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Background. Although multiple types of cancers demonstrated favorable outcome after immunotherapy of PD-1/PD-L1 blockade, the specific regulatory mechanism of PD genes in gastric cancer (GC) remains largely unknown. Materials and Methods. Expression of RNA, copy number variants, and clinical parameters of GC individuals from TCGA were analyzed. Coexpressed genes for PD-1, PD-L1, and PD-L2 were selected by correlation analysis and confirmed by STRING. Gene Ontology and KEGG pathway analyses were performed by clusterProfiler. The influence of PD-1/PD-L1/PD-L2 on immune cell infiltration was investigated by MCP-counter. Results. PD-L2 demonstrated significant relation with clinical stage of GC (P = 0.043). Survival analysis showed that PD-1 expression was correlated with better prognosis of GC patients (HR = 0.70 , P = 0.031), but PD-L2 expression was related with worse survival (HR = 1.42 , P = 0.032). Mutation of PIK3CA could alter the level of PD-1, PD-L1, and PD-L2 (P < 0.001), and TP53 mutation demonstrated significant correlation with PD-L1 (P = 0.015) and PD-L2 (P = 0.014) expression. Enrichment analysis of PD-1/PD-L1/PD-L2 coexpressed genes indicated a biological process of mononuclear cell proliferation, leukocyte cell-cell adhesion, and lymphocyte activation as well as KEGG pathways including cell differentiation of Th1 and Th2, cell differentiation of Th17, and hematopoietic cell landscape. As for immune infiltration analysis, PD-1 was mainly related with cytotoxic lymphocytes and endothelial cells; PD-L1 were associated with monocytic lineage; PD-L2 showed significant correlation with myeloid dendritic cells. Conclusion. PD-1 expression showed association with better prognosis of GC, and PD-L2 expression was related with worse survival. Mutations of PIK3CA and TP53 significantly correlated with PD-1/PD-L1/PD-L2 axis. PD-1/PD-L1/PD-L2 coexpressed genes demonstrated enrichment in mononuclear cell proliferation, leukocyte cell-cell adhesion, and lymphocyte activation as well as KEGG pathways including cell differentiation of Th1, Th2, and Th17. [ABSTRACT FROM AUTHOR]

Background: Competitive endogenous RNA (ceRNA) regulation suggested complex network of all transcript RNAs including long noncoding RNAs (lncRNAs), which can act as natural miRNA sponges to inhibit miRNA functions and modulate mRNA expression. Until now, the specific ceRNA regulatory mechanism of lncRNA-miRNA-mRNA in colorectal cancer (CRC) still remains unclear.Materials and Methods: RNA sequencing data of 478 colon adenocarcinoma cases and 41 controls as well as 166 rectum adenocarcinoma cases and 10 controls were obtained from The Cancer Genome Atlas (TCGA) to investigate the significant changes of lncRNAs, miRNAs and mRNAs in colorectal carcinogenesis. The target lncRNAs and mRNAs of miRNAs were predicted by miRWalk. Functional and enrichment analyses were conducted by DAVID database. The lncRNA-miRNA-mRNA interaction network was constructed using Cytoscape.Results: We constructed ceRNA regulatory networks including 22 up-regulated lncRNAs, 12 down-regulated miRNAs and 122 up-regulated mRNAs, as well as 8 down-regulated lncRNAs, 43 up-regulated miRNAs and 139 down-regulated mRNAs. The GO enrichment showed that up-regulated genes mainly enriched in biological process including organic anion transport, collagen catabolic process, wound healing, Wnt receptor signalling and in pathways of tyrosine metabolism, taurine and hypotaurine metabolism, melanogenesis and phenylalanine metabolism. For down-regulated genes, significant enrichment was found in biological process of metal ion homeostasis, transmission of nerve impulse, cell-cell signalling, transmembrane transport and in pathways of ABC transporters, neuroactive ligand-receptor interaction, retinol metabolism, nitrogen metabolism and steroid hormone biosynthesis.Conclusion: We identified significantly altered lncRNAs, miRNAs and mRNAs in colorectal carcinogenesis, which might serve as potential biomarkers for tumorigenesis of CRC. In addition, the ceRNA regulatory network of lncRNA-miRNA-mRNA was constructed, which would elucidate novel molecular mechanisms involved in initiation and progression of CRC, thus providing promising clues for clinical diagnosis and therapy. [ABSTRACT FROM AUTHOR]

