AI Article Synopsis
- Hepatocellular carcinoma (HCC) progresses through defined stages from liver cirrhosis to advanced cancer, with distinct genomic, epigenomic, and transcriptomic changes occurring at each step.
- Initial DNA methylation changes and loss of tumor suppressor gene copy numbers are observed during the early stages of cancer, providing survival advantages to cancer cells as the disease advances.
- Significant findings highlight the role of SPINK1 in early HCC development, suggesting that ER stress contributes to its demethylation and expression, shedding light on potential mechanisms involved in liver cancer progression.
Article Abstract
Hepatocellular carcinoma (HCC) undergoes a stepwise progression from liver cirrhosis to low-grade dysplastic nodule (LGDN), high-grade dysplastic nodule (HGDN), early HCC (eHCC), and progressed HCC (pHCC). Here, we profiled multilayered genomic, epigenomic, and transcriptomic aberrations in the stepwise hepatocarcinogenesis. Initial DNA methylation was observed in eHCC (e.g., , and ) while more extensive methylation was observed in pHCC. In addition, eHCCs showed an initial loss of DNA copy numbers of tumor suppressor genes in the 4q and 13q regions, thereby conferring survival benefits to cancer cells. Transcriptome analysis revealed that HGDNs expressed endoplasmic reticulum (ER) stress-related genes, while eHCC started to express oncogenes. Furthermore, integrative analysis indicated that expression of the serine peptidase inhibitor, Kazal type 1 (SPINK1), played a pivotal role in eHCC development. Significant demethylation of SPINK1 was observed in eHCC compared to HGDN. The study also demonstrated that ER stress may induce SPINK1 demethylation and expression in liver cancer cells. In conclusion, these results reveal the dynamics of multiomic aberrations during malignant conversion of liver cancer, thus providing novel pathobiological insights into hepatocarcinogenesis. SIGNIFICANCE: Multiomics profiling and integrative analyses of stepwise hepatocarcinogenesis reveal novel mechanistic and clinical insights into hepatocarcinogenesis.
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| http://dx.doi.org/10.1158/0008-5472.CAN-19-0991 | DOI Listing |
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