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Gastric intestinal metaplasia (GIM) is the essential pre-malignancy of gastric cancer. Chronic inflammation and bile acid reflux are major contributing factors. As an intestinal development transcription factor, caudal-related homeobox 2 (CDX2) is key in GIM. Resveratrol has potential chemopreventive and anti-tumour effects. The aim of the study is to probe the effect of resveratrol in bile acid-induced GIM. We demonstrated that resveratrol could reduce CDX2 expression in a time- and dose-dependent manner in gastric cell lines. A Cignal Finder 45-Pathway Reporter Array and TranSignal Protein/DNA Array Kit verified that resveratrol could increase Forkhead box O4 (FoxO4) activity and that Chenodeoxycholic acid (CDCA) could reduce FoxO4 activity. Furthermore, bioinformatics analysis showed that FoxO4 could bind to the CDX2 promoter, and these conjectures were supported by chromatin-immunoprecipitation (ChIP) assays. Resveratrol can activate FoxO4 and decrease CDX2 expression by increasing phospho-FoxO4 nucleus trans-location. Resveratrol could increase FoxO4 phosphorylation through the PI3K/AKT pathway. Ectopic FoxO4 expression can up-regulate FoxO4 phosphorylation and suppress CDCA-induced GIM marker expression. Finally, we found a reverse correlation between p-FoxO4 and CDX2 in tissue arrays. This study validates that resveratrol could reduce bile acid-induced GIM through the PI3K/AKT/p-FoxO4 signalling pathway and has a potential reversing effect on GIM, especially that caused by bile acid reflux.

Berberine (BBR), a natural isoquinoline alkaloid, has been shown to be a promising therapeutic agent for colorectal cancer (CRC), but the molecular mechanism remains unclear. Here, we used mass spectrometry-based label-free proteomics to explore the potential targets of BBR in CRC cells. Comprehensive proteomic profiles demonstrated that of 8051 identified proteins, 503 and 277 differentially expressed proteins (DEPs) were screened out of CACO2 and LOVO cells, respectively. 83 DEPs were overlapped and most of these were down-regulated. A pathway enrichment analysis pinpointed mitochondrial translation, respiratory electron transport and the citric acid (TCA) cycle as biological effectors. The data of proteomics was subsequently confirmed by citrate synthase (CS), Tu translation elongation factor (TUFM), pentatricopeptide repeat domain 3 (PTCD3) and mitochondrial ribosomal protein L48 (MRPL 48) protein measurement. CS protein expression in CRC cells and tissues was higher than it was in normal specimens. Additionally, forcible downregulation of CS led to remarkable cell proliferation inhibition. Taken together, we concluded that the anticancer effects of BBR are attributable to mitochondrial protein synthesis, TCA and respiratory electron transport inhibition and that CS might be a useful therapeutic target in CRC treatment.

Background The small GTPase Ran is upregulated in multiple cancers and fundamental for cancer cell survival and progression, but its significance and molecular mechanisms in colorectal cancer (CRC) remain elusive. Methods Ran expression was detected in CRC cell lines and tumour tissues. In vitro and in vivo functional assays were performed to examine the effects of Ran on cell proliferation and metastasis. The pathways and effectors regulated by Ran were explored by an unbiased screening. Bioinformatics prediction and experimental validation were used to identify the miRNA regulator for Ran. Results Ran expression was frequently increased in metastatic CRC cells and tissues, especially in metastatic tissues. The upregulation of Ran correlated with poor CRC patient prognosis. Ran silencing reduced proliferation and metastasis of CRC cells both in vitro and in vivo. Ran regulated the expression of EGFR and activation of ERK and AKT signalling pathways. miR-802 was identified as an upstream regulator of Ran and miR-802 overexpression resulted in antiproliferative and antimetastatic activities. Conclusion Our study demonstrates the oncogenic roles and underlying mechanisms of Ran in CRC and the novel miR-802/Ran/EGFR regulatory axis may provide potential biomarkers for the treatment of CRC.

