Genomic and transcriptomic analyses of chemical hepatocarcinogenesis aggravated by oncoprotein loss

Xinyi Wang; Yingluo Liu; Shuo Zhang; Jiemeng Zhang; Xiaoxue Lin; Yan Liang; Min Zong; Kaisa L Hanley; Jin Lee; Michael Karin; Gen-Sheng Feng

doi:10.1097/HEP.0000000000001037

Genomic and transcriptomic analyses of chemical hepatocarcinogenesis aggravated by oncoprotein loss

Hepatology. 2024 Jul 30. doi: 10.1097/HEP.0000000000001037. Online ahead of print.

Authors

Xinyi Wang^{1

2

3}, Yingluo Liu^{1

2

3}, Shuo Zhang^{1

2

3}, Jiemeng Zhang^{1

2

3}, Xiaoxue Lin^{1

2

3}, Yan Liang^{1

2

3}, Min Zong^{1

2

3}, Kaisa L Hanley^{1

2

3}, Jin Lee^{1

2

3}, Michael Karin⁴, Gen-Sheng Feng^{1

2

3}

Affiliations

¹ Department of Pathology, School of Medicine, La Jolla, California, USA.
² Department of Molecular Biology, School of Biological Sciences, La Jolla, California, USA.
³ Moores Cancer Center, University of California at San Diego, La Jolla, California, USA.
⁴ Departments of Pharmacology and Pathology, University of California at San Diego, La Jolla, California, USA.

PMID: 39397357
DOI: 10.1097/HEP.0000000000001037

Abstract

Background and aims: The chemical carcinogen diethylnitrosamine (DEN) is often used to induce HCC in mice. Curiously, several labs have reported that the removal of oncoproteins from hepatocytes exacerbated DEN-induced HCC, with mechanisms unknown. This study aimed at deciphering molecular mechanisms underlying the tumor suppressive effect of oncoproteins.

Approach and results: We generated mutant mouse lines with hepatocyte-specific deletions of Met, Ptpn11/Shp2, Ikkβ, or Ctnnb1/β-catenin and assessed DEN-induced tumorigenesis in the wild-type and mutant mice. To systematically examine genetic and molecular signaling alterations, we performed whole exome and RNA-sequencing on liver samples collected at the pre-cancer and established cancer stages. Although the mutational profiles of DEN-induced tumors were barely different in wild-type and mutant mice, oncoprotein ablation increased DEN-induced mutational burdens, especially in Shp2-deficient tumors. RNA-sequencing revealed multiple changes in signaling pathways, in particular, upregulated epithelial-mesenchymal transition, cell migration, and tumor metastasis, as well as downregulated small molecule metabolism that was affected by oncoprotein ablation. We identified key molecules and pathways that are associated with hepatic innate immunity and implicated in liver tumorigenesis. In addition, we unveiled markedly changed expression of a few miRNAs in the human HCC database.

Conclusions: The aggravation of DEN-induced HCC progression seen on oncoprotein ablation could be caused by common and distinct genomic and signaling alterations. This study reveals a new level of complexity in hepatocarcinogenesis and elucidates molecular mechanisms underlying tumor evolution and recurrence.