Inactivation of TIF1gamma cooperates with Kras to induce cystic tumors of the pancreas.
Inactivation of TIF1gamma cooperates with Kras to induce cystic tumors of the pancreas.
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TIF1GAMMA的灭活与KRAS合作诱导胰腺的囊性肿瘤。
DOI：
10.1371/journal.pgen.1000575
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发表时间：
2009-07
期刊：
影响因子：
4.5
通讯作者：
Bartholin L
中科院分区：
文献类型：
--
作者：
Vincent DF;Yan KP;Treilleux I;Gay F;Arfi V;Kaniewski B;Marie JC;Lepinasse F;Martel S;Goddard-Leon S;Iovanna JL;Dubus P;Garcia S;Puisieux A;Rimokh R;Bardeesy N;Scoazec JY;Losson R;Bartholin L
转化生长因子-β(转化生长因子-β)抑癌通路的失活导致了胰腺导管腺癌的进展，因为它几乎在所有的胰腺癌病例中都是失活的。在小鼠模型中，基因损伤使这一途径失活有助于胰腺肿瘤的进展。转录中介因子1-γ(TIF1-γ)最近被认为参与转化生长因子β信号转导，作为该途径的正负调节因子发挥作用。在这里，我们讨论了TIF1γ在胰腺癌发生中的作用。利用条件性Tif1γ基因敲除小鼠(Tif1γlox/lox)，我们选择性地抑制了pdx1-Cre；Tif1γlox/lox小鼠胰腺组织中Tif1的表达。我们还建立了Pdx1-Cre；Ls1-KrasG12D；Tif1KrasG12D；Tif1KrasG12Dγlox/lox小鼠，以研究Tif1γ功能丧失在致癌KrasG12D诱导的癌前病变中的作用。最后，我们分析了TIF1γ在人胰腺肿瘤中的表达。在我们的小鼠模型中，我们发现Tif1γ对于正常的胰腺发育是必不可少的，但与Kras的激活协同诱导胰腺肿瘤，使人想起人导管内乳头状黏液肿瘤(IPMN)。有趣的是，这些囊性病变类似于其他人在Pdx1-CRE、LSL-KrasG12D、Smad4lox/lox小鼠中观察到的病变。然而，独特的特征，如乳头状投射内系统性内分泌假性胰岛的存在，表明Smad4和TIF1γ并不具有严格意义上的冗余功能。最后，通过定量RT-PCR法和免疫组织化学方法，我们发现TIF1γ在人胰腺肿瘤中的表达显著下调，这支持了这些发现与人类恶性肿瘤的相关性。本研究提示TIF1γ在胰腺肿瘤抑制中起关键作用，为胰腺癌的遗传学研究提供了新的思路，并为阐明Smad4和TIF1γ在转化生长因子β在肿瘤发生发展中的多方面作用提供了一个有前景的模型。转化生长因子β抑癌通路的失活导致了胰腺导管腺癌的发展，胰腺导管腺癌是一种毁灭性的恶性肿瘤。转录中介因子1γ(TIF1γ)最近被认为与转化生长因子β信号转导有关，该信号通路在几乎所有恶性肿瘤中都处于失活状态。为了阐明Tif1γ在胰腺癌发生中的作用，我们使用了条件性Tif1γ基因敲除小鼠。Tif1γ失活可导致胰腺癌前病变，与Smad4缺失时的胰腺癌前病变相似，Smad4是参与转化生长因子β信号转导的关键因素。这一观察结果强化了TIF1γ在转化生长因子β信号转导中发挥积极作用的观点。有趣的是，我们还发现TIF1γ在人类胰腺肿瘤中的表达显著下调，这支持了我们的发现与人类恶性肿瘤的相关性。早期胰腺病变的暴发，最终演变为侵袭性胰腺癌，其新参与者的特征对于及早发现疾病并最终开发新的治疗药物至关重要。
Inactivation of the Transforming Growth Factor Beta (TGFβ) tumor suppressor pathway contributes to the progression of Pancreatic Ductal AdenoCarcinoma (PDAC) since it is inactivated in virtually all cases of this malignancy. Genetic lesions inactivating this pathway contribute to pancreatic tumor progression in mouse models. Transcriptional Intermediary Factor 1 gamma (TIF1γ) has recently been proposed to be involved in TGFβ signaling, functioning as either a positive or negative regulator of the pathway. Here, we addressed the role of TIF1γ in pancreatic carcinogenesis. Using conditional Tif1γ knockout mice (Tif1γlox/lox), we selectively abrogated Tif1γ expression in the pancreas of Pdx1-Cre;Tif1γlox/lox mice. We also generated Pdx1-Cre;LSL-KrasG12D;Tif1γlox/lox mice to address the effect of Tif1γ loss-of-function in precancerous lesions induced by oncogenic KrasG12D. Finally, we analyzed TIF1γ expression in human pancreatic tumors. In our mouse model, we showed that Tif1γ was dispensable for normal pancreatic development