1 Andersen Group, BRIC Research Groups, BRIC, Københavns Universitet2 Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.3 Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.4 Institute of Pathology, University of Medicine, Greifswald 17487, Germany.5 Department of Internal Medicine I, University of Ulm, Ulm 89070, Germany.6 Institute of Pathology, University Hospital Heidelberg and Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.7 Institute of Pathology, University Hospital Heidelberg, Heidelberg 69120, Germany.8 Andersen Group, BRIC Research Groups, BRIC, Københavns Universitet
The p53 tumor suppressor coordinates a series of antiproliferative responses that restrict the expansion of malignant cells, and as a consequence, p53 is lost or mutated in the majority of human cancers. Here, we show that p53 restricts expression of the stem and progenitor-cell-associated protein nestin in an Sp1/3 transcription-factor-dependent manner and that Nestin is required for tumor initiation in vivo. Moreover, loss of p53 facilitates dedifferentiation of mature hepatocytes into nestin-positive progenitor-like cells, which are poised to differentiate into hepatocellular carcinomas (HCCs) or cholangiocarcinomas (CCs) in response to lineage-specific mutations that target Wnt and Notch signaling, respectively. Many human HCCs and CCs show elevated nestin expression, which correlates with p53 loss of function and is associated with decreased patient survival. Therefore, transcriptional repression of Nestin by p53 restricts cellular plasticity and tumorigenesis in liver cancer.