Wu Guang, Wilson George, George Jacob, Qiao Liang
Storr Liver Center, Westmead Millennium Institute for Medical Research, University of Sydney at Westmead Clinical School at Westmead Hospital, Westmead, NSW 2145, Australia.
Curr Gene Ther. 2015;15(2):171-81. doi: 10.2174/1566523214666141224100319.
Notch signaling is an evolutionarily conserved pathway crucial for the development and homeostasis of many organs including liver. Aberrant Notch signaling has been mechanistically linked to cancer development including liver cancer. The two principal types of liver cancer are hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (IHCC). HCCs comprise over 80% of all liver cancers and are the 6(th) most common malignancy worldwide. Hepatocellular carcinoma is also a cancer with an extremely poor prognosis, being the 3(rd) commonest cause of cancer-related mortality. Accumulating evidence indicates that the role of Notch signaling in liver cancer is more complex than once thought and is dependent on the expression of specific Notch signaling components and the complex crosstalk with other signaling pathways. Currently there are a variety of gene therapy based approaches used to target Notch signaling in preclinical studies to successfully treat liver cancer including neutralizing antibodies, siRNA, shRNA and miRNA. The use of targeted anti-Notch therapy in the clinic to treat liver cancer will require considerable refinement of our current knowledge on the regulation of Notch signaling components and their effects in both normal and malignant liver cells in order to target specific Notch subunits which are critical to liver cancer tumorigenesis but not to the homeostasis of normal cells. Using this approach will reduce the major side effects, which are frequently seen in patients treated with GSIs to inhibit the entire Notch signaling pathway. Here our understanding of Notch signaling is reviewed, highlighting its function in liver cancer initiation, progress and opportunities for liver cancer therapies.
Notch信号通路是一条在进化上保守的信号通路，对包括肝脏在内的许多器官的发育和内环境稳定至关重要。异常的Notch信号通路在机制上与包括肝癌在内的癌症发展相关。肝癌的两种主要类型是肝细胞癌（HCC）和肝内胆管癌（IHCC）。HCC占所有肝癌的80%以上，是全球第六大常见恶性肿瘤。肝细胞癌也是一种预后极差的癌症，是癌症相关死亡的第三大常见原因。越来越多的证据表明，Notch信号通路在肝癌中的作用比以往认为的更为复杂，并且取决于特定Notch信号成分的表达以及与其他信号通路的复杂相互作用。目前，在临床前研究中有多种基于基因治疗的方法用于靶向Notch信号通路以成功治疗肝癌，包括中和抗体、siRNA、shRNA和miRNA。在临床上使用靶向抗Notch疗法治疗肝癌将需要我们对Notch信号成分的调节及其在正常和恶性肝细胞中的作用的现有知识进行大量完善，以便靶向对肝癌肿瘤发生至关重要但对正常细胞内环境稳定不重要的特定Notch亚基。采用这种方法将减少主要副作用，这些副作用在使用γ-分泌酶抑制剂（GSIs）抑制整个Notch信号通路的患者中经常出现。在此，我们对Notch信号通路的理解进行综述，重点介绍其在肝癌起始、进展中的作用以及肝癌治疗的机会。