but cooperated with Kras activation to induce pancreatic tumors reminiscent of human Intraductal Papillary Mucinous Neoplasms (IPMNs). Interestingly, these cystic lesions resemble those observed in Pdx1-Cre;LSL-KrasG12D;Smad4lox/lox mice described by others. However, distinctive characteristics, such as the systematic presence of endocrine pseudo-islets within the papillary projections, suggest that SMAD4 and TIF1γ don't have strictly redundant functions. Finally, we report that TIF1γ expression is markedly down-regulated in human pancreatic tumors by quantitative RT–PCR and immunohistochemistry supporting the relevance of these findings to human malignancy. This study suggests that TIF1γ is critical for tumor suppression in the pancreas, brings new insight into the genetics of pancreatic cancer, and constitutes a promising model to decipher the respective roles of SMAD4 and TIF1γ in the multifaceted functions of TGFβ in carcinogenesis and development. Inactivation of the TGFβ tumor suppressor pathway contributes to the progression of Pancreatic Ductal AdenoCarcinoma (PDAC), a devastating malignancy. Transcriptional Intermediary Factor 1γ (TIF1γ) has recently been proposed to be involved in TGFβ signaling, a pathway inactivated in virtually all cases of this malignancy. To address the role of TIF1γ in pancreatic carcinogenesis, we used conditional Tif1γ knockout mice. In a genetic background expressing a constitutively active mutation of KRAS oncogene (KrasG12D) recurrently found in patients with PDAC, Tif1γ inactivation induces pancreatic precancerous lesions resembling those observed in the absence of Smad4, a key player involved TGFβ signal transduction. This observation strengthens the notion that TIF1γ plays an active role in TGFβ signaling. Interestingly, we also found that TIF1γ expression was markedly down-regulated in human pancreatic tumors supporting the relevance of our findings to human malignancy. Characterization of new players involved in the outbreak of early pancreatic lesions that will eventually evolve into invasive pancreatic cancer is crucial to detect the disease earlier and eventually develop new therapeutic drugs.
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DOI：
10.1073/pnas.0810111105
发表时间：
2008-12-02
影响因子：
11.1
作者：
Jean-Paul, De La O.;Emerson, Lyska L.;Murtaugh, L. Charles
通讯作者：
Murtaugh, L. Charles
影响因子：
2
作者：
Albores-Saavedra, Jorge;Weimersheimer-Sandoval, Mariana;Henson, Donald Earl
通讯作者：
Henson, Donald Earl
影响因子：
3.5
作者：
Furukawa, T;Klöppel, G;Yonezawa, S
通讯作者：
Yonezawa, S
影响因子：
64.5
作者：
Dupont, Sirio;Mamidi, Anant;Piccolo, Stefano
通讯作者：
Piccolo, Stefano
影响因子：
50.3
作者：
Hingorani, SR;Wang, LF;Tuveson, DA
通讯作者：
Tuveson, DA