Smad4 loss synergizes with TGFα overexpression in promoting pancreatic metaplasia, PanIN development, and fibrosis.
Smad4 loss synergizes with TGFα overexpression in promoting pancreatic metaplasia, PanIN development, and fibrosis.
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DOI：
10.1371/journal.pone.0120851
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Su GH
中科院分区：
文献类型：
--
作者：
Garcia-Carracedo D;Yu CC;Akhavan N;Fine SA;Schönleben F;Maehara N;Karg DC;Xie C;Qiu W;Fine RL;Remotti HE;Su GH
虽然在人胰腺导管腺癌（PDAC）中报告了TGFα的过表达，但TGFα过表达的小鼠发生癌前胰腺腺泡至导管化生（ADM），而不是PDAC。TGF-β信号通路在PDAC和组织纤维化的发生发展中起着关键作用。在此，我们试图研究TGFα和TGF-β信号转导在胰腺肿瘤发生和纤维化中的相互作用，即通过Smad 4失活。将MT-TGFα小鼠与新的Smad 4条件性敲除小鼠（Smad 4flox/flox;p48-Cre或S4）杂交，以产生Smad 4flox/flox;MT-TGFα;p48-Cre（STP）。在用硫酸锌水诱导TGFα过表达8个月后，检查STP、MT-TGFα和S4小鼠的胰腺的肿瘤发展和纤维化反应。计数PanIN病变和导管数量，并通过Ki 67免疫组织化学（IHC）测量增殖。纤维化的定性分析通过Trichrome Masson和Sirius Red染色进行分析，而波形蛋白用于定量。通过IHC和/或qRT-PCR进行纤维化、胰腺炎或结缔组织增生相关标志物（α-SMA、Shh、考克斯-2、Muc 6、Col 1a 1和Ctgf）的表达分析。与MT-TGFα小鼠相比，我们的STP小鼠表现出晚期ADM、纤维化增加、PanIN病变数量增加、慢性胰腺炎相关标志物Muc 6过表达以及结缔组织增生相关标志物Col 1A 1表达升高。Smad 4在胰腺外分泌区室中的失活是胰腺中PanIN形成和纤维化增强的原因。STP小鼠的表型代表了从ADM到PanIN的短暂状态，与PDAC相关的人类慢性胰腺炎中观察到的界面区域非常相似。我们已经记录了一种新的小鼠模型，STP小鼠，其组织学表现令人想起人类慢性胰腺炎的早期肿瘤发生的迹象。STP小鼠是探讨慢性胰腺炎向胰腺癌转变的理想动物模型。
While overexpression of TGFα has been reported in human pancreatic ductal adenocarcinoma (PDAC), mice with overexpressed TGFα develop premalignant pancreatic acinar-to-ductal metaplasia (ADM) but not PDAC. TGF-β signaling pathway is pivotal to the development of PDAC and tissue fibrosis. Here we sought to investigate the interplay between TGFα and TGF-β signaling in pancreatic tumorigenesis and fibrosis, namely via Smad4 inactivation. The MT-TGFα mouse was crossed with a new Smad4 conditional knock-out mouse (Smad4flox/flox;p48-Cre or S4) to generate Smad4flox/flox;MT-TGFα;p48-Cre (STP). After TGFα overexpression was induced with zinc sulfate water for eight months, the pancreata of the STP, MT-TGFα, and S4 mice were examined for tumor development and fibrotic responses. PanIN lesions and number of ducts were counted, and proliferation was measured by Ki67 immunohistochemistry (IHC). Qualitative analysis of fibrosis was analyzed by Trichrome Masson and Sirius Red staining, while vimentin was used for quantification. Expression analyses of fibrosis, pancreatitis, or desmoplasia associated markers (α-SMA, Shh, COX-2, Muc6, Col1a1, and Ctgf) were performed by IHC and/or qRT-PCR. Our STP mice exhibited advanced ADM, increased fibrosis, increased numbers of PanIN lesions, overexpression of chronic pancreatitis-related marker Muc6, and elevated expression of desmoplasia-associated marker Col1A1, compared to the MT-TGFα mice. The inactivation of Smad4 in the exocrine compartment was responsible for both the enhanced PanIN formation and fibrosis in the pancreas. The phenotype of the STP mice represents a transient state from ADMs to PanINs, closely mimicking the interface area seen in human chronic pancreatitis associated with PDAC. We have documented a novel mouse model, the STP mice, which displayed histologic presentations reminiscent to those of human chronic pancreatitis with signs of early tumorigenesis. The STP mice could be a suitable animal model for interrogating the transition of chronic pancreatitis to pancreatic cancer.
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影响因子：
9.2
作者：
Qiu, Wanglong;Su, Gloria H.
通讯作者：
Su, Gloria H.
影响因子：
30.8
作者：
Kawaguchi, Y;Cooper, B;Wright, CVE
通讯作者：
Wright, CVE
影响因子：
5.7
作者：
Hill R;Li Y;Tran LM;Dry S;Calvopina JH;Garcia A;Kim C;Wang Y;Donahue TR;Herschman HR;Wu H
通讯作者：
Wu H
影响因子：
3.8
作者：
Chen YW;Hsiao PJ;Weng CC;Kuo KK;Kuo TL;Wu DC;Hung WC;Cheng KH
通讯作者：
Cheng KH
影响因子：
15.9
作者：
KORC, M;CHANDRASEKAR, B;BEGER, HG
通讯作者：
BEGER, HG