. RESULTS: Overall, miR-210 yieled the area under curve (AUC) of 0.80 (95%CI: 0.76-0.83) with sensitivity of 0.66 (0.59-0.73) and specificity of 0.79 (0.74-0.84) for being applied to discriminate NSCLC cases from normal individuals. Besides, the combination biomarkers based on miR-210 had a higher diagnostic value accuracy than individual miR-210, with the sensitivity of 0.76 (0.72-0.79), specificity of 0.88 (0.86-0.90) and AUC of 0.91 (0.88-0.93). Through bioinformatics analysis including gene ontology, pathway enrichment, protein-protein interaction networks construction and analysis, crucial genes, pathways, modules and functional terms were identified, which were proved highly involved in the initiation and development of NSCLC. CONCLUSIONS: In summary, the current study suggests that miR-210 may function as a potential biomarker in NSCLC detection. Particularly, combination biomarkers may be more comprehensive indicators than single miR-210. However, the clinical diagnostic utilization and additional exploration still remain to be further tested and verified through more future studies.

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Background: Previous studies demonstrated that microRNA-92a (miR-92a) may serve as a novel promising biomarker in colorectal cancer (CRC) patients. However, a comprehensive analysis of the contribution of miR-92a in CRC is lacking. We aimed to systematically summarize the diagnostic and prognostic values of miR-92a in CRC. Methods: The diagnostic and prognostic roles of individual miR-92a and the combination biomarkers based on miR-92a were evaluated through comprehensive meta-analyses. Meanwhile, the function and potential mechanisms of miR-92a were assessed by an integrative bioinformatics analysis. Results: According to the results, we found that miR-92a yielded a pooled area under ROC curve (AUC) of 0.82 (sensitivity: 76%, specificity: 75%) in discriminating CRC from controls. Notably, the combination biomarkers based on miR-92a increased the diagnostic performance, yielding an AUC of 0.91, with a sensitivity of 83% and a specificity of 87%. For the prognostic meta-analysis, patients with higher expression of miR-92a had significant shorter overall survival (pooled HR: 2.30; 95% CI: 1.03-5.12). In addition, the regulated genes of miR-92a were retrieved and enriched through gene ontology and pathway analysis, indicating their correlations with the initiation and progression of CRC. Furthermore, protein-protein interaction network was set up with miR-92a targets and screened for hub nodes and significant modules, which were confirmed strongly involved in the occurrence and development of CRC again. Conclusions: Current evidences suggest miR-92a is a promising biomarker for early detection and prognosis of CRC while miRNA combination biomarkers may be considered as the right way for clinical practice. However, more prospective studies are required to highlight the theoretical strengths.

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Currently, neoadjuvant chemoradiotherapy (CRT) followed by radical surgery is the standard of care for locally advanced rectal cancer. However, to the best of our knowledge, there are no effective biomarkers for predicting patients who may benefit from neoadjuvant treatment. The aim of the current study was to screen potential crucial genes and pathways associated with the response to CRT in rectal cancer, and provide valid biological information to assist further investigation of CRT optimization. In the current study, differentially expressed (DE) genes were identified from the tumor samples of responders and non-responders to neoadjuvant CRT in the GSE35452 gene expression profile. Seven hub genes and one significant module were identified from the protein-protein interaction (PPI) network. Functional enrichment analysis of all the DE genes and the hub genes, retrieved from PPI network analysis, revealed their associations with CRT response. Genes were identified that may be used to discriminate patients who would or would not clinically benefit from neoadjuvant CRT. Several important pathways enriched by the DE genes, hub genes and selected module were identified, and revealed to be closely associated with radiation response, including excision repair, homologous recombination, Ras signaling pathway, the forkhead box O signaling pathway, focal adhesion and the Wnt signaling pathway. In conclusion, the current study demonstrated that the identified gene signatures and pathways may be used as molecular biomarkers for predicting CRT response. Furthermore, combinations of these biomarkers may be helpful for optimizing CRT treatment and promoting understanding of the molecular basis of response differences; this needs to be confirmed by further experiments.

