Tschida Barbara R, Temiz Nuri A, Kuka Timothy P, Lee Lindsey A, Riordan Jesse D, Tierrablanca Carlos A, Hullsiek Robert, Wagner Sandra, Hudson Wendy A, Linden Michael A, Amin Khalid, Beckmann Pauline J, Heuer Rachel A, Sarver Aaron L, Yang Ju Dong, Roberts Lewis R, Nadeau Joseph H, Dupuy Adam J, Keng Vincent W, Largaespada David A
Department of Pediatrics, Masonic Cancer Center and Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota.
Pacific Northwest Research Institute, Seattle, Washington.
Cancer Res. 2017 Dec 1;77(23):6576-6588. doi: 10.1158/0008-5472.CAN-17-2281. Epub 2017 Oct 9.
Hepatic steatosis is a strong risk factor for the development of hepatocellular carcinoma (HCC), yet little is known about the molecular pathology associated with this factor. In this study, we performed a forward genetic screen using (SB) transposon insertional mutagenesis in mice treated to induce hepatic steatosis and compared the results to human HCC data. In humans, we determined that steatosis increased the proportion of female HCC patients, a pattern also reflected in mice. Our genetic screen identified 203 candidate steatosis-associated HCC genes, many of which are altered in human HCC and are members of established HCC-driving signaling pathways. The protein kinase A/cyclic AMP signaling pathway was altered frequently in mouse and human steatosis-associated HCC. We found that activated PKA expression drove steatosis-specific liver tumorigenesis in a mouse model. Another candidate HCC driver, the -acetyltransferase , which we found to be overexpressed in human steatosis-associated HCC and associated with decreased survival in human HCC, also drove liver tumorigenesis in a steatotic mouse model. This study identifies genes and pathways promoting HCC that may represent novel targets for prevention and treatment in the context of hepatic steatosis, an area of rapidly growing clinical significance. .
肝脂肪变性是肝细胞癌（HCC）发生的一个重要危险因素，但与该因素相关的分子病理学却知之甚少。在本研究中，我们利用睡美人（SB）转座子插入诱变技术，对经处理诱导肝脂肪变性的小鼠进行了正向遗传学筛选，并将结果与人类HCC数据进行了比较。在人类中，我们确定脂肪变性增加了女性HCC患者的比例，这一模式在小鼠中也有体现。我们的基因筛选确定了203个与脂肪变性相关的HCC候选基因，其中许多基因在人类HCC中发生改变，并且是已确立的HCC驱动信号通路的成员。蛋白激酶A/环磷酸腺苷信号通路在小鼠和人类脂肪变性相关的HCC中经常发生改变。我们发现，激活的蛋白激酶A表达在小鼠模型中驱动了脂肪变性特异性肝肿瘤发生。另一个候选的HCC驱动因子，我们发现其在人类脂肪变性相关的HCC中过表达，并且与人类HCC患者生存率降低相关，它在脂肪变性小鼠模型中也驱动了肝肿瘤发生。这项研究确定了促进HCC发生的基因和信号通路，它们可能代表了在肝脂肪变性背景下预防和治疗的新靶点，而肝脂肪变性是一个临床意义迅速增加的领域。
