AUTHOR=Cheng Yun-Hsin , Ko Ying-Chieh , Ku Hsiang-Ju , Huang Ching-Chun , Yao Yu-Ching , Liao Yi-Tzu , Chen Ying-Tsong , Huang Shiu-Feng , Huang Li-Rung 

TITLE=Novel Paired Cell Lines for the Study of Lipid Metabolism and Cancer Stemness of Hepatocellular Carcinoma

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=10

YEAR=2022

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2022.821224

DOI=10.3389/fcell.2022.821224

ISSN=2296-634X

ABSTRACT=<p>There are few well-characterized syngeneic murine models for hepatocellular carcinoma (HCC), which limits immunological studies and the development of immunotherapies for HCC. We previously established an oncogene-induced spontaneous HCC mouse model based on transposon-mediated oncogene (<italic>AKT</italic> and <italic>NRASV12</italic>) insertion into the genome of hepatocytes to induce tumorigenesis. Two tumor clones with different levels of lipid droplets (LDs) showed similar <italic>in vitro</italic> growth but distinctive <italic>in vivo</italic> phenotypes, including divergent proliferative capability and varying induction of myeloid-derived suppressor cells (MDSCs). The two clones showed distinct gene expression related to lipid metabolism, glycolysis, and cancer stemness. Endogenous fatty acid (FA) synthesis and exogenous monounsaturated fatty acid (MUFA) consumption promoted both tumor proliferation and cancer stemness, and upregulated c-Myc in the HCC cell lines. Moreover, the LD<sup>hi</sup> HCC cell line expressed a higher level of type II IL-4 receptor, which promoted tumor proliferation through binding IL-4 or IL-13. The chromosomal DNA of two tumor clones, NHRI-8-B4 (LD<sup>hi</sup>) and NHRI-1-E4 (LD<sup>lo</sup>) showed five identical <italic>AKT</italic> insertion sites in chromosomes 9, 10, 13, 16 and 18 and two <italic>NRAS</italic> integration sites in chromosomes 2 and 3. Herein, we describe two novel HCC cell lines with distinct features of lipid metabolism related to cancer stemness and differential interplay with the immune system, and present this syngeneic HCC mouse model as a practical tool for the study of cancer stemness and discovery of new therapies targeting liver cancers.</p>