Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, Michigan.
Department of Pathology, University of Michigan, Ann Arbor, Michigan; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan.
Gastroenterology. 2014 Mar;146(3):822-834.e7. doi: 10.1053/j.gastro.2013.11.052. Epub 2013 Dec 6.
BACKGROUND & AIMS: Kras signaling via mitogen-activated protein kinase (MAPK) is highly up-regulated in pancreatic cancer cells. We investigated whether MAPK signaling is required for the initiation and maintenance of pancreatic carcinogenesis in mice.
We studied the formation and maintenance of pancreatic intraepithelial neoplasia (PanINs) in p48Cre; TetO-KrasG12D; Rosa26(rtTa-IRES-EGFP) (iKras*) mice and LSL-KrasG12D mice bred with p48Cre mice (KC). Mice were given oral PD325901, a small-molecule inhibitor of MEK1 and MEK2 (factors in the MAPK signaling pathway), along with injections of cerulein to induce pancreatitis. Other mice were given PD325901 only after PanINs developed. Pancreatic tissues were collected and evaluated using histologic, immunohistochemical, immunofluorescence, and electron microscopy analyses. Acinar cells were isolated from the tissues and the effects of MEK1 and 2 inhibitors were assessed.
PD325901 prevented PanIN formation, but not pancreatitis, in iKras* and KC mice. In iKras* or KC mice given PD325901 at 5 weeks after PanINs developed, PanINs regressed and acinar tissue regenerated. The regression occurred through differentiation of the PanIN cells to acini, accompanied by re-expression of the acinar transcription factor Mist1.
In iKras* and KC mice, MAPK signaling is required for the initiation and maintenance of pancreatic cancer precursor lesions. MAPK signaling promotes formation of PanINs by enabling dedifferentiation of acinar cells into duct-like cells that are susceptible to transformation.
丝裂原活化蛋白激酶（MAPK）途径中的 Kras 信号在胰腺癌细胞中高度上调。我们研究了 MAPK 信号是否对小鼠胰腺发生起始和维持是必需的。
我们研究了 p48Cre；TetO-KrasG12D；Rosa26(rtTa-IRES-EGFP)（iKras*）小鼠和 LSL-KrasG12D 小鼠中胰腺上皮内瘤变（PanIN）的形成和维持情况，这些小鼠与 p48Cre 小鼠（KC）杂交。给予小鼠口服 MEK1 和 MEK2（MAPK 信号通路中的因子）小分子抑制剂 PD325901，并注射 cerulein 以诱导胰腺炎。其他小鼠在 PanIN 形成后才给予 PD325901。收集胰腺组织并进行组织学、免疫组织化学、免疫荧光和电子显微镜分析。从组织中分离出腺泡细胞，并评估 MEK1 和 2 抑制剂的作用。
PD325901 可预防 iKras和 KC 小鼠的 PanIN 形成，但不能预防胰腺炎。在 iKras或 KC 小鼠中，在 PanIN 形成后 5 周给予 PD325901，PanIN 消退，腺泡组织再生。这种消退是通过 PanIN 细胞向腺泡分化，同时重新表达腺泡转录因子 Mist1 而发生的。
在 iKras*和 KC 小鼠中，MAPK 信号对于胰腺癌前病变的起始和维持是必需的。MAPK 信号通过使腺泡细胞去分化为易转化的导管样细胞来促进 PanIN 的形成。
