| First Author | Ge W | Year | 2022 |
| Journal | Gastroenterology | Volume | 162 |
| Issue | 1 | Pages | 269-284 |
| PubMed ID | 34547282 | Mgi Jnum | J:316409 |
| Mgi Id | MGI:6836623 | Doi | 10.1053/j.gastro.2021.09.029 |
| Citation | Ge W, et al. (2022) miR-802 Suppresses Acinar-to-Ductal Reprogramming During Early Pancreatitis and Pancreatic Carcinogenesis. Gastroenterology 162(1):269-284 |
| abstractText | 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 Ptf1a(Cre/+)LSL-Kras(G12D/+) and Ptf1a(Cre/+)LSL-Kras(G12D/+)LSL-p53R172H/(+) and caerulein-induced acute pancreatitis mice models were used. 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 Kras(G12D)-induced transformation. Genetic ablation of mir-802 cooperates with Kras(G12D) by promoting ADM formation. miR-802 deficiency results in de-repression 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. Consistently 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. |
