MYC‐regulated genes involved in liver cell dysplasia identified in a transgenic model of liver cancer

Abstract

Foci of liver cell dysplasia (LCD) are distinct morphological entities and may evolve into hepatocellular carcinomas (HCCs). While most HCCs overexpress c-Myc, its role in LCD remains uncertain. Therefore, a c-Myc transgenic model of HCC was investigated to understand the genetic events forcing liver cells into dysplasia and subsequent malignant transformation. Specifically, whole genome scans enabled fingerprinting of genes at different stages of disease, ie LCD and HCC, while laser microdissected LCD lesions were used to validate regulation of candidate genes by quantitative real-time RT-PCR, ie Mybbp1a, Rps7, Rps19, Rpl10a, Skp1a, Tfdp1, Nhp2, and Bola2. EMSA band shift assays confirmed c-Myc DNA binding at regulatory sequences of candidate gene-specific promoters. Additionally, published ChIP-seq data helped to define the candidate genes as c-Myc bona fide targets. Treatment of the human hepatoma cell line HepG2 with hepatic growth factor (Hgf) caused c-Myc protein induction and transcriptional up-regulation of candidate genes, albeit at different levels when individual genes were compared. A significant increase of HepG2 entering the G1-phase was associated with up-regulation of the candidate genes in an Hgf concentration-dependent matter. Finally, we confirmed regulation of candidate genes in patients' samples with low- and high-grade dysplasia and HCC staged T1 to T3, while their expression was unchanged in focal nodular hyperplasia and hepatic adenoma, therefore asserting the diagnostic value and clinical significance of these candidate genes. Overall, novel c-Myc targeted genes were identified and may contribute to hepatocyte transformation by altering cell cycle control, thereby contributing to c-Myc's oncogenic activity.

MicroRNA‑543 suppresses liver cancer growth and induces apoptosis via the JAK2/STAT3 signaling pathway

“…Consequently, it can be concluded that positive c-Myc expression is associated with the degree of tumor differentiation. c-Myc is slightly increased in slow-growing and highly differentiated adenocarcinoma, whereas it is significantly increased in fast-growing and poorly differentiated adenocarcinoma (16,18). In addition, in the present study, it was identified that microRNA-543 activation represses c-Myc expression of MHCC97 and Hep3B cells.…”

“…The cell cycle is a series of ordered cellular activities which cause the division and duplication of its DNA to create two daughter cells (16). The entire process is divided into two periods: Silence period and proliferative period.…”

Trunk mutational events present minimal intra- and inter-tumoral heterogeneity in hepatocellular carcinoma

“…(1q) and/or MDM4 (1q). In this regard, the role of MYC in HCC malignant conversion has been previously described 22,23 . Interestingly, a recent sequencing study in multiple HCC lesions also reported gains in chr 1q and 8q and deletions in 8q as common trunk events further supporting our observations 24 .…”

RNAi silencing of c-Myc inhibits cell migration, invasion, and proliferation in HepG2 human hepatocellular carcinoma cell line: c-Myc silencing in hepatocellular carcinoma cell

“…A mutated version of Myc is found in many cancers, which causes Myc to be constitutively (persistently) expressed. This further induces an unregulated expression of several genes, some of which are involved in cell proliferation [4]. A frequent genetic abnormality seen in HCC is the overexpression of c-Myc [5,6].…”