RRC ID 45268
Author Akita H, Marquardt JU, Durkin ME, Kitade M, Seo D, Conner EA, Andersen JB, Factor VM, Thorgeirsson SS.
Title MYC activates stem-like cell potential in hepatocarcinoma by a p53-dependent mechanism.
Journal Cancer Res.
Abstract Activation of c-MYC is an oncogenic hallmark of many cancers, including liver cancer, and is associated with a variety of adverse prognostic characteristics. Despite a causative role during malignant transformation and progression in hepatocarcinogenesis, consequences of c-MYC activation for the biology of hepatic cancer stem cells (CSC) are undefined. Here, distinct levels of c-MYC overexpression were established by using two dose-dependent tetracycline-inducible systems in four hepatoma cell lines with different p53 mutational status. The CSCs were evaluated using side population (SP) approach as well as standard in vitro and in vivo assays. Functional repression of p53 was achieved by lentiviral shRNA transduction. The results show that c-MYC expression levels have a differential impact on liver CSC characteristics. At low levels, c-MYC activation led to increased proliferation and enhanced CSC properties including activation of reprogramming transcription factors and CSC marker expression (e.g., NANOG, OCT4, and EpCAM), expansion of SP, and acceleration of tumor growth upon subcutaneous transplantation into immunocompromised mice. However, when exceeding a threshold level, c-MYC induced a proapoptotic program and loss of CSC potential both in vitro and in vivo. Mechanistically, c-MYC-induced self-renewal capacity of liver cancer cells was exerted in a p53-dependent manner. Low c-MYC activation increased spheroid formation in p53-deficient tumor cells, whereas p53-dependent effects were blunted in the absence of c-MYC overexpression. Together, our results confirm the role of c-MYC as a master regulator during hepatocarcinogenesis and establish a new gatekeeper role for p53 in repressing c-MYC-induced CSC phenotype in liver cancer cells.
Volume 74(20)
Pages 5903-13
Published 2014-10-15
DOI 10.1158/0008-5472.CAN-14-0527
PII 0008-5472.CAN-14-0527
PMID 25189530
PMC PMC4199878
MeSH Animals Carcinogenesis / metabolism Carcinoma, Hepatocellular / metabolism* Carcinoma, Hepatocellular / pathology Hep G2 Cells Humans Liver Neoplasms / metabolism* Liver Neoplasms / pathology Mice, Inbred NOD Mice, SCID Neoplasm Transplantation Neoplastic Stem Cells / physiology* Phenotype Proto-Oncogene Proteins c-myc / physiology* Tumor Burden Tumor Suppressor Protein p53 / metabolism*
IF 8.378
Times Cited 24
Human and Animal Cells