Extrachromosomal circular MiR-17-92 amplicon promotes HCC

Area of Science:

• Genomics
• Cancer Biology
• Molecular Oncology

Background:

• Extrachromosomal circular DNAs (eccDNAs) are recognized as significant oncogenic drivers in cancer genomes.
• The specific role, structure, and prevalence of eccDNAs in hepatocellular carcinoma (HCC), a leading cause of cancer mortality, remain largely uninvestigated.

Purpose of the Study:

• To comprehensively characterize eccDNAs in human HCC.
• To elucidate the oncogenic function of microRNA (miRNA)-17-92-containing eccDNAs in HCC tumor progression.

Main Methods:

• Circle-sequencing to identify and quantify eccDNAs from HCC and adjacent non-tumor tissues.
• Outward PCR and Sanger sequencing for eccDNA validation.
• Quantitative PCR to assess miRNA and eccDNA levels.
• Functional assays using artificial DNA circles with the miR-17-92 cluster.

Main Results:

• Over 230,000 eccDNAs were identified, showing enrichment in HCC tumors and specific chromosomal origins.
• eccDNAs containing the miRNA-17-92 cluster were validated and found to be elevated in HCC.
• Elevated miRNA-17-92 eccDNAs correlated with poor patient outcomes and advanced age.
• Exogenous expression of miR-17-92 eccDNAs accelerated HCC cell proliferation and migration.

Conclusions:

• This study provides the first genome-wide eccDNA profile for HCC.
• Highlights the functional importance of miRNA-containing eccDNAs in HCC tumorigenesis.
• Offers novel insights into HCC pathogenesis, potential therapeutic targets, and eccDNA/miRNA biology.