MicroRNAs are small non-coding RNA molecules that control expression of target genes. Previous studies showed that microRNA-107 (miR-107) is overexpressed in gastric cancer tissues compared with the matched normal tissues. However, it remains largely unclear as to how miR-107 exerts its function and modulates the malignant phenotypes of gastric cancer, because our understanding of miR-107 signalling pathways is limited. In this study, we demonstrate that miR-107 is frequently up-regulated in gastric cancers and its overexpression is significantly associated with gastric cancer metastasis. Furthermore, silencing the expression of miR-107 could inhibit gastric cancer cell migration and invasion in vitro and in vivo. Subsequent investigation characterized DICER1 as a direct target of miR-107. Up-regulation of DICER1 resulted in a dramatic reduction of in vitro migration, invasion, in vivo liver metastasis of nude mice, which is similar to that occurs with the silencing of miR-107, indicating that DICER1 functions as a metastasis suppressor in gastric cancer. Furthermore, the restoration of DICER1 can inhibit miR-107-induced gastric cancer cell invasion and metastasis. In conclusion, our results suggested that miR-107, an oncogene miRNA promoting gastric cancer metastasis through down-regulation of DICER1. Inhibition of miR-107 or restoration of DICER1 may represent a new potential therapeutic target for gastric cancer treatment.

The shortening of telomeres may result in chromosome instability and thus promote tumorigenesis. Previous studies have demonstrated clear involvement of telomere shortening in the carcinogenesis of several malignancies. However, the association between constitutive telomere shortening and gastric cancer development has yet to be established. Therefore, in the present study, we measured average telomere length using quantitative real-time PCR in peripheral blood lymphocytes from a gastric cancer (GC) case-control study consisting of 396 cases and 378 controls. The results showed that GC patients had significantly shorter average telomere length than matched controls (mean ± SD 0.89 ± 0.19 vs 1.06 ± 0.25, P < 0.001). We further categorized telomere length using the 50% value in the controls as a cut-off point and assessed the association between telomere length and GC risk using multivariate logistic regression analysis. We found that short telomere length was associated with a significantly increased GC risk (adjusted odds ratio = 2.14, 95% confidence interval = 1.52-2.93). Quartile stratification revealed a dose-response relationship between telomere shortening and GC risk (P for trend < 0.001). Stratified analysis showed that sex, age, and alcohol drinking, but not smoking and Helicobacter pylori infection, seem to have a modulating effect on the average telomere length in both cases and controls. We also found that telomere shortening and smoking had a significant joint effect on GC risk. Collectively, our findings provide the first evidence linking the short telomere length in peripheral blood lymphocytes to elevated GC risk, which warrants further investigation in other populations. (Cancer Sci 2009; 100: 1300-1305)

Most tumor cells take up more glucose than normal cells. Splicing dysregulation is one of the molecular hallmarks of cancer. However, the role of splicing factor in glucose metabolism and tumor development remains poorly defined. Here, we show that upon glucose intake, the splicing factor SRSF5 is specifically induced through Tip60-mediated acetylation on K125, which antagonizes Smurf1-mediated ubiquitylation. SRSF5 promotes the alternative splicing of CCAR1 to produce CCAR1S proteins, which promote tumor growth by enhancing glucose consumption and acetyl-CoA production. Conversely, upon glucose starvation, SRSF5 is deacetylated by HDAC1, and ubiquitylated by Smurf1 on the same lysine, resulting in proteasomal degradation of SRSF5. The CCAR1L proteins accumulate to promote apoptosis. Importantly, SRSF5 is hyperacetylated and upregulated in human lung cancers, which correlates with increased CCAR1S expression and tumor progression. Thus, SRSF5 responds to high glucose to promote cancer development, and SRSF5–CCAR1 axis may be valuable targets for cancer therapeutics.