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

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.

SUBMITTER: Zhang B

PROVIDER: S-EPMC9947337 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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

Zhang Bei B Ren Zhiyao Z Zheng Hongmei H Lin Meilan M Chen Guobing G Luo Oscar Junhong OJ Zhu Guodong G

iScience 20230202 3

Hepatocellular carcinoma (HCC) remains a major cause of cancer-related mortality worldwide. Here we described a genome-wide screen by CRISPR activation (CRISPRa) library <i>in vivo</i> for drivers of HCC growth and metastasis. Pathological results showed the cell population formed highly metastatic tumors in lung after being mutagenized with CRISPRa. <i>In vitro</i> validation indicated overexpression of XAGE1B, PLK4, LMO1 and MYADML2 promoted cells proliferation and invasion, and the inhibition ...[more]

PMID: 36843840

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Project description:Background & aimsLong noncoding RNAs (lncRNAs) are found to have profound impacts on diverse cellular processes. Although high-throughput sequencing studies have shown the differential lncRNA expression profiles between hepatocellular carcinoma (HCC) and nontumor livers, the functional impacts of lncRNAs on HCC development await further investigation. Herein, we sought to address the functional roles of lncRNAs in HCC pathogenesis by in vivo functional screening.MethodsWe performed genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)/dead CRISPR-associated protein 9 (dCas9) lncRNA activation screening in HCC xenografts. We characterized the clinical relevance of positively selected lncRNAs using transcriptomic data sets. We used CRISPR-based gene activation and knockdown approaches to show the functional roles of positively selected lncRNAs including Cancer Susceptibility 11 (CASC11) in HCC. RNA sequencing and chromatin isolation by RNA purification sequencing were used to investigate the molecular mechanisms of CASC11 in HCC progression.ResultsThe in vivo functional screening identified 1603 positively selected lncRNAs, 538 of which were overexpressed in HCC patients. Systematic transcriptomic data analysis and clinical investigation showed that patients with high expression of these lncRNA candidates correlated with aggressive tumor behaviors. Overexpression of these lncRNAs aggravated HCC cell growth. Detailed characterization of a lncRNA candidate, CASC11, showed its pivotal role in cell proliferation and tumor growth. Mechanistically, chromatin isolation by RNA purification sequencing showed that CASC11 was bound to the CASC11/MYC proto-oncogene shared promoter region on chromosome 8q24. CASC11 modulated the transcriptional activity of MYC in a cis-regulatory manner, which affected the expression of MYC downstream target genes, consequently promoting G1/S progression.ConclusionsOur study showed the power of in vivo CRISPR screening, which comprehensively investigated the functionality of lncRNAs in HCC progression, providing a rationale for targeting these lncRNAs clinically.

Dataset Information

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

Publications

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

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