BACKGROUND: Gastric cancer is the fourth most common cancer in the world and the 
second most prevalent cause of cancer related death. The development of gastric 
cancer is mainly associated with H. Pylori infection leading to a focus in 
pathology studies on bacterial and environmental factors, and to a lesser extent 
on the mechanistic development of the tumour. MicroRNAs are small non-coding RNA 
molecules involved in post-transcriptional gene regulation. They are found to 
regulate genes involved in diverse biological functions and alterations in 
microRNA expression have been linked to the pathogenesis of many malignancies. 
The current study is focused on identifying microRNAs involved in gastric 
carcinogenesis and to explore their mechanistic relevance by characterizing 
their targets.
RESULTS: Invitrogen NCode miRNA microarrays identified miR-449 to be decreased 
in 1-year-old Gastrin KO mice and in H. Pylori infected gastric tissues compared 
to tissues from wild type animals. Growth rate of gastric cell lines 
over-expressing miR-449 was inhibited by 60% compared to controls. FACS cell 
cycle analysis of miR-449 over-expressing cells showed a significant increase in 
the sub-G1 fraction indicative of apoptosis. ß-Gal assays indicated a senescent 
phenotype of gastric cell lines over-expressing miR-449. Affymetrix 133v2 arrays 
identified GMNN, MET, CCNE2, SIRT1 and CDK6 as miR-449 targets. Luciferase 
assays were used to confirm GMNN, MET, CCNE2 and SIRT1 as direct targets. We 
also show that miR-449 over-expression activated p53 and its downstream target 
p21 as well as the apoptosis markers cleaved CASP3 and PARP. Importantly, qPCR 
analyses showed a loss of miR-449 expression in human clinical gastric tumours 
compared to normal tissues.
CONCLUSIONS: In this study, we document a diminished expression of miR-449 in 
Gastrin KO mice and further confirmed its loss in human gastric tumours. We 
investigated the function of miR-449 by identifying its direct targets. 
Furthermore we show that miR-449 induces senescence and apoptosis by activating 
the p53 pathway.