BackgroundMicroRNAs (miRNAs) are involved in cancer development and progression, acting as tumor suppressors or oncogenes. Our previous studies have revealed that miR-148a and miR-152 are significantly down-regulated in gastrointestinal cancers. Interestingly, miR-148b has the same "seed sequences" as miR-148a and miR-152. Although aberrant expression of miR-148b has been observed in several types of cancer, its pathophysiologic role and relevance to tumorigenesis are still largely unknown. The purpose of this study was to elucidate the molecular mechanisms by which miR-148b acts as a tumor suppressor in gastric cancer.ResultsWe showed significant down-regulation of miR-148b in 106 gastric cancer tissues and four gastric cancer cell lines, compared with their non-tumor counterparts by real-time RT-PCR. In situ hybridization of ten cases confirmed an overt decrease in the level of miR-148b in gastric cancer tissues. Moreover, the expression of miR-148b was demonstrated to be associated with tumor size (P = 0.027) by a Mann-Whitney U test. We also found that miR-148b could inhibit cell proliferation in vitro by MTT assay, growth curves and an anchorage-independent growth assay in MGC-803, SGC-7901, BGC-823 and AGS cells. An experiment in nude mice revealed that miR-148b could suppress tumorigenicity in vivo. Using a luciferase activity assay and western blot, CCKBR was identified as a target of miR-148b in cells. Moreover, an obvious inverse correlation was observed between the expression of CCKBR protein and miR-148b in 49 pairs of tissues (P = 0.002, Spearman's correlation).ConclusionsThese findings provide important evidence that miR-148b targets CCKBR and is significant in suppressing gastric cancer cell growth. Maybe miR-148b would become a potential biomarker and therapeutic target against gastric cancer.

MiR-148a and miR-152 may be involved in the carcinogenesis of gastrointestinal cancers and might be potential biomarkers in these cancers.

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The seventh edition of TNM staging system on TDs satisfactorily predicts patients' outcome for those without LNM. Patients who categorized as T3N2bM0TD (+) and T4N2bM0TD (-/+) should be reclassified as stage IV. Number of TDs was not an independent prognostic parameter in the TNM staging system.

The existence of microvascular invasion (MVI) formation is one of the most important risk factors predicting poor outcome in hepatocellular carcinoma (HCC) and its mechanism remains largely unknown. Epithelial-Mesenchymal Transition (EMT) has been suggested to be involved in many steps of the invasion-metastasis cascade. To elucidate the possible contribution of EMT to MVI, we initially evaluated the expression of 8 EMT-related transcription factors (TFs) in HCC patients with or without MVI and found that FOXC1 expression was significantly higher in patients with MVI than those without MVI (P < 0.05). Knockdown of FOXC1 expression in HCC cells resulted in a partial conversion of their EMT progresses, mainly regulating the mesenchymal component. Ectopic expression of snail, twist or TGF-β1 could induce expression of FOXC1, but none of the expression of snail, twist, slug or TGF-β was consistently down-regulated in response to FOXC1 silencing, suggesting FOXC1 might operate the downstream of other EMT regulators. In addition, knockdown of FOXC1 expression led to cytoskeleton modification accompanied by decreased ability of cell proliferation, migration, and invasion. Meanwhile, some matrix metalloproteinases (MMPs) and VEGF-A were also simultaneously down-regulated. Together, our findings demonstrate that FOXC1 is one of candidate predictive markers of MVI, and that inhibition of FOXC1 expression can partially reverse EMT program, offering a potential molecular therapeutic target for reducing tumor metastasis in HCC patients.

Abstract. microRNAs (miRNAs) are small, non-coding RNAs of endogenous origin. They have been increasingly shown to have aberrant expression in a number of tumor types. miR-192, -194 and -215 have not been comprehensively investigated using a large number of cases in colorectal cancer (CRC). We extracted total RNA from 107 CRC tissues and three CRC cell lines. Following polyadenylation and reverse transcription, the expression levels of miR-192, -194 and -215 were determined for evaluation of the association between expression levels and clinicopathological characteristics by a quantitative real-time polymerase chain reaction (real-time PCR) method. Finally, we studied the impact of miR-194 on cell proliferation in HCT-116 cells by MTT assay. miR-192, -194 and -215 were significantly downregulated in CRC tissues (all p<0.001, paired t-test) and cancer cell lines (all p<0.05) compared to non-tumor counterparts. Moreover, the expression levels of miR-192, -194 and -215 were demonstrated to be associated with increased tumor sizes (p=0.027, p=0.018, and p=0.027, respectively; Mann-Whitney U test). Also, there were marked correlations among these miRNAs in CRC tissues (all p<0.001, Pearson's regression analysis). Furthermore, we found that the overexpression of miR-194 could significantly inhibit cell proliferation in may be important biological markers as tumor suppressors in the carcinogenesis of CRC.