Dickkopf-related protein 1 (DKK1) is essential to gastric cancer as an inhibitor of Wnt signaling. Gastric intestinal metaplasia (GIM) is an important precancerous lesion of gastric cancer that can be activated by bile acid reflux and chronic inflammation. However, the exact mechanism of DKK1 in bile acid-induced GIM has not been completely elucidated. We aimed to explore the epigenetic alterations and biological functions of DKK1 in the development of GIM. In the present study, bile acid was found to induce the expression of intestinal markers in gastric epithelial cells, whereas DKK1 was downregulated in response to bile acid stimulation. The mRNA and protein expression levels of DKK1 were decreased in GIM tissues as evidenced by qRT-PCR and immunohistochemical staining. Surprisingly, the methylation of the DKK1 promoter increased in GIM tissues, and we discovered 28 differential methylation sites of the DKK1 promoter in GIM tissues. Bile acid was able to induce the partial methylation of the DKK1 promoter, while 5-aza could increase DKK1 expression as well as decrease intestinal markers expression in gastric epithelial cells. In conclusion, the promoter methylation and downregulation of DKK1 might play important roles in the development of GIM, especially bile acid-induced GIM.

The Slit family is a family of secreted proteins that play important roles in various physiologic and pathologic activities via interacting with Robo receptors. Slit/Robo signaling was first identified in the nervous system, where it functions in neuronal axon guidance; nevertheless, an increasing number of studies have shown that Slit/Robo signaling even regulates other activities, such as angiogenesis, inflammatory cell chemotaxis, tumor cell migration and metastasis. Although the precise role of the ligand-receptor in organisms has been obscure and the conclusions drawn are sometimes paradoxical, tremendous advances in understanding the Slit/Robo signaling pathway have been made. As such, our review summarizes the characteristics of the Slit/Robo signaling pathway and its role in various cell types.

Background. Metallothioneins (MTs) family comprises many isoforms, most of which are frequently dysregulated in a wide range of cancers. However, the expression pattern and exact role of each distinct MT family isoform which contributes to tumorigenesis, progression, and drug resistance of gastric cancer (GC) are still unclear. Methods. Publicly available databases including Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), Kaplan-Meier plotter, SurvExpress, MethHC, cBioportal, and GeneMANIA were accessed to perform an integrated bioinformatic analysis and try to detect fundamental relationships between each MT family member and GC. Results. Bioinformatic data indicated that the mRNA expression of all MT family members was almost lowly expressed in GC compared with normal gastric tissue (P Conclusion. MTs were nearly downregulated, and distinct type of MT harbored different prognostic role in GC patients. Methylation in gene promoter region of MTs partially contributed to their reduced expression in GC. Our comprehensive analyses from multiple independent databases may further lead researches to explore MT-targeting reagents or potential diagnostic and prognostic markers for GC patients.

Transcription factors (TFs) and microRNAs (miRNAs) are tightly linked to each other in tumor development and progression, but their interactions in gastric cancer (GC) metastasis remain elusive. Here we report a novel suppressive role of GATA6 in inhibiting GC metastasis by transactivating miR-520b. We found that GATA6 expression was significantly downregulated in metastatic GC cells and tissues and that its downregulation was correlated with a poor GC prognosis. Overexpression of GATA6 suppressed GC cell migration, invasion and metastasis both in vitro and in vivo. Luciferase reporter assays and chromatin immunoprecipitation assays demonstrated that miR-520b is a direct transcriptional target of GATA6. Moreover, miR-520b expression was positively correlated with GATA6 expression in GC tissues, and ectopic expression of miR-520b inhibited the migration and invasion of GC cells. Furthermore, cAMP responsive element binding protein 1 (CREB1) was identified as a direct and functional target of miR-520b, and GATA6 could suppress GC cell migration and metastasis via miR-520b-mediated repression of CREB1. Downregulation of GATA6 and miR-520b may partly account for the overexpression of CREB1 in GC. In conclusion, our results provide novel insight into the TF-miRNA regulatory network involved in GC metastasis. Targeting the GATA6/miR-520b/CREB1 axis may be an effective approach for GC treatment.