Institute of Molecular Health Sciences, ETH Zürich, Zürich, Switzerland.
Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, Zürich, Switzerland.
Gastroenterology. 2022 Jan;162(1):269-284. doi: 10.1053/j.gastro.2021.09.029. Epub 2021 Sep 20.
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.
The Ptf1aLSL-Kras and Ptf1aLSL-KrasLSL-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.
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-induced transformation. Genetic ablation of mir-802 cooperates with Kras 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.
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.
胰腺导管腺癌（PDAC）是一种高度侵袭性肿瘤，在人类中几乎普遍致命。超过 90%的人类 PDAC 中存在 KRAS 的激活突变，这些突变足以在肿瘤起始时促进腺泡到导管的化生（ADM）。miRNA 在致癌 Kras 诱导的 ADM 中的作用尚不完全清楚。
使用 Ptf1aLSL-Kras 和 Ptf1aLSL-KrasLSL-p53R172H/和 caerulein 诱导的急性胰腺炎小鼠模型。条件性敲除腺泡细胞中的 mir-802 以研究 miR-802 在 ADM 中的功能。
我们表明，miR-802 是一种高度丰富且在胰腺中富集的 miRNA，在损伤或致癌 Kras 诱导的转化早期被沉默。mir-802 的遗传缺失与 Kras 协同作用，促进 ADM 的形成。miR-802 缺陷导致 miR-802 靶标 Arhgef12、RhoA 和 Sdc4 的去抑制、RhoA 的激活以及下游 RhoA 效应物 ROCK1、LIMK1、COFILIN1 和 EZRIN 的诱导，从而增加 F-肌动蛋白重排。mir-802 缺失还激活 SOX9，导致导管水平增加和腺泡身份基因表达减弱。与这些发现一致，我们表明，这种 miR-802-RhoA-F-肌动蛋白网络在胰腺癌患者的活检中被激活，并与不良预后相关。
我们表明，miR-802 通过抑制致癌 Kras 诱导的 ADM 来抑制胰腺癌细胞的起始。miR-802 在 ADM 中的作用填补了我们对致癌 Kras 诱导的 F-肌动蛋白重排、腺泡重编程和 PDAC 起始的理解空白。调节 miR-802-RhoA-F-肌动蛋白网络可能是一种干扰胰腺发生的新策略。