MicroRNAs (miRNAs) play an important role in the regulation of a variety of cellular processes, including cell growth, differentiation, apoptosis and carcinogenesis. The purpose of this study was to elucidate the molecular mechanisms by which miR-148b acts as a tumor suppressor in colorectal cancer. The expression of miR-148b was significantly downregulated in 96 pairs of human colorectal cancer tissues (p < 0.0001) and three cell lines (p < 0.01) compared with non-tumor adjacent tissues by quantitative real-time PCR. The results of in situ hybridization highlighted that miR-148b was important in the cancer transformation process. Using statistical analysis, we found that the expression level of miR-148b was associated with tumor size (p 5 0.033) in colorectal cancer patients. Moreover, overexpression of miR-148b in HCT-116 and HT-29 cells could inhibit cell proliferation in vitro and suppress tumorigenicity in vivo. Importantly, the result of luciferase activity assay and western blot showed that the cholecystokinin-2 receptor gene (CCK2R) was a target of miR-148b and was downregulated by miR-148b at the translational level. Then, we used siRNA, radioimmunoassay and ELISA to demonstrate that miR-148b might have an effect on cell proliferation by regulating the expression of CCK2R which functioned depending on the gastrin in colorectal cancer. Taken together, our data provides the first evidences that miR-148b acts as a tumor suppressor in colorectal cancer and should be further evaluated as a biomarker and therapeutic tool against colorectal cancer.Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. 1 The CRC incidence and mortality rates in China have increased rapidly in the past several decades. 2 Although the pathogenesis of CRC is well characterized, new molecules that play a role in this process are still being discovered. MicroRNAs (miRNAs) are $22 nucleotide noncoding RNA molecules that regulate a variety of cellular processes, including cell differentiation, cell cycle progression and apoptosis. [3][4][5][6] It has been demonstrated that miRNAs play a significant role in tumorigenesis by downregulating tumor suppressor genes or oncogenes. 7,8 An increasing number of studies have found miRNA related mechanisms in the development of CRC, potential miRNAs as biomarkers in the diagnosis and prognosis of CRC and promising effects with miRNAs in the treatment of cancer at the molecular level. [9][10][11][12]

BackgroundMethylation plays an important role in the etiology and pathogenesis of colorectal cancer (CRC). This study aimed to identify aberrantly methylated-differentially expressed genes (DEGs) and pathways in CRC by comprehensive bioinformatics analysis.MethodsData of gene expression microarrays (GSE68468, GSE44076) and gene methylation microarrays (GSE29490, GSE17648) were downloaded from GEO database. Aberrantly methylated-DEGs were obtained by GEO2R. Functional and enrichment analyses of selected genes were performed using DAVID database. Protein–protein interaction (PPI) network was constructed by STRING and visualized in Cytoscape. MCODE was used for module analysis of the PPI network.ResultsTotally 411 hypomethylation-high expression genes were identified, which were enriched in biological processes of response to wounding or inflammation, cell proliferation and adhesion. Pathway enrichment showed cytokine–cytokine receptor interaction, p53 signaling and cell cycle. The top 5 hub genes of PPI network were CAD, CCND1, ATM, RB1 and MET. Additionally, 239 hypermethylation-low expression genes were identified, which demonstrated enrichment in biological processes including cell–cell signaling, nerve impulse transmission, etc. Pathway analysis indicated enrichment in calcium signaling, maturity onset diabetes of the young, cell adhesion molecules, etc. The top 5 hub genes of PPI network were EGFR, ACTA1, SST, ESR1 and DNM2. After validation in TCGA database, most hub genes still remained significant.ConclusionIn summary, our study indicated possible aberrantly methylated-differentially expressed genes and pathways in CRC by bioinformatics analysis, which may provide novel insights for unraveling pathogenesis of CRC. Hub genes including CAD, CCND1, ATM, RB1, MET, EGFR, ACTA1, SST, ESR1 and DNM2 might serve as aberrantly methylation-based biomarkers for precise diagnosis and treatment of CRC in the future.