Guo Jun, Deng Nan, Xu Yong, Li Lei, Kuang Dong, Li Min, Li Xiaolei, Xu Zhong, Xiang Ming, Xu Chuanrui
School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Department of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Pharmacol Res. 2021 Feb;164:105365. doi: 10.1016/j.phrs.2020.105365. Epub 2020 Dec 8.
Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the most prevalent types of primary liver cancer. Compared with HCC, for which several drugs have been approved, ICC is associated with shorter survival, and no drug has been approved for this type. Previously, we reported that Bmi1 drives HCC and is required for HCC development and growth. However, whether Bmi1 plays a critical role in ICC is not clear, although it reportedly is highly expressed in ICC. Therefore, we investigated its role in ICC. Here, we report that Bmi1 promotes ICC initiation and progression independent of the Ink4A/Arf pathway, a canonical downstream pathway of Bmi1. We found that Bmi1 is overexpressed in human ICC. Co-expression of Bmi1 and NRas induced ICC formation in mice. Knockdown or inactivation of Bmi1 inhibited ICC growth in vitro. Liver-specific knockout or inactivation of Bmi1 remarkably suppressed ICC tumor formation and development in vivo. Mechanistically, no correlation between Bmi1 and Ink4A/Arf levels was found in mouse and human ICC tissues. Together, our data indicate that Bmi1 functions as an oncogene independent of repression of the Ink4A/Arf locus in ICC and that it can serve as a target for ICC treatment.
肝细胞癌（HCC）和肝内胆管癌（ICC）是原发性肝癌最常见的类型。与已获批多种药物治疗的HCC相比，ICC患者的生存期较短，且尚无获批用于该类型癌症的药物。此前，我们报道过Bmi1驱动HCC发生，并且是HCC发生和生长所必需的。然而，尽管据报道Bmi1在ICC中高表达，但它是否在ICC中发挥关键作用尚不清楚。因此，我们研究了它在ICC中的作用。在此，我们报告Bmi1促进ICC的起始和进展，且不依赖于Bmi1的经典下游通路Ink4A/Arf通路。我们发现Bmi1在人类ICC中过表达。Bmi1与NRAS共表达可诱导小鼠发生ICC。敲低或失活Bmi1可在体外抑制ICC生长。肝脏特异性敲除或失活Bmi1可在体内显著抑制ICC肿瘤的形成和发展。从机制上来说，在小鼠和人类ICC组织中未发现Bmi1与Ink4A/Arf水平之间存在相关性。总之，我们的数据表明，Bmi1在ICC中作为一种癌基因发挥作用，且不依赖于对Ink4A/Arf基因座的抑制作用，它可作为ICC治疗的一个靶点。
