CRISPR activation screening in a mouse model for drivers of hepatocellular carcinoma growth and metastasis

Bei Zhang; Zhiyao Ren; Hongmei Zheng; Meilan Lin; Guobing Chen; Oscar Junhong Luo; Guodong Zhu

doi:10.1016/j.isci.2023.106099

CRISPR activation screening in a mouse model for drivers of hepatocellular carcinoma growth and metastasis

iScience. 2023 Feb 2;26(3):106099. doi: 10.1016/j.isci.2023.106099. eCollection 2023 Mar 17.

Authors

Bei Zhang^{1

2}, Zhiyao Ren^{2

3

4}, Hongmei Zheng⁵, Meilan Lin¹, Guobing Chen^{6

7}, Oscar Junhong Luo^{2

7}, Guodong Zhu^{1

3}

Affiliations

¹ Departments of Geriatrics and Oncology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China.
² Department of Systems Biomedical Sciences, School of Medicine, Jinan University, Guangzhou, China.
³ Guangzhou Geriatric Hospital, Guangzhou, China.
⁴ Collaborative Innovation Center for Civil Affairs of Guangzhou, Guangzhou, China.
⁵ Department of Breast Surgery, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology and Hubei Provincial Clinical Research Center for Breast Cancer, Wuhan, Hubei, China.
⁶ Guangdong-Hong Kong-Macau Great Bay Area Geroscience Joint Laboratory, Guangzhou, China.
⁷ Department of Microbiology and Immunology, Institute of Geriatric Immunology, School of Medicine, Jinan University, Guangzhou, China.

Abstract

Hepatocellular carcinoma (HCC) remains a major cause of cancer-related mortality worldwide. Here we described a genome-wide screen by CRISPR activation (CRISPRa) library in vivo for drivers of HCC growth and metastasis. Pathological results showed the cell population formed highly metastatic tumors in lung after being mutagenized with CRISPRa. In vitro validation indicated overexpression of XAGE1B, PLK4, LMO1 and MYADML2 promoted cells proliferation and invasion, and the inhibition suppressed HCC progress. In addition, we reported high MYADML2 protein level exhibited worse overall survival in HCC, which increased significantly in patients over 60 years. Moreover, high MYADML2 reduced the sensitivity to chemotherapeutic drugs. Interestingly, immune cell infiltration analysis showed that the dendritic cells, macrophages, and so forth might play important role in HCC progress. In brief, we provides a roadmap for screening functional genes related to HCC invasion and metastasis in vivo, which may provide new potential targets for the treatment of HCC.

Keywords: Cancer; Cell biology; Molecular biology.