Proteomics identifies new therapeutic targets of early-stage hepatocellular carcinoma
Ying Jiang, Aihua Sun, Yang Zhao, Wantao Ying, Huichuan Sun, Xinrong Yang, Baocai Xing, Wei Sun, Liangliang Ren, Bo Hu, Chaoying Li, Li Zhang, Guangrong Qin, Menghuan Zhang, Ning Chen, Manli Zhang, Yin Huang, Jinan Zhou, Yan Zhao, Mingwei Liu, Xiaodong Zhu, Yang Qiu, Yanjun Sun, Cheng Huang, Meng Yan, Mingchao Wang, Wei Liu, Fang Tian, Huali Xu, Jian Zhou, Zhenyu Wu, Tieliu Shi, Weimin Zhu, Jun Qin, Lu Xie, Jia Fan, Xiaohong Qian, Fuchu He & Chinese Human Proteome Project (CNHPP) Consortium
Abstract
Hepatocellular carcinoma is the third leading cause of deaths from cancer worldwide. Infection with the hepatitis B virus is one of the leading risk factors for developing hepatocellular carcinoma, particularly in East Asia1. Although surgical treatment may be effective in the early stages, the five-year overall rate of survival after developing this cancer is only 50–70%2. Here, using proteomic and phospho-proteomic profiling, we characterize 110 paired tumour and non-tumour tissues of clinical early-stage hepatocellular carcinoma related to hepatitis B virus infection. Our quantitative proteomic data highlight heterogeneity in early-stage hepatocellular carcinoma: we used this to stratify the cohort into the subtypes S-I, S-II and S-III, each of which has a different clinical outcome. S-III, which is characterized by disrupted cholesterol homeostasis, is associated with the lowest overall rate of survival and the greatest risk of a poor prognosis after first-line surgery. The knockdown of sterol O-acyltransferase 1 (SOAT1)—high expression of which is a signature specific to the S-III subtype—alters the distribution of cellular cholesterol, and effectively suppresses the proliferation and migration of hepatocellular carcinoma. Finally, on the basis of a patient-derived tumour xenograft mouse model of hepatocellular carcinoma, we found that treatment with avasimibe, an inhibitor of SOAT1, markedly reduced the size of tumours that had high levels of SOAT1 expression. The proteomic stratification of early-stage hepatocellular carcinoma presented in this study provides insight into the tumour biology of this cancer, and suggests opportunities for personalized therapies that target it.
文章链接：https://www.nature.com/articles/s41586-019-0987-8
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