p53-Dependent Nestin Regulation Links Tumor Suppression to Cellular Plasticity in Liver Cancer

Abstract

Summary The p53 tumor suppressor coordinates a series of anti-proliferative 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.

The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration

“…9c). As Nestin is also a well-described mediator of stemness and plasticity in the liver (Tschaharganeh et al 2014), this further supports that the SASP can induce stem cell properties in surrounding tissue.…”

Germline loss of PKM2 promotes metabolic distress and hepatocellular carcinoma

“…Although a subset of HCCs is thought to arise from hepatic progenitor cells (HPCs), most HCCs arise from differentiated hepatocytes (Tschaharganeh et al 2014;Marquardt et al 2015). The PK isoform expression of HPCs is unknown; however, differentiated hepatocytes do not express PKM2 (Supplemental Fig.…”

Anti-tumor effects and cellular mechanisms of resveratrol

“…P21 (WAF1) binds to the G1-S/CDK (CDK1, CDK2 and CDK4/6) complexes (responsible for the G1/S transition in the cell cycle) inhibiting their activity. Many studies demonstrated that the activation of p21 might be due to a p53-dependent pathway (37) and p21 has been shown to be essential for p53-mediated G1/S boundary cell-cycle arrest and cellular senescence triggered by DNA damage (38).…”