c-Myc-driven Hepatocarcinogenesis

Abstract

Background/Aim: Dysregulation of the c-Myc gene is frequently found in human hepatocellular carcinoma (HCC), often accompanied by genetic and epigenetic alterations in other cancer-related genes. Here, we investigated the tumorigenic potential of c-Myc in diverse genetic environments in which the Ras, Wnt/β-catenin, Sonic hedgehog, or P53 pathways were either activated or inactivated. Materials and Methods: Hydrodynamic tail vein injection was employed to administer expression transposons and generate transgenic livers expressing c-Myc together with a constitutively active form of RAS (HRAS G12V ), βcatenin (β-catenin S33Y ), Smo (SmoM2), or short hairpin RNA targeting P53 (shp53). Results: c-Myc was most tumorigenic when the RAS signaling pathway was activated, whereas no tumors were found in mice when either β-catenin S33Y or SmoM2 was co-expressed with c-Myc. Approximately 40% of mice had HCC when c-Myc was over-expressed under P53 inactivation. Furthermore, we investigated the effect of mutation in c-Myc on hepatocarcinogenesis. Conclusion: No significant differences in tumorigenic potential were found between wild type c-Myc and c-Myc T58A , minimizing the role of the mutation in hepatocarcinogenesis.

Identification of a Vitamin-D Receptor Antagonist, MeTC7, which Inhibits the Growth of Xenograft and Transgenic Tumors In Vivo

“…MYCN overexpression predicts poor overall and event-free survival in patients with ovarian cancer and neuroblastoma (Figure S7) and other malignancies. − We investigate whether targeting VDR by 5 can inhibit MYCN expression and, in turn, control the MYCN-orchestrated neuroblastoma growth. Prior to testing antineuroblastoma activities of 5 using the well-established TH-MYCN+/+ transgenic mice, which spontaneously develop neuroblastoma and recapitulate human neuroblastoma disease closely, , we establish via immunohistochemistry that celiac ganglia harvested from homozygous TH-MYCN+/+ mice exhibit positive expressions of VDR, MYCN, and TH antigens (Figure a–c).…”

“…The rationale to identify a VDR antagonist such as MeTC7 ( 5 ) and investigate its antitumor effects stemmed from (1) VDR mRNA overexpression in ovarian, breast, lung, pancreatic, neuroblastoma, and bladder malignancies and association with poor prognosis; (2) the role of Vitamin-D/VDR in increased immune checkpoint inhibitor ligand PD-L1 expression in head-neck cancer, leukemia, and ovarian cancer cells (unpublished data); and (3) VDR’s role in expression of MYCN, an oncogene dysregulated in ∼70% of human cancers. − Further, RXRα and Importin-4, the critical downstream signaling nodes of VDR, are also shown to be altered in malignant cells and predict poor prognoses in malignancies − (Figures S3 and S4).…”

“…Further, 5 inhibits MYCN expression in neuroblastoma cells. MYCN expression is altered in over 70% of human cancers − and predicts poor prognoses in ovarian cancer ( p = 0.0033) and neuroblastoma (Figure S7). MYCN-driven cancers are aggressive and chemoresistant and await a targeted therapy. − VDR is a key regulator of MYCN expression, and therefore, targeting the VDR/MYCN axis can be exploited to control such malignancies.…”

A20 Enhances the Expression of the Proto-Oncogene C-Myc by Downregulating TRAF6 Ubiquitination after ALV-A Infection

“…C-myc is a classic oncogene that plays an important role in the occurrence and development of tumors. More than 70% of tumors have c-myc mutations or changes in expression [ 29 , 30 ]. The relative expression levels of tumor-related cytokines, Y box-binding protein-1 (YB-1), cyclin D1, p53, B-cell lymphoma-2 (Bcl-2), Cystatin A (CSTA), and c-myc were determined after ALV-A infection.…”

“…The role of A20 in avian tumorigenic diseases, however, is undocumented. C-myc plays an important role in cell proliferation, growth, survival, and differentiation, and when its expression is disordered, can cause tumorigenesis [ 29 , 30 ].…”