Molecular profiling of nonalcoholic fatty liver disease-associated hepatocellular carcinoma using SB transposon mutagenesis.
Molecular profiling of nonalcoholic fatty liver disease-associated hepatocellular carcinoma using SB transposon mutagenesis.
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DOI：
10.1073/pnas.1808968115
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发表时间：
2018-10-30
影响因子：
11.1
通讯作者：
Copeland NG
中科院分区：
文献类型：
--
作者：
Kodama T;Yi J;Newberg JY;Tien JC;Wu H;Finegold MJ;Kodama M;Wei Z;Tamura T;Takehara T;Johnson RL;Jenkins NA;Copeland NG
非酒精性脂肪性肝病(NAFLD)是西方国家肝细胞癌(HCC)上升最快的原因，然而，NAFLD-HCC的分子机制仍不清楚。利用睡美人转座子在两种NAFLD-HCC小鼠模型中的突变，我们鉴定了数百个NAFLD-HCC候选癌症基因，这些基因在通常与NAFLD和肝癌相关的途径中富含。我们还发现，Sav1在河马信号通路中发挥作用，也是SB在两次筛查中发现的最频繁的突变基因，它通过抑制河马信号通路的下游效应因子Yap，与PI3K信号协同作用，阻止脂肪性肝炎的进展和随后的肝细胞癌的发展。因此，我们的正向基因筛查已经确定了驱动NAFLD-肝细胞癌发展的途径和基因。非酒精性脂肪性肝病(NAFLD)是西方国家肝细胞癌(HCC)发病率上升最快的原因，但其发病的分子机制仍不清楚。为了确定NAFLD-肝癌的分子驱动因素，我们在肝脏特异的Pten基因敲除和高脂饮食喂养的小鼠中进行了睡美人(SB)转座子突变筛选，这些小鼠是NAFLD-HCC的小鼠模型。SB突变在两个模型中都加速了肝癌的形成，并分别确定了588和376个候选癌症基因(CCG)；257个CCG在两个筛查中都是共同的，并在已知对人类肝细胞癌重要的信号通路中丰富。将这些CCG与以前在乙肝病毒诱导的肝细胞癌SB筛查中确定的CCG进行比较，发现在所有筛查中都发生突变的141个CCG的核心集合。41个CCG似乎是NAFLD-HCC的特异性基因，包括Sav1，它是河马信号通路的一个组成部分，也是在两次NAFLD-HCC筛查中发现的最频繁突变的基因。肝脏特异性Sav1的缺失被发现促进肝脏脂质堆积、细胞凋亡和纤维化，导致肝脏特异性Pten突变小鼠肝癌发生的加速。Sav1/Pten双突变肝脏还显示出肝脏祖细胞(LPCS)标志物的显著上调，以及作为河马信号主要下游效应因子的YAP的协同激活。YAP激活联合Pten失活可促进体外LPCs的生长和球体形成，并诱导其在同种异体移植体内恶性转化。因此，我们在小鼠身上进行的正向遗传筛查已经确定了驱动NAFLD-HCC发展的途径和基因。
Nonalcoholic fatty liver disease (NAFLD) is the fastest rising cause of hepatocellular carcinoma (HCC) in Western countries; however, the molecular mechanisms driving NAFLD-HCC remain elusive. Using Sleeping Beauty transposon mutagenesis in two mouse models of NAFLD-HCC, we identified hundreds of NAFLD-HCC candidate cancer genes that were enriched in pathways often associated with NAFLD and HCC. We also showed that Sav1, which functions in the Hippo signaling pathway and was the most frequently mutated gene identified by SB in both screens, prevents progression of steatohepatitis and subsequent HCC development in coordination with PI3K signaling via suppression of Yap, a downstream effector of the Hippo pathway. Our forward genetic screens have thus identified pathways and genes driving the development of NAFLD-HCC. Nonalcoholic fatty liver disease (NAFLD) is the fastest rising cause of hepatocellular carcinoma (HCC) in Western countries; however, the molecular mechanisms that cause NAFLD-HCC remain elusive. To identify molecular drivers of NAFLD-HCC, we performed Sleeping Beauty (SB) transposon mutagenesis screens in liver-specific Pten knockout and in high-fat diet-fed mice, which are murine models of NAFLD-HCC. SB mutagenesis accelerated liver tumor formation in both models and identified 588 and 376 candidate cancer genes (CCGs), respectively; 257 CCGs were common to both screens and were enriched in signaling pathways known to be important for human HCC. Comparison of these CCGs with those identified in a previous SB screen of hepatitis B virus-induced HCC identified a core set of 141 CCGs that were mutated in all screens. Forty-one CCGs appeared specific for NAFLD-HCC, including Sav1, a component of the Hippo signaling pathway and the most frequently mutated gene identified in both NAFLD-HCC screens. Liver-specific deletion of Sav1 was found to promote hepatic lipid accumulation, apoptosis, and fibrogenesis, leading to the acceleration of hepatocarcinogenesis in liver-specific Pten mutant mice. Sav1/Pten double-mutant livers also showed a striking up-regulation of markers of liver progenitor cells (LPCs), along with synergistic activation of Yap, which is a major downstream effector of Hippo signaling. Lastly, Yap activation, in combination with Pten inactivation, was found to accelerate cell growth and sphere formation of LPCs in vitro and induce their malignant transformation in allografts. Our forward genetic screens in mice have thus identified pathways and genes driving the development of NAFLD-HCC.
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影响因子：
30.8
作者：
Bard-Chapeau, Emilie A.;Nguyen, Anh-Tuan;Rust, Alistair G.;Sayadi, Ahmed;Lee, Philip;Chua, Belinda Q.;New, Lee-Sun;de Jong, Johann;Ward, Jerrold M.;Chin, Christopher K. Y.;Chew, Valerie;Han Chong Toh;Abastado, Jean-Pierre;Benoukraf, Touati;Soong, Richie;Bard, Frederic A.;Dupuy, Adam J.;Johnson, Randy L.;Radda, George K.;Chan, Eric Chun Yong;Wessels, Lodewyk F. A.;Adams, David J.;Jenkins, Nancy A.;Copeland, Neal G.
通讯作者：
Copeland, Neal G.
影响因子：
10.5
作者：
Meng Z;Moroishi T;Guan KL
通讯作者：
Guan KL
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.5
作者：
Cancer Genome Atlas Research Network. Electronic address: wheeler@bcm.edu;Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
DOI：
10.1038/nrc1299
发表时间：
2004-03
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
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