Mutant IDH inhibits HNF-4α to block hepatocyte differentiation and promote biliary cancer.
Mutant IDH inhibits HNF-4α to block hepatocyte differentiation and promote biliary cancer.
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DOI：
10.1038/nature13441
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发表时间：
2014-09-04
期刊：
影响因子：
64.8
通讯作者：
Bardeesy, Nabeel
中科院分区：
文献类型：
--
作者：
Saha, Supriya K.;Parachoniak, Christine A.;Ghanta, Krishna S.;Fitamant, Julien;Ross, Kenneth N.;Najem, Mortada S.;Gurumurthy, Sushma;Akbay, Esra A.;Sia, Daniela;Cornella, Helena;Miltiadous, Oriana;Walesky, Chad;Deshpande, Vikram;Zhu, Andrew X.;Hezel, Aram F.;Yen, Katharine E.;Straley, Kimberly S.;Travins, Jeremy;Popovici-Muller, Janeta;Gliser, Camelia;Ferrone, Cristina R.;Apte, Udayan;Llovet, Josep M.;Wong, Kwok-Kin;Ramaswamy, Sridhar;Bardeesy, Nabeel
异柠檬酸脱氢酶1 （IDH1）和IDH2突变是肝内胆管癌（IHCC）中最常见的基因改变。IHCC和其他恶性肿瘤中的突变IDH蛋白获得异常的酶活性，使其能够将α -酮戊二酸（αKG）转化为2-羟基戊二酸（2HG），从而抑制多种αKG依赖性双加氧酶的活性，并导致细胞分化、存活和细胞外基质成熟的改变。然而，IDH突变导致肿瘤形成的分子途径尚不清楚。在这里，我们发现突变型IDH通过产生2HG和抑制HNF4α（肝细胞身份和静止的主要调节因子）来阻止肝祖细胞进行肝细胞分化。相应地，在成年肝脏中表达突变型IDH的基因工程小鼠模型（GEMMs）对肝损伤表现出异常反应，其特征是HNF4α沉默、肝细胞分化受损和细胞增殖水平显著升高。此外，突变的IDH和激活的Kras，这些基因改变在人类IHCC中共存，共同驱动肝祖细胞的扩张，恶性前胆道病变的发展，并发展为转移性IHCC。这些研究提供了IDH突变、肝细胞命运和IHCC发病机制之间的功能联系，并提出了IDH驱动的恶性肿瘤的一种新的GEMM。
Mutations in Isocitrate dehydrogenase 1 (IDH1) and IDH2 are among the most common genetic alterations in intrahepatic cholangiocarcinoma (IHCC), a deadly liver cancer. Mutant IDH proteins in IHCC and other malignancies acquire an abnormal enzymatic activity allowing them to convert alpha-ketoglutarate (αKG) to 2-hydroxyglutarate (2HG), which inhibits the activity of multiple αKG-dependent dioxygenases, and results in alterations in cell differentiation, survival, and extracellular matrix maturation. However, the molecular pathways by which IDH mutations lead to tumour formation remain unclear. Here we show that mutant IDH blocks liver progenitor cells from undergoing hepatocyte differentiation through the production of 2HG and suppression of HNF4α, a master regulator of hepatocyte identity and quiescence. Correspondingly, genetically engineered mouse models (GEMMs) expressing mutant IDH in the adult liver show aberrant response to hepatic injury, characterized by HNF4α silencing, impaired hepatocyte differentiation and markedly elevated levels of cell proliferation. Moreover, mutant IDH and activated Kras, genetic alterations that co-exist in a subset of human IHCCs, cooperate to drive the expansion of liver progenitor cells, development of premalignant biliary lesions, and progression to metastatic IHCC. These studies provide a functional link between IDH mutations, hepatic cell fate, and IHCC pathogenesis, and present a novel GEMM of IDH-driven malignancy.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.8
作者：
Lu, Chao;Ward, Patrick S.;Kapoor, Gurpreet S.;Rohle, Dan;Turcan, Sevin;Abdel-Wahab, Omar;Edwards, Christopher R.;Khanin, Raya;Figueroa, Maria E.;Melnick, Ari;Wellen, Kathryn E.;O'Rourke, Donald M.;Berger, Shelley L.;Chan, Timothy A.;Levine, Ross L.;Mellinghoff, Ingo K.;Thompson, Craig B.
通讯作者：
Thompson, Craig B.
影响因子：
29.4
作者：
Sia D;Hoshida Y;Villanueva A;Roayaie S;Ferrer J;Tabak B;Peix J;Sole M;Tovar V;Alsinet C;Cornella H;Klotzle B;Fan JB;Cotsoglou C;Thung SN;Fuster J;Waxman S;Garcia-Valdecasas JC;Bruix J;Schwartz ME;Beroukhim R;Mazzaferro V;Llovet JM
通讯作者：
Llovet JM
影响因子：
5.8
作者：
Michalopoulos, George K.
通讯作者：
Michalopoulos, George K.
影响因子：
30.8
作者：
Bluteau, O;Jeannot, E;Zucman-Rossi, J
通讯作者：
Zucman-Rossi, J