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.

中文翻译：

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miR-802 在早期胰腺炎和胰腺癌发生过程中抑制腺泡到导管的重编程

背景与目标

胰腺导管腺癌 (PDAC) 是一种高度侵袭性的肿瘤，在人类中几乎都是致命的。KRAS 的激活突变存在于 >90% 的人类 PDAC 中，并且足以在肿瘤起始期间促进腺泡-导管化生 (ADM)。miRNA 在致癌Kras诱导的 ADM 中的作用尚不完全清楚。

方法

使用Ptf1a ^Cre/+ LSL-Kras ^G12D/+和Ptf1a ^Cre/+ LSL-Kras ^G12D/+ LSL-p53R172H/ ⁺和雨蛙素诱导的急性胰腺炎小鼠模型。在腺泡细胞中条件性消融mir-802以研究 miR-802 在 ADM 中的功能。

结果

我们表明 miR-802 是一种高度丰富且富含腺泡的胰腺 miRNA，在损伤的早期阶段或致癌Kras ^G12D诱导的转化过程中会被沉默。mir-802的基因消融通过促进 ADM 形成与Kras ^{G12D合作。}miR-802 缺乏导致 miR-802 靶标Arhgef12、RhoA和Sdc4的去抑制、RhoA的激活以及下游 RhoA 效应器 ROCK1、LIMK1、COFILIN1 和 EZRIN 的诱导，从而增加 F-肌动蛋白重排。mir-802消融还激活 SOX9，导致腺泡识别基因的导管和减弱表达水平增加。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，并与较差的生存率相关。

结论

我们显示 miR-802 通过抑制致癌Kras诱导的 ADM来抑制胰腺癌的发生。miR-802 在 ADM 中的作用填补了我们对致癌Kras诱导的 F-肌动蛋白重组、腺泡重编程和 PDAC 启动的理解空白。调节 miR-802-RhoA-F-actin 网络可能是干扰胰腺癌发生的新策略。