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BACKGROUND: Recently, accumulating evidences have revealed that microRNA-106 (miR-106) may serve as a non-invasive and cost-effective biomarker in gastric cancer (GC) detection. However, inconsistent results have prevented its application to clinical practice. METHODS: As a result of this, a comprehensive meta-analysis was conducted to evaluate the diagnostic performance of miR-106 alone and miR-106-related combination markers for GC detection. Meanwhile, an integrative bioinformatics analysis was performed to explore the function of miR-106 at the systems biology level. RESULTS: The results in our work showed that sensitivity of 0.71 (95% CI 0.65-0.76) and specificity of 0.82 (0.72-0.88), with the under area AUC (area under the curve) value of 0.80 (0.76-0.83) for miR-106 alone. Prospectively, miR-106-related combination markers improved the combined sensitivity, specificity and AUC, describing the discriminatory ability of 0.78 (0.65-0.87), 0.83 (0.77-0.89) and 0.88 (0.85-0.90) in the present analysis. Furthermore, targets of miR-106 were obtained and enriched by gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis, revealing their associations with the occurrence and development of GC. Hub genes and significant modules were identified from the protein-protein interaction networks constructed by miR-106 targets and found closely associated with the initiation and progression of GC again. CONCLUSIONS: Our comprehensive and integrative analysis revealed that miR-106 may be suitable as a diagnostic biomarker for GC while microRNA combination biomarkers may provide a new alternative for clinical application. However, it is necessary to conduct large-scale population-based studies and biological experiments to further investigate the diagnostic value of miR-106.

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INTRODUCTION: More and more findings have demonstrated that right-sided colon cancers (RCC) and left-sided colon cancers (LCC) are distinct clinical and biological entities and suggest that they should be treated as different diseases. However, the reasons why RCC and LCC harbor different clinical and biological features remain unclear. MATERIALS AND METHODS: To identify the genomic expression differences between RCC and LCC and uncover the mechanisms underlying these differences, we chose the gene expression profiles of GSE14333 from the Gene Expression Omnibus (GEO) database as an object of study. Then, a systematic and integrative bioinformatics analysis was performed to research the possible mechanism of the differentially expressed (DE) genes from the Gene Expression Omnibus dataset including gene ontology (GO) analysis, pathway enrichment analysis, protein-protein interaction (PPI) network construction, and module analysis. Totally, we extracted 3,793 DE genes from samples of colon cancer including 1,961 genes upregulated in RCC and 1,832 genes upregulated in LCC from the selected dataset. RESULTS: The results of GO and pathway enrichment analysis indicated that RCC and LCC could predispose to different pathways regulated by different genes. Based on the PPI network, PCNA, TP53, HSP90AA1, CSNK2A1, UBB, LRRK2, ABL1, PRKACA, CAV1, and JUN were identified as the key hub genes. Also, significant modules were screened from the PPI network. CONCLUSION: In conclusion, the present study indicated that the identified genes and pathways may promote new insights into the underlying molecular mechanisms contributing to the difference between RCC and LCC and might be used as specific therapeutic targets and prognostic markers for the personalized treatment of RCC and LCC.

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In this article, we review the origin and therapeutic perspectives of bladder cancer stem cells (BCSCs), which are integral to the initiation, high recurrence and chemoresistance of bladder cancer. BCSCs are heterogenous and originate from multiple cell types, including urothelial stem cells and differentiated cell types, including basal, intermediate stratum and umbrella cells. Cell surface markers, including CD44, CD67LR, EMA, ALDH1A1 and BCMab1, are used to identify and isolate BCSCs. The Hedgehog, Notch, Wnt and JAK-STAT signaling pathways play key roles in maintaining the stemness, self-renewal and proliferative potential of BCSCs. High expression of ABC transporters, acetaldehyde dehydrogenase, antioxidants and apoptosis resistance proteins in BCSCs play a critical role in chemoresistance. Consequently, a greater understanding of the biology of BCSCs will be important for identifying effective therapeutic targets to improve clinical outcomes for bladder cancer patients.

