Abstract
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide due to its high rate of recurrence, in part because of cancer stem cell (CSC)-dependent “field cancerization”. Recently, we identified that the oncogene v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN) marked CSC-like subpopulations in heterogeneous HCC and served as a therapeutic target and prognostic marker for HCC. In this study, we explored the molecular basis of upregulated MYCN gene expression in HCC cells. Liquid chromatograph time-of-flight mass spectrometry-based metabolome analysis demonstrated that the content of unsaturated fatty acids was increased in MYCN high expression (MYCNhigh) CSC-like HCC cells. Inhibition of lipid desaturation using either the chemical inhibitor or siRNA/shRNA against stearoyl-CoA desaturase-1 (SCD1) suppressed cell proliferation as well as MYCN gene expression in MYCNhigh HCC cells, grown as both monolayer and spheres. Further mechanistic study using RNA-seq based transcriptome analysis revealed that endoplasmic reticulum (ER) stress related signaling networks such as endocannabinoid cancer inhibition pathway were under the control of SCD1 in MYCNhigh HCC cells. Furthermore, the expression of ER stress-inducible transcription suppressor cyclic AMP-dependent transcription factor (ATF3) was downregulated in MYCNhigh CSC-like HCC cells and CSC-rich spheroids, which was upregulated by inhibition of lipid desaturation or treatment with acyclic retinoid (ACR). Lipid profiling using NMR spectroscopy revealed that the ACR dramatically reduced the content of unsaturated fatty acids in HCC cells. The chemical inducer of ER stress inhibited MYCN gene expression, while the chemical inhibitor of ER stress or knockdown of ATF3 gene expression partially rescued the suppression of MYCN gene expression by ACR in MYCNhigh HCC cells. These data suggested that lipid desaturation-mediated ER stress signaling regulates MYCN gene expression in HCC cells and serves as a promising therapeutic target for the treatment and prevention of HCC.
Highlights
Hepatocellular carcinoma (HCC) is a well-characterized inflammation-driven cancer[1] and is the second most lethal cancer worldwide due to its poor prognosis[2]
We have previously reported that (1) inhibition of biosynthesis of unsaturated fatty acids, but not glucose metabolism plays a crucial role in the prevention of hepatocellular carcinogen diethylnitrosamine (DEN)induced hepatic tumorigenesis by acyclic retinoid (ACR) in the obesity mice model[31]; (2) ACR can inhibit myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN) gene expression and selectively kill MYCNhigh epithelial cell adhesion molecule (EpCAM)+ cancer stem cell (CSC)-like HCCs, providing a molecular basis by which ACR prevents HCC recurrence[20]; (3) proteome analysis has shown that MYCNhigh EpCAM+ CSC-like HCC cells are enriched in enzymes involved in lipid desaturation such as stearoyl-CoA desaturase-1 (SCD1), fatty acid desaturase-1 (FADS1) and FADS222
We further provided evidence that (1) the content of unsaturated fatty acids was increased in MYCNhigh EpCAM+ CSC-like HCC cells; (2) inhibition of lipid desaturation using either the chemical inhibitor or siRNA/short hairpin RNA (shRNA) against SCD1 suppressed cell proliferation as well as MYCN gene expression in the MYCNhigh HCC cells grown as both monolayer and spheres
Summary
Hepatocellular carcinoma (HCC) is a well-characterized inflammation-driven cancer[1] and is the second most lethal cancer worldwide due to its poor prognosis[2]. Persistent infections of hepatitis B virus (HBV) and hepatitis C virus (HCV) are the major risk factors for HCC3. Advances in antiviral therapy have reduced the risk of developing both HBV-4 and HCV-related HCC5. Obesity-associated inflammation is responsible for increased death rates for all the cancers[6]. Non-alcoholic steatohepatitis (NASH), which is characterized by continuous hepatocyte death and compensatory proliferation[7], has attracted much attention and is believed that it will soon be the leading etiology of HCC8. Lipogenesis is known to be high in individuals with
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