Hepatocyte-specific deletion of the antiapoptotic protein myeloid cell leukemia-1 triggers proliferation and hepatocarcinogenesis in mice.
Hepatocyte-specific deletion of the antiapoptotic protein myeloid cell leukemia-1 triggers proliferation and hepatocarcinogenesis in mice.
复制标题
DOI：
10.1002/hep.23479
复制
发表时间：
2010-04
期刊：
影响因子：
13.5
通讯作者：
Schulze-Bergkamen, Henning
中科院分区：
文献类型：
--
作者：
Weber, Achim;Boger, Regina;Vick, Binje;Urbanik, Toni;Haybaeck, Johannes;Zoller, Stefan;Teufel, Andreas;Krammer, Peter H.;Opferman, Joseph T.;Galle, Peter R.;Schuchmann, Marcus;Heikenwalder, Mathias;Schulze-Bergkamen, Henning
肝细胞凋亡的调节对肝脏的稳态至关重要。肝细胞对细胞凋亡的敏感性增加导致慢性肝损伤，而细胞凋亡抵抗与肝癌发生和对治疗诱导的细胞死亡无反应性有关。最近，我们已经证明了抗凋亡Bcl-2家族成员髓样细胞白血病-1（Mcl-1）在肝细胞存活中的重要作用。在肝细胞特异性缺乏Mcl-1的小鼠中（Mcl-1Δhep），自发性细胞凋亡引起严重的肝损伤。在这里，我们表明，慢性增加的肝细胞凋亡与肝细胞增殖导致肝细胞癌（HCC）。在>50%的Mcl-1Δhep小鼠中，在8月龄时就已经观察到肝细胞肿瘤形成，而12月龄的野生型和杂合Mcl-1flox/wt小鼠没有肿瘤。肿瘤表现为异质性谱，从小的异型增生结节到HCC。肿瘤的肿瘤性质通过组织学、HCC标志物谷氨酰胺合成酶的表达和染色体畸变来证实。Mcl-1Δhep小鼠的肝癌发生被生存素水平的显著增加所阻止，生存素是有丝分裂的重要调节因子，在常见的人类癌症中选择性过表达。目前的研究提供了体内证据，肝细胞凋亡的增加不仅损害肝脏的稳态，但也伴随着肝细胞增殖和肝癌的发生。我们的研究结果可能对理解与糖尿病相关的人类肝脏疾病有意义。多细胞生物的生存依赖于组织内环境的稳定。在生理条件下，细胞凋亡通过清除受损的肝细胞而有助于肝脏稳态。增殖、生长和程序性肝细胞死亡是正常肝脏中高度协调和严格控制的事件。一方面，增加的凋亡敏感性有助于肝损伤。另一方面，有缺陷的细胞凋亡被证明会导致过度的肝细胞存活，并已成为癌前肝细胞获得比正常肝细胞竞争优势的主要机制。各种分子改变已被表征为引起细胞凋亡调节的不平衡。其中包括p53信号传导、死亡受体表达、生长因子和线粒体完整性的改变。促凋亡信号的活性降低以及抗凋亡事件的活性增加与HCC的发展和进展相关。触发肝细胞凋亡的主要细胞变化是线粒体外膜的透化，随后释放促凋亡因子。Bcl-2蛋白家族对线粒体完整性起着关键作用，并且促凋亡和抗凋亡家族成员之间的选择性相互作用调节线粒体活化。Bcl-2家族成员在Bcl-2同源区（BH 1-BH 4）内是相似的，并且可以分为促凋亡和抗凋亡Bcl-2蛋白。促凋亡Bcl-2蛋白包括多结构域成员，其缺乏BH 4结构域（例如Bax、巴克），和（2）仅BH 3蛋白，其缺乏BH 1、2和4结构域（例如Bid、Noxa、Puma）。仅BH 3蛋白通过感知细胞损伤启动线粒体信号级联。在活化后，仅BH 3蛋白被释放以中和抗凋亡Bcl-2蛋白。随后，Bax和巴克触发线粒体膜渗漏和线粒体蛋白质的释放，包括细胞色素c、Smac/DIABLO（第二种来源于caspase的激活剂/具有低pI的直接IAP结合蛋白）和凋亡诱导因子（AIF）。Smac/DIABLO蛋白属于凋亡抑制蛋白（inhibitors of apoptosis proteins，IAP）家族，包括IAP 1/2、布鲁斯、NAIP、ILP 2、ML-IAP、survivin和XIAP。XIAP是一种直接的半胱天冬酶抑制剂。其他IAP包括生存素，除了半胱天冬酶抑制外，还具有多种功能，例如，触发泛素化过程。抗凋亡Bcl-2家族成员（例如Bcl-2、Bcl-xL和Mcl-1）与Bax和巴克相互作用以抑制线粒体的活化。Bcl-xL和Mcl-1都已被鉴定为肝脏中主要的抗凋亡Bcl-2蛋白。Mcl-1Δhep小鼠的肝脏稳态严重紊乱。在Mcl-1Δhep小鼠肝脏中观察到自发性肝细胞凋亡，肝细胞严重损伤，肝细胞对促凋亡刺激的敏感性增加。此外，Mcl-1已被证明在人HCC的亚组中高度表达，有助于癌细胞的凋亡抗性。因此，通过降低Mcl-1的水平或通过使其功能失活来消除Mcl-1的促存活功能，已经显示出关于HCC治疗的有希望的结果。在这项研究中，我们发现，肝脏特异性的Mcl-1耗竭增加肝细胞凋亡，诱导肝细胞增殖，并导致在没有明显炎症的情况下发生HCC。
Regulation of hepatocellular apoptosis is crucial for liver homeostasis. Increased sensitivity of hepatocytes towards apoptosis results in chronic liver injury, whereas apoptosis resistance is linked to hepatocarcinogenesis and non-responsiveness to therapy-induced cell death. Recently, we have demonstrated an essential role of the anti-apoptotic Bcl-2 family member Myeloid cell leukemia-1 (Mcl-1) in hepatocyte