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Purpose: Bladder cancer is one of the most common urinary malignancies worldwide characterized by a high rate of recurrence and no targeted therapy method. Bladder cancer stem cells (BCSCs) play a crucial role in tumor initiation, metastasis, and drug resistance. However, the regulatory signaling and self-renewal mechanisms of BCSCs remain largely unknown. Here, we identified a novel signal, the KMT1A-GATA3-STAT3 circuit, which promoted the self-renewal and tumorigenicity of human BCSCs.Experimental Design: In a discovery step, human BCSCs and bladder cancer non-stem cells (BCNSCs) isolated from primary bladder cancer samples #1 and #2, and the bladder cancer cell line EJ were analyzed by transcriptome microarray. In a validation step, 10 paired bladder cancer and normal tissues, different tumor cell lines, the public microarray datasets of human bladder cancer, and The Cancer Genome Atlas database were applied for the verification of gene expression.Results: KMT1A was highly expressed and responsible for the increase of tri-methylating lysine 9 of histone H3 (H3K9me3) modification in BCSCs compared with either BCNSCs or normal bladder tissue. GATA3 bound to the -1710∼-1530 region of STAT3 promoter and repressed its transcription. H3K9me3 modification on the -1351∼-1172bp region of the GATA3 promoter mediated by KMT1A repressed the transcription of GATA3 and upregulated the expression of STAT3. In addition, the activated STAT3 triggered self-renewal of BCSCs. Furthermore, depletion of KMT1A or STAT3 abrogated the formation of BCSC tumorspheres and xenograft tumors.Conclusions: KMT1A positively regulated the self-renewal and tumorigenicity of human BCSCs via KMT1A-GATA3-STAT3 circuit, in which KMT1A could be a promising target for bladder cancer therapy. Clin Cancer Res; 23(21); 6673-85. ©2017 AACR.

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Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide and there is an urgent need to identify effective pharmacological strategies to treat NAFLD. For this purpose, in the present study, we examined the the possible molecular mechanisms responsible for the effects of MgIG and the protective effects of MgIG in a model of NAFLD. The human hepatic L02 cell line and oleic acid were employed to establish an in vitro model of NAFLD. The CCK-8 assay, Hoechst 33258 staining and Annexin V-PI staining were performed in order to evaluate cell viability and apoptosis. Oil red O staining was used to detect lipid accumulation within the L02 cells. We found that MgIG significantly inhibited lipid accumulation and protected the L02 cells against lipid accumulation-induced apoptosis. Key molecules involved in unfolded protein response (UPR) signaling were upregulated in lipid-overloaded hepatic cells whereas MgIG suppressed the activation of the UPR. Furthermore, MgIG significantly inhibited the expression of the downstream inflammatory cytokines which had been induced by lipid accumulation. Taken together, these findings suggest that the activation of UPR signaling induces the expression of inflammatory cytokines through the activation of nuclear factor-κB (NF-κB) in lipid-overloaded hepatic cells. In addition, MgIG may suppress the activation of UPR signaling thereby protecting hepatic cells from NAFLD­induced injury.

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Hepatocellular carcinoma (HCC) and colorectal cancer (CRC) are among the most common cancers across the world. Particularly, a large number of patients with CRC also have liver metastasis. Currently, there are just a few targeted drugs against these two kinds of tumors which can only benefit a very small population of patients. Therefore, the need of more effective therapeutic drugs or strategies for these two types of cancers is urgent. PS341 (Bortezomib) is the first proteasome inhibitor drug which has been approved in clinical treatment for multiple myeloma. Here we demonstrated that PS341 negatively regulated HCC and CRC both in vitro and in vivo, including the inhibition of cell proliferation, epithelial-mesenchymal transition (EMT), the expression of stemness-related genes, cell migration and invasiveness. Mechanically, PS341 upregulated the expression of FOXO3, which inhibited the transcriptional activation of CTNNB1. The downregualtion of CTNNB1 led to apoptosis, cell cycle arrest, and the inhibition of migration, invasion, self-renewal and tumor formation of these two cancer types. In sum, our findings shed light on the PS341 mediated targeted therapy against both HCC and CRC in the future.

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