Abstract
Upregulated MYCN gene expression is restricted to specialized cell populations such as EpCAM+ cancer stem cells in liver cancer, regardless of DNA amplification and mutation. Here, we reviewed the role of MYCN gene expression in liver homeostasis, regeneration, and tumorigenesis, and discussed the potential non-genomic mechanisms involved in controlling MYCN gene expression in liver cancer, with a focus on inflammation-mediated signal transduction and microRNA-associated post-transcriptional regulation. We concluded that dynamic MYCN gene expression is an integrated consequence of multiple signals in the tumor microenvironment, including tumor growth-promoting signals, lipid desaturation-mediated endoplasmic reticulum stress adaptation signals, and tumor suppressive miRNAs, making it a potential predictive biomarker of tumor stemness and plasticity. Therefore, understanding and tracing the dynamic changes and functions of MYCN gene expression will shed light on the origin of liver tumorigenesis at the cellular level and the development of novel therapeutic and diagnostic strategies for liver cancer treatment.
Highlights
Liver cancer, mostly hepatocellular carcinoma (HCC), is a highly lethal cancer (>600,000 deaths per year worldwide) in which approximately 10% of patients survive the first 5 years after diagnosis [1]
Liver cancer is recognized as an inflammation-related cancer, since more than 90% of HCC cases arise in the context of chronic liver injury and unresolved inflammatory microenvironment due to viral infection, alcohol consumption, or high-fat diet (HFD) hypernutrition [2,3,4]
Mature hepatocytes exhibit remarkable plasticity by direct dedifferentiation into an undifferentiated state in the tumor microenvironment, which are believed to represent the cells of origin for liver cancer [88]
Summary
Mostly hepatocellular carcinoma (HCC), is a highly lethal cancer (>600,000 deaths per year worldwide) in which approximately 10% of patients survive the first 5 years after diagnosis [1]. Data mining in TCGA showed that the expression of MYCN in human HCC was not correlated with that of c-MYC, another MYC family membranes known to be crucial for liver cancer maintenance [19] and oncogenic reprogramming of terminally differentiated hepatocytes into liver cancer stem cells (CSCs) [20] (Figure S1B).
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