The Stoffel lab in collaboration with the Schwank group investigated the role of miR-802 in cellular repropramming occuring during early pancreatitis and carcinogenesis, and conclude that targeting the miR-802-RhoA-F-Action network could be used to combat carcinogenesis. Their findings have been published in the Gastroenterology article "miR-802 Suppress Acinar-to-Ductal Reprogramming during Early Pancreatitis and Pancreatic Carcinogenesis".
Background & aims: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumor that is almost uniformly lethal in humans. Activating mutations of KRAS are found in >90% of human PDACs and are sufficient to promote acinar-to-ductal metaplasia (ADM) during tumor initiation. The roles of miRNAs in oncogenic Kras-induced ADM are incompletely understood.
Methods: The Ptf1aCre/+; LSL-KrasG12D/+ and Ptf1aCre/+; LSL-KrasG12D/+; LSL-p53R172H/+ and caerulein-induced acute pancreatitis mice models were used. The mir-802 was conditionally ablated in acinar cells to study the function of miR-802 in ADM.
Results: We show that miR-802 is a highly abundant and acinar-enriched pancreatic miRNA that is silenced during early stages of injury or oncogenic KrasG12D-induced transformation. Genetic ablation of mir-802 cooperates with KrasG12D by promoting ADM formation. miR-802 deficiency results in derepression of the miR-802 targets Arhgef12, RhoA and Sdc4, activation of RhoA and induction of the downstream RhoA effectors ROCK1, LIMK1, COFILIN1 and EZRIN, thereby increasing F-Actin rearrangement. miR-802 ablation also activates SOX9, resulting in augmented levels of ductal and attenuated expression of acinar identity genes. Consistent with these findings, we show that this miR-802-RhoA-F-Actin network is activated in biopsies of pancreatic cancer patients and correlates with poor survival.
Conclusions: We show miR-802 suppresses pancreatic cancer initiation by repressing oncogenic Kras-induced ADM. The role of miR-802 in ADM fills the gap in our understanding of oncogenic Kras-induced F-actin reorganization, acinar reprogramming and PDAC initiation. Modulation of the miR-802-RhoA-F-Actin network may be a new strategy to interfere with pancreatic carcinogenesis.