MAPK signaling is required for dedifferentiation of acinar cells and development of pancreatic intraepithelial neoplasia in mice.
MAPK signaling is required for dedifferentiation of acinar cells and development of pancreatic intraepithelial neoplasia in mice.
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DOI：
10.1053/j.gastro.2013.11.052
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发表时间：
2014-03
期刊：
影响因子：
29.4
通讯作者：
Pasca di Magliano M
中科院分区：
文献类型：
--
作者：
Collins MA;Yan W;Sebolt-Leopold JS;Pasca di Magliano M
KRAS信号通路通过丝裂原活化蛋白激酶(MAPK)在胰腺癌细胞中高度上调。我们研究了MAPK信号是否在小鼠胰腺癌的发生和维持中起作用。我们研究了p48Cre、Teto-KrasG12D、Rosa26rtTa-IRES-EGFP(iKras*)小鼠和与p48Cre小鼠配种的LSL-KrasG12D小鼠胰腺上皮内瘤变的形成和维持。给小鼠口服PD325901，这是一种MEK1和MEK2(MAPK信号通路中的因子)的小分子抑制剂，并注射雨蛙素诱导胰腺炎。其他小鼠只有在潘-INS形成后才给予PD325901。收集胰腺组织，用组织学、免疫组织化学、免疫荧光和电子显微镜分析进行评估。从组织中分离腺泡细胞，评估MEK1和2抑制剂的作用。PD325901可预防iKras*和KC小鼠体内泛宁的形成，但不能预防胰腺炎。在iKras*或KC小鼠中，在Panins发育后5周给予PD325901，Panins退化，腺泡组织再生。这种退化是由于Panin细胞分化为腺泡细胞，伴随着腺泡转录因子Mist1的重新表达而发生的。在iKras*和KC小鼠中，MAPK信号在胰腺癌前体病变的启动和维持中是必需的。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Panins的形成。
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 (Pan-INs) inp48Cre; TetO-KrasG12D; Rosa26rtTa-IRES-EGFP (iKras*) mice and LSL-KrasG12D mice bred with p48Cre mice (KC mice). Mice were given oral PD325901, which is 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 Pan-INs 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.
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影响因子：
28.2
作者：
Collisson EA;Trejo CL;Silva JM;Gu S;Korkola JE;Heiser LM;Charles RP;Rabinovich BA;Hann B;Dankort D;Spellman PT;Phillips WA;Gray JW;McMahon M
通讯作者：
McMahon M
影响因子：
15.9
作者：
Collins, Meredith A.;Bednar, Filip;di Magliano, Marina Pasca
通讯作者：
di Magliano, Marina Pasca
影响因子：
30.8
作者：
Kawaguchi, Y;Cooper, B;Wright, CVE
通讯作者：
Wright, CVE
影响因子：
29.4
作者：
Kanda M;Matthaei H;Wu J;Hong SM;Yu J;Borges M;Hruban RH;Maitra A;Kinzler K;Vogelstein B;Goggins M
通讯作者：
Goggins M
影响因子：
50.3
作者：
Guerra C;Collado M;Navas C;Schuhmacher AJ;Hernández-Porras I;Cañamero M;Rodriguez-Justo M;Serrano M;Barbacid M
通讯作者：
Barbacid M