Retinoic acid receptor antagonists inhibit miR-10a expression and block metastatic behavior of pancreatic cancer.
OBJECTIVE
The infiltrating ductal adenocarcinoma of the pancreas is among the most lethal of all solid malignancies, largely owing to a high frequency of early metastasis. We identified microRNA-10a (miR-10a) as an important mediator of metastasis formation in pancreatic tumor cells and investigated the upstream and downstream regulatory mechanisms of miR-10a.


METHODS
Northern blot analysis revealed increased expression levels of miR-10a in metastatic pancreatic adenocarcinoma. The role of miR-10a was analyzed by Morpholino and short interfering RNA transfection of pancreatic carcinoma cell lines and resected specimens of human pancreatic carcinoma. Metastatic behavior of primary pancreatic tumors and cancer cell lines was tested in xenotransplantation experiments in zebrafish embryos.


RESULTS
We show that miR-10a expression promotes metastatic behavior of pancreatic tumor cells and that repression of miR-10a is sufficient to inhibit invasion and metastasis formation. We further show that miR-10a is a retinoid acid target and that retinoic acid receptor antagonists effectively repress miR-10a expression and completely block metastasis. This antimetastatic activity can be prevented by specific knockdown 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 behavior in pancreatic cancer, which regulates metastasis via suppression of HOXB1 and HOXB3. Inhibition of miR-10a expression (with retinoic acid receptor antagonists) or function (with specific inhibitors) is a promising starting point for antimetastatic therapies.
Weiss
Frank Ulrich
FU
Universitätsklinikum Greifswald, Klinik für Innere Medizin A, Greifswald, Germany.
Marques
Ines J
IJ
Woltering
Joost M
JM
Vlecken
Danielle H
DH
Aghdassi
Ali
A
Partecke
Lars Ivo
LI
Heidecke
Claus-Dieter
CD
Lerch
Markus M
MM
Bagowski
Christoph P
CP
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000556:secondary / Q000628:therapy*; D000818:Animals; D015703:Antigens, CD; D001565:Benzoates / Q000494:pharmacology*; D015152:Blotting, Northern; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D002839:Chromans / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D015316:Genetic Therapy / Q000379:methods; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D009025:Morpholines / Q000378:metabolism; D009361:Neoplasm Invasiveness; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary / Q000628:therapy*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012176:Retinoids / Q000494:pharmacology; D014162:Transfection; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays; D015027:Zebrafish / Q000196:embryology; D051178:alpha Catenin / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
D015703:Antigens, CD; D001565:Benzoates; C513384:CDH1 protein, human; C495270:CTNNB1 protein, human; D015820:Cadherins; D002839:Chromans; C101121:HOXB1 homeodomain protein; D018398:Homeodomain Proteins; C542921:HoxB3 protein, human; D035683:MicroRNAs; D009025:Morpholines; D016376:Oligonucleotides, Antisense; D034741:RNA, Small Interfering; D018168:Receptors, Retinoic Acid; D012176:Retinoids; D051178:alpha Catenin; D051176:beta Catenin; C084904:Ro 41-5253