Background: Liver metastasis is a major cause of mortality in colorectal cancer (CRC). Epigenetic alternations could serve as biomarkers for cancer diagnosis and prognosis. In this study, we analyzed microarray data in order to identify core genes and pathways which contribute to liver metastasis in CRC under epigenetic regulations.Materials and Methods: Data of miRNAs (GSE35834, GSE81582), DNA methylation (GSE90709, GSE77955), and mRNA microarrays (GSE68468, GSE81558) were downloaded from GEO database. Differentially expressed genes (DEGs), differentially expressed miRNAs (DEMs), and differentially methylated genes (DMGs) were obtained by GEO2R. The target genes of DEMs were predicted by miRWalk. Functional and enrichment analyses were conducted by DAVID database. Protein-protein interaction (PPI) network was constructed in STRING and visualized using Cytoscape.Results: In liver metastasis, miR-143-3p, miR-10b-5p, miR-21-5p, and miR-518f-5p were down-regulated, while miR-122-5p, miR-885-5p, miR-210-3p, miR-130b-5p, miR-1275, miR-139-5p, miR-139-3p, and miR-1290 were up-regulated compared with primary CRC. DEGs targeted by altered miRNAs were enriched in pathways including complement, PPAR signaling, ECM-receptor interaction, spliceosome, and focal adhesion. In addition, aberrant DNA methylation-regulated genes showed enrichment in pathways of amino acid metabolism, calcium signaling, TGF-beta signaling, cell cycle, spliceosome, and Wnt signaling.Conclusion: Our study identified a series of differentially expressed genes which are associated with epigenetic alternations of miRNAs and DNA methylation in colorectal liver metastasis. Up-regulated genes of SLC10A1, MAPT, SHANK2, PTH1R, and C2, as well as down-regulated genes of CAB39, CFLAR, CTSC, THBS1, and TRAPPC3 were associated with both miRNA and DNA methylation, which might become promising biomarker of colorectal liver metastasis in future. [ABSTRACT FROM AUTHOR]

Background: MicroRNAs (miRNAs) are small, non-coding RNAs of endogenous origin, they have been increasingly shown to have aberrant expression in many tumor types. miR-203 has not been comprehensively investigated in gastric and colorectal cancers.Methods: Total RNA was extracted from tissues of 212 patients with gastric or colorectal cancer as well as from seven gastric and colorectal cell lines. We determined the expression of miR-203 by real-time PCR and calculated using the 2-ΔΔCt method. Then, we assessed miR-203 expression and clinicopathologic characteristics. Finally, we studied the effect of miR-203 on cell proliferation in SGC-7901 cells by MTT.Results: miR-203 has significantly low expression in colorectal cancer tissues (p < 0.001, paired t test) and cancer cell lines compared to non-tumor counterparts. Moreover, low expression of miR-203 was correlated with tumor size (p = 0.015, non-parametric test) and pT stage (p = 0.005) in colorectal cancer. Although expression of miR-203 was not significant in gastric cancer tissues (p = 0.124), interestingly, miR-203 was correlated with tumor size (p = 0.023), macroscopic type (p = 0.045), and pT stage (p = 0.013). Furthermore, we found miR-203 can inhibit the cell proliferation in SGC-7901 cells.Conclusion: miR-203 may be related to the proliferation and invasion of gastric and colorectal cancers. [ABSTRACT FROM AUTHOR]

Background: MicroRNAs are endogenous small noncoding RNAs that aberrantly expressed in various carcinomas. MiR-148a and miR-152, which have the same "seed region", have not been comprehensively investigated in gastrointestinal cancers.Methods: Total RNA was extracted from the tissues of 101 patients with gastric cancer and 101 patients with colorectal cancer as well as their matched nontumor adjacent tissues. After polyadenylation and reverse transcription, the expression of miR-148a and miR-152 was determined using quantitative real-time polymerase chain reaction. The protein level of cholecystokinin B receptor, which might be the target gene of miR-148a and miR-152, was analyzed by Western blot in 40 patients with gastric cancer.Results: Expression levels of miR-148a and miR-152 in human gastric (p < 0.001 and p = 0.038, respectively, t-test) and colorectal (all p < 0.001) cancers were significantly lower than that in their matched nontumor adjacent tissues. Moreover, their low expression was also found in several gastrointestinal cancer cell lines compared with normal gastric epithelial cell line and normal colorectal tissue, respectively. A strong correlation was found between the expression of miR-148a and miR-152 (all p < 0.001, Pearson's correlation). Furthermore, low expression of miR-152 was correlated with increased tumor size (p = 0.023 and 0.004, respectively, Mann-Whitney U test) and advanced pT stage (p = 0.018 and 0.002, respectively) in gastrointestinal cancers. Low expression of miR-148a was also correlated with increased tumor size (p = 0.045 and 0.018, respectively) in gastrointestinal cancers, but only correlated with advanced pT stage (p = 0.023) in colorectal cancer. We also found the expression of miR-148a (p < 0.001, chi-square test) and miR-152 (p = 0.002) inversely correlated with cholecystokinin B receptor protein in gastric cancer.Conclusion: MiR-148a and miR-152 may be involved in the carcinogenesis of gastrointestinal cancers and might be potential biomarkers in these cancers. [ABSTRACT FROM AUTHOR]