survival. In mice lacking Mcl-1 specifically in hepatocytes (Mcl-1Δhep) spontaneous apoptosis caused severe liver damage. Here, we demonstrate that chronically increased apoptosis of hepatocytes coincides with strong hepatocyte proliferation resulting in hepatocellular carcinoma (HCC). Liver cell tumor formation was observed in >50% of Mcl-1Δhep mice already by the age of 8 months, whereas 12 month-old wild-type and heterozygous Mcl-1flox/wt mice lacked tumors. Tumors revealed a heterogenous spectrum ranging from small dysplastic nodules to HCC. The neoplastic nature of the tumors was confirmed by histology, expression of the HCC marker glutamine synthetase and chromosomal aberrations. Liver carcinogenesis in Mcl-1Δhep mice was paralleled by markedly increased levels of survivin, an important regulator of mitosis which is selectively overexpressed in common human cancers. The present study provides in vivo evidence that increased apoptosis of hepatocytes not only impairs liver homeostasis but is also accompanied by hepatocyte proliferation and hepatocarcinogenesis. Our findings might have implications for understanding apoptosis-related human liver diseases. The survival of multicellular organisms depends on the maintenance of tissue homeostasis. Under physiological conditions apoptosis contributes to liver homeostasis by removing damaged hepatocytes. Proliferation, growth and programmed hepatocyte cell death are highly coordinated and tightly controlled events in the normal liver. On the one hand, increased apoptosis sensitivity contributes to liver injury. On the other hand, defective apoptosis was demonstrated to lead to excessive hepatocellular survival and has emerged as a major mechanism by which pre-malignant hepatocytes obtain a competitive advantage over normal liver cells. Various molecular alterations have been characterized causing an imbalance in the regulation of apoptosis. Among these are alterations in p53 signalling, expression of death receptors, growth factors and mitochondrial integrity. Decreased activity of pro-apoptotic signalling as well as increased activity of anti-apoptotic events are associated with HCC development and progression. Among the main cellular changes that trigger apoptosis of hepatocytes is the permeabilization of the outer mitochondrial membrane followed by the release of pro-apoptotic factors. The Bcl-2 protein family plays a pivotal role for mitochondrial integrity and the selective interactions between pro- and anti-apoptotic family members regulate mitochondrial activation. Bcl-2 family members are similar within the Bcl-2 