Retinoic acid receptor (RAR) antagonists inhibit miR-10a expression and block metastatic behaviour of pancreatic cancer

BACKGROUND & AIMS:: The infiltrating ductal adenocarcinoma of the pancreas is among the most lethal of all solid malignancies, largely due to a high frequency of early metastasis. We identify microRNA-10a (miR-10a) as an important mediator of metastasis formation in pancreatic tumour cells and investigate the upstream and downstream regulatory mechanisms of miR-10a. METHODS:: Northern blot analysis revealed elevated expression levels of miR-10a in metastatic pancreatic adenocarcinoma. The role of miR-10a was analysed by Morpholino and siRNA transfection of pancreatic carcinoma cell lines and resected specimen of human pancreatic carcinoma. Metastatic behaviour of primary pancreatic tumours and cancer cell lines was tested in xenotransplantation experiments in zebrafish embryos. RESULTS:: We show that miR-10a expression promotes metastatic behaviour of pancreatic tumour cells and that repression of miR-10a is sufficient to inhibit invasion and metastasis formation. We further demonstrate that miR-10a is a retinoid acid target and that retinoic acid receptor (RAR) antagonists effectively repress miR-10a expression and completely block metastasis. This anti-metastatic activity can be prevented by specific knock down of HOX genes, HOXB1 and HOXB3. Interestingly, suppression of HOXB1 and HOXB3 in pancreatic cancer cells is sufficient to promote metastasis formation. CONCLUSIONS:: These findings suggest that miR-10a is a key mediator of metastatic behaviour in pancreatic cancer which regulates metastasis via suppression of HOXB1 and HOXB3. Inhibition of miR-10a expression (with RAR antagonists) or function (with specific inhibitors) is a promising starting point for anti-metastatic therapies.