Sleeping Beauty insertional mutagenesis screen identifies the pro-metastatic roles of CNPY2 and ACTN2 in hepatocellular carcinoma tumor progression

Lilian H. Lo (Corresponding Author), Coco Y. Lam, Jeffrey C. To, Cynthia H. Chiu, Vincent W. Keng (Corresponding Author)

Research output: Journal article publicationJournal articleAcademic researchpeer-review

1 Citation (Scopus)

Abstract

A forward genetic Sleeping Beauty (SB) insertional mutagenesis screen, followed by high-throughput transcriptome sequencing, was used to identify driver genes responsible for hepatocellular carcinoma (HCC)-associated metastasis. Using RNA-sequencing (RNA-seq) to identify transposon-endogenous transcriptome fusion genes, the phylogenetic lineage between the parental liver tumor and secondary metastasis can be determined to provide mechanistic insight to genetic changes involved in the metastatic evolution process. In the current study, two novel candidate genes were identified to be potentially involved in HCC-associated metastatic progression, canopy FGF signaling regulator 2 (Cnpy2) and actinin alpha 2 (Actn2). Transposon-Cnpy2 fusion transcripts were identified in both primary liver tumors and lung metastases. Its significant association with clinicopathological characteristics and correlated gene enrichment in metastasis-related mechanisms suggest its potential role in modulating local invasion and angiogenesis. Other known driver genes for human HCC that can also promote metastatic progression include epidermal growth factor receptor (Egfr) and RNA imprinted and accumulated in nucleus (Rian). Metabolic pathway related gene carbamoyl phosphate synthetase (Cps1) was identified to play an important role in early HCC development, while cell junction-related pathway gene Rac family small GTPase 1 (Rac1) was identified to take part in both HCC and pro-metastatic progression. Importantly, actinin alpha 2 (Actn2) was identified exclusively in the secondary metastasis site and its role in HCC-related metastatic process was elucidated using in vitro approaches. ACTN2-overexpression in human liver cancer cells displayed enhanced cellular motility and invasion abilities, indicating its possible function in later stage of metastasis, such as extravasation and lung colonization.

Original languageEnglish
Pages (from-to)70-77
Number of pages8
JournalBiochemical and Biophysical Research Communications
Volume541
DOIs
Publication statusPublished - 19 Feb 2021

Keywords

  • ACTN2
  • CNPY2
  • Forward genetic screen
  • Hepatocellular carcinoma
  • Metastasis
  • Sleeping Beauty

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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