Discovery of Prognostic Signature Genes for Overall Survival Prediction in Gastric Cancer.

BACKGROUND: Gastric cancer (GC) is one of the most common malignant tumors in the digestive system with high mortality globally. However, the biomarkers that accurately predict the prognosis are still lacking. Therefore, it is important to screen for novel prognostic markers and therapeutic targets. METHODS: We conducted differential expression analysis and survival analysis to screen out the prognostic genes. A stepwise method was employed to select a subset of genes in the multivariable Cox model. Overrepresentation enrichment analysis (ORA) was used to search for the pathways associated with poor prognosis. RESULTS: In this study, we designed a seven-gene-signature-based Cox model to stratify the GC samples into high-risk and low-risk groups. The survival analysis revealed that the high-risk and low-risk groups exhibited significantly different prognostic outcomes in both the training and validation datasets. Specifically, CGB5, IGFBP1, OLFML2B, RAI14, SERPINE1, IQSEC2, and MPND were selected by the multivariable Cox model. Functionally, PI3K-Akt signaling pathway and platelet-derived growth factor receptor (PDGFR) were found to be hyperactive in the high-risk group. The multivariable Cox regression analysis revealed that the risk stratification based on the seven-gene-signature-based Cox model was independent of other prognostic factors such as TNM stages, age, and gender. CONCLUSION: In conclusion, we aimed at developing a model to predict the prognosis of gastric cancer. The predictive model could not only effectively predict the risk of GC but also be beneficial to the development of therapeutic strategies.

MiR-92a promotes stem cell-like properties by activating Wnt/ß-catenin signaling in colorectal cancer.

We previously reported the oncogenic function of miR-92a in colorectal cancer. This study identified that miR-92a was upregulated in chemoresistant colorectal cancer cells and tissues. Ectopic expression of miR-92a conferred resistance to 5-fluorouracil-induced apoptosis in vitro, while antagomiR-92a significantly enhanced chemosensitivity in vivo. Moreover, Overexpression of miR-92a promoted the tumor sphere formation and the expression of stem cell markers. MiR-92a overexpression also displayed higher tumourigenesis in vivo. Furthermore, we demonstrated that miR-92a upregulates the Wnt/ß-catenin signaling activity via directly targeting KLF4, GSK3ß and DKK3, which are multiple level negative regulators of the Wnt/ß-catenin signaling cascade. In addition, our results indicate IL-6/STAT3 pathway increases miR-92a expression by directly targeting its promoter, resulting in Wnt/ß-catenin signaling activation and consequent promotion of stem-like phenotypes of colorectal cancer cells. Our present results suggest the essential role of IL-6/STAT3/miR-92a/Wnt/ß-catenin pathway in regulating the stem cell-like traits of colorectal cancer cells and provide a potential target for colorectal cancer therapy.

MicroRNA-22 suppresses the growth, migration and invasion of colorectal cancer cells through a Sp1 negative feedback loop.

MicroRNAs have recently emerged as regulators of many biological processes including cell proliferation, development and differentiation. This study identified that miR-22 was statistically decreased in colorectal cancer clinical specimens and highly metastatic cell lines. Moreover, low miR-22 expression was associated with tumor metastasis, advanced clinical stage and relapse. Consistent with clinical observations, miR-22 significantly suppressed the ability of colorectal cancer cells to growth and metastasize in vitro and in vivo. Sp1 was validated as a target of miR-22, and ectopic expression of Sp1 compromised the inhibitory effects of miR-22. In addition, Sp1 repressed miR-22 transcription by binding to the miR-22 promoter, hence forming a negative feedback loop. Further study has shown that miR-22 suppresses the activity of PTEN/AKT pathway by Sp1. Our present results implicate the newly indentified miR-22/Sp1/PTEN/AKT axis might represent a potential therapeutic target for colorectal cancer.

Effects of gastric bypass on FoxO1 expression in the liver and pancreas of diabetic rats.

AIM: To explore the mechanism by which gastric bypass surgery (GBS) ameliorates type 2 diabetes mellitus (T2DM) by investigating whether FoxO1 (a transcription factor that plays a crucial role in the regulation of glycolipid metabolism) expression is altered in the liver and pancreatic islet cells in a rat model of GBS-treated T2DM. METHODS: Sprague-Dawley rats were randomly divided into four groups (n = 10 rats each): diabetic rats treated by GBS (DM + GBS), diabetic rats subjected to sham operation (DM + sham), normal control rats (control), and diabetic rats without surgery (DM). Fasting levels of blood glucose (BG), insulin, and glucagon-like peptide-1 (GLP-1) were measured in all groups before and 4, 8, 16, and 24 weeks after operation. Rats were killed 24 weeks after surgery. Liver and pancreas expressions of FoxO1 were investigated by immunohistochemistry and Western blotting analyses. RESULTS: In the DM + GBS group, fasting BG before and 24 weeks after surgery decreased from 20.2 ± 2.1 to 7.7 ± 1.1 mmol/L, respectively; fasting insulin showed no change (2.9 ± 0.1 and 3.0 ± 0.1 mU/L, respectively); and fasting GLP-1 increased from 8.7 ± 0.9 to 23.5 ± 0.2 pmol/L, respectively. Fasting BG levels after surgery in the DM + GBS group were significantly lower than those in the DM + sham and DM groups. FoxO1 expression levels in the liver and pancreatic islets of the DM + GBS group were reduced compared to those in the DM + sham and DM groups. FoxO1 in the pancreatic ß-cells was expressed mainly in the cytoplasm. CONCLUSIONS: Gastric bypass may improve type 2 diabetes mellitus by changing FoxO1 expression in the liver and pancreatic islet cells.

Gastrointestinal intervention ameliorates high blood pressure through antagonizing overdrive of the sympathetic nerve in hypertensive patients and rats.

BACKGROUND: We investigated the hypothesis that the favorable effects of gastrointestinal (GI) intervention on hypertension (HTN) and cardiovascular (CV) disturbances are mediated by antagonizing overdrive of the sympathetic nervous system (SNS). METHODS AND RESULTS: Hypertensive patients with metabolic disturbances underwent laparoscopic Roux-en-Y gastric bypass surgery, and spontaneously hypertensive rats (SHRs) underwent RYGB or sham surgery. Blood pressure (BP), heart rate (HR), endothelium-dependent flow-mediated dilation, and anthropometric as well as laboratory parameters were measured at baseline and during follow-up. Changes of BP and HR in response to cold stress, renal sympathetic nervous activity (RSNA), vasoconstriction induced by electrical field stimulation, microinjection of nucleus of the solitary tract (NTS), and CV function and structure were examined in SHRs with or without surgery. Compared with baseline, BP and HR were significantly reduced in both hypertensive patients with type 2 diabetes and rats. Impaired endothelial-dependent vasodilatation and metabolic disturbances in hypertensive patients were also ameliorated after surgery. CV disturbances were reversed by surgery in SHRs. Under acute cold exposure, the variations in BP and HR were smaller in surgically treated SHRs, compared to sham SHRs. RSNA and vasoconstriction induced by perivascular nerve stimulation as well as NTS-mediated changes of BP were decreased in surgically treated SHRs, compared to sham SHR. Weight loss did not affect BP and RSNA in sham SHRs. CONCLUSIONS: GI intervention ameliorates HTN in both hypertensive patients and rats by inhibiting overdrive of the SNS. Therefore, targeting gastrointestine could be a novel strategy to treat HTN with metabolic disturbances.