homology regions (BH1-BH4) and can be divided in pro- and anti-apoptotic Bcl-2 proteins. Pro-apoptotic Bcl-2 proteins comprise multi-domain members, which lack the BH4 domain (e.g. Bax, Bak), and (2) BH3-only proteins, which lack BH1, 2 and 4 domains (e.g. Bid, Noxa, Puma). BH3-only proteins initiate the mitochondrial signalling cascade by sensing cellular damage. After activation, BH3-only proteins are released to neutralise anti-apoptotic Bcl-2 proteins. Subsequently, Bax and Bak trigger mitochondrial membrane leakage and the release of mitochondrial proteins, including cytochrome c, Smac/DIABLO (second mitochondria-derived activator of caspases/direct IAP-binding protein with low pI) and apoptosis-inducing factor (AIF). Smac/DIABLO proteins inactivate the IAP (inhibitors of apoptosis proteins) family, which consists of IAP1/2, BRUCE, NAIP, ILP2, ML-IAP, survivin and XIAP. XIAP is a direct caspase inhibitor. Other IAPs including survivin have several functions apart from caspase inhibition, eg, triggering of ubiquitination processes. Anti-apoptotic Bcl-2 family members (eg, Bcl-2, Bcl-xL and Mcl-1), interact with Bax and Bak to inhibit the activation of mitochondria. Both Bcl-xL and Mcl-1 have been identified as major anti-apoptotic Bcl-2 proteins in the liver. Liver homeostasis is severely disturbed in Mcl-1Δhep mice. Spontaneous hepatocyte apoptosis was observed in livers of Mcl-1Δhep mice in profound liver cell damage and increased susceptibility of hepatocytes towards pro-apoptotic stimuli. In addition, Mcl-1 has been shown to be highly expressed in a subset of human HCC, contributing to apoptosis resistance of cancer cells. Thus, abrogation of the pro-survival function of Mcl-1 either by diminishing its levels or by inactivating its function, have shown promising results with regards to treatment of HCC. In this study, we show that liver-specific depletion of Mcl-1 increases hepatocyte apoptosis, induces hepatocellular proliferation and causes HCC in the absence of overt inflammation.
登录
查看更多内容
影响因子：
3.8
作者：
Schulze-Bergkamen H;Fleischer B;Schuchmann M;Weber A;Weinmann A;Krammer PH;Galle PR
通讯作者：
Galle PR
影响因子：
50.3
作者：
Luedde, Tom;Beraza, Naiara;Pasparakis, Manolis
通讯作者：
Pasparakis, Manolis
影响因子：
6.4
作者：
Nakagawa, Hayato;Maeda, Shin;Omata, Masao
通讯作者：
Omata, Masao
影响因子：
50.3
作者：
Haybaeck J;Zeller N;Wolf MJ;Weber A;Wagner U;Kurrer MO;Bremer J;Iezzi G;Graf R;Clavien PA;Thimme R;Blum H;Nedospasov SA;Zatloukal K;Ramzan M;Ciesek S;Pietschmann T;Marche PN;Karin M;Kopf M;Browning JL;Aguzzi A;Heikenwalder M
通讯作者：
Heikenwalder M
影响因子：
4.8
作者：
Li, SC;Zhao, YG;Yin, XM
通讯作者：
Yin, XM