ObjectivesThe objective of this study was to evaluate the association between metformin therapy and the incidence of gastric cancer (GC) in patients with type 2 diabetes mellitus (T2DM).MethodsWe systemically searched the following databases for studies published between the databases’ dates of inception and Nov. 2016: PubMed, Embase, the Cochrane Library, the Web of Science, and the China National Knowledge Infrastructure (CNKI). Hazard ratios (HR)and corresponding 95% confidence intervals (CIs) for the association between metformin therapy and the incidence of GC in patients with T2DM were the outcome measures assessed in this study. STATA 12.0 (Stata Corporation, College Station, Texas, USA) was used to conduct the statistical analysis.ResultsA total of seven cohort studies including 591,077 patients met all the criteria for inclusion in the analysis. Our data showed that metformin therapy was associated with a significantly lower incidence of GC in patients with T2DM than other types of therapy (HR=0.763, 95% CI: 0.642˜0.905). Subgroup analysis showed that patients living in Taiwan benefitted more from metformin therapy than patients living in any other region, as metformin significantly decreased the risk of GC in patients living in Taiwan but did not significantly decrease the risk of GC in patients living in other regions (HR=0.514, 95% CI: 0.384-0.688). The results of the present analysis support the idea that metformin facilitates reductions in the risk of T2DM-related GC.ConclusionsThe risk of GC among patients with T2DM is lower in patients receiving metformin therapy than in patients not receiving metformin therapy.

Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy with poor prognosis in China. Chemotherapy now is one of the most frequently used treatments for patients with ESCC in middle or late stage, however the effects were often limited by increased chemoresistance or treatment toxicity. So it is urgent to find new drugs to treat ESCC patients. Metformin with low cost and toxicity has proved to have anti-cancer effects in numerous cancers, while its role and mechanism in ESCC has seldom been studied. In the present study, we found that metformin exhibited not only an anti-proliferation ability in a dose and time dependent manner but also a proapoptosis effect in a dose dependent manner in ESCC cell line KYSE450. Our in vivo experiment also showed that metformin markedly inhibited KYSE450 xenograft tumors growth compared to those treated with normal saline. What’s more, no obvious toxic reactions were observed. To further explore the underlying mechanism, we found that metformin treatment could significantly damp the expression of 4EBP1 and S6K1 in KYSE 450 cells in vitro and in vivo, furthermore, the p-4EBP1 and p-S6K1 expression in KYSE 450 cells were also inhibited greatly in vitro and in vivo. During the therapy of cancer, in order to overcome side effects, combination therapy was often used. In this paper, we demonstrated that metformin potentiated the effects of cisplatin via inhibiting cell proliferation and promoting cell apoptosis. Taken together, metformin owned the potential anti-cancer effect on ESCC in monotherapy or was combined with cisplatin and these results laid solid basis for the use of metformin in ESCC.

Cancer stem cells (CSCs) are defined as a rare subpopulation of undifferentiated cells with biological characteristics that include the capacity for self-renewal, differentiation into various lineages, and tumor initiation. To explore the mechanism of CSCs in esophageal squamous cell carcinoma (ESCC), we focused on Leucine-rich repeat containing G protein-coupled receptor 5 (Lgr5), a target gene of the Wnt signaling pathway, which has been identified as a marker of intestinal stem cells and shown to be overexpressed in several human malignancies. Lgr5 expression was significantly correlated with lymph node metastasis, increased depth of invasion, increased tumor size, advanced differentiation, higher AJCC stage and poorer survival. Silencing of Lgr5 expression in the ESCC cell line KYSE450 by small interfering RNA (siRNA) strongly inhibited cell proliferation, migration and invasion ability, the expression of CSCs-related genes and Wnt/β-catenin signaling. In addition, Lgr5 was highly expressed in ESCC spheroid body cells, which were identified by high expression of CSCs-related genes, and high tumorigenicity in vivo. Taken together, these results demonstrate that Lgr5 activation of Wnt/β-catenin signaling is a potential mechanism to promote the progression of ESCC and ESCC stem cell renewal, and Lgr5 may be used as a molecular target for the development of treatments for ESCC.

Cerebral ischemic stroke is a huge threat to the health and life of many people. Electroacupuncture (EA) at Baihui (GV20) and Shenting (GV24) acupoints can notably alleviate cerebral ischemia/reperfusion injury (CIRI). However, the molecular basis underlying the effectiveness of EA at the GV20 and GV24 acupoints for CIRI remains largely unknown. Our present study demonstrated that EA treatment at the GV20 and GV24 acupoints markedly alleviated middle cerebral artery occlusion/reperfusion (MCAO/R)-induced cognitive deficits and cerebral infarction in rats. Proteomics analysis revealed that 195 and 218 proteins were dysregulated in rat hippocampal tissues in the MCAO/R vs. sham group and thhhe EA vs. MCAO/R group, respectively. Moreover, 62 proteins with converse alteration trends in MCAO/R vs. sham and EA vs. MCAO/R groups were identified. These proteins might be implicated in the EA-mediated protective effect against MCAO/R-induced cerebral injury. GO enrichment analysis showed that 39 dysregulated proteins in the MCAO/R vs. sham group and 40 dysregulated proteins in the EA vs. MCAO/R group were related to brain and nerve development. Protein–protein interaction analysis of the abovementioned dysregulated proteins associated with brain and nerve development suggested that Pten/Akt pathway-related proteins might play major roles in regulating EA-mediated protective effects against MCAO/R-induced brain and nerve injury. Western blot assays demonstrated that Pak4, Akt3, and Efnb2 were expressed at low levels in the MCAO/R group vs. the sham group but at high levels in the EA group vs. the MCAO/R group. In conclusion, multiple proteins related to the protective effect of EA at the GV20 and GV24 acupoints against CIRI were identified in our study.