MicroRNA-451 regulates macrophage migration inhibitory factor production and proliferation of gastrointestinal cancer cells
Eva Bandres (1), Nerea Bitarte (1),FernandoArias (6), Jackeline Agorreta (1),Puri Fortes (2), Xabi Agirre (1), Ruth Zarate (1),Juan A. Diaz-Gonzalez (3), Natalia Ramirez (1), Jesus J. Sola (4), Paula Jimenez (7), Javier Rodriguez (5) and Jesus Garcia-Foncillas (1,5)
(1) Divisions of Oncology and (2) Hepatology and GeneTherapy,Center for Applied Medical Research
(3) Departments of Radiation Oncology
(4) Pathology, and (5) Oncology, Clinica Universitaria, University of Navarra
(6) Department of Radiotherapy, Navarra Hospital, Pamplona, Spain
(7) Department of Oncology, Hospital Central deAsturias, Asturias, Spain
MicroRNAs (miRNA) are small RNAs that function as post-transcriptional regulators of gene expression. Recent evidence has shown that some miRNAs can act as oncogenes or tumor suppressors.This study was conducted to evaluate the potential association of miRNA expression with clinical outcome in patients with gastric cancer.
Expression of 250 human mature miRNAs was measured by real-time PCR on paraffin-embedded tumor samples of 21 patients with gastric cancer stage III uniformly treated with surgical resection followed by chemoradiation. We identified the miRNAs correlated with disease-free and overall survival times, and the results were evaluated including 24 other patients. In vitro cell proliferation and radiosensitivity studies were done to support clinical data.
The results revealed that down-regulation of miR-451 was associated with worse prognosis. miR-451 was detected by in situ hybridization in epithelial cells and showed decreased expression in gastric and colorectal cancer versus non tumoral tissues. Over expression of miR-451 in gastric and colorectal cancer cells reduced cell proliferation and increased sensitivity to radiotherapy. Microarray and bioinformatic analysis identified the novel oncogene macrophage migration inhibitory factor (MIF) as a potential target of miR-451. In fact, over expression of miR-451 down-regulated mRNA and protein levels of MIF and decreased expression of reporter genes with MIF target sequences. More over, we found a significant inverse correlation between miR-451 and MIF expression in tumoral gastric biopsies.
These findings support the role of miR-451 as a regulator of cancer proliferation and open new perspectives for the development of effective therapies for chemoradioresistant cancers.
CITATION Clin Cancer Res. 2009 Apr 1;15(7):2281-90