Acquiring a selective growth advantage by breaking the proliferation barrier established by gatekeeper genes is a centrally important event in tumor formation. Removal of the mammalian Hippo kinase Mst1 and Mst2 in hepatocytes leads to rapid hepatocellular carcinoma (HCC) formation, indicating that the Hippo signaling pathway is a critical gatekeeper that restrains abnormal growth in hepatocytes. By rigorous genetic approaches, we identified an interacting network of the Hippo, Wnt/β-catenin and Notch signaling pathways that control organ size and HCC development. We found that in hepatocytes, the loss of Mst1/2 leads to the activation of Notch signaling, which forms a positive feedback loop with Yap/Taz (transcription factors controlled by Mst1/2). This positive feedback loop results in severe liver enlargement and rapid HCC formation. Blocking the Yap/Taz-Notch positive feedback loop by Notch inhibition
The liver has a remarkable regeneration property after an injury, and is able to adjust to its original size (El-Serag,
A recently discovered Hippo signaling plays an essential role in organ size control and tumor suppression (Dong
Wnts are secreted proteins that regulate many important developmental and physiological processes. β-catenin is a centrally important transcription co-activator that activates the Wnt target gene expression in the Wnt/β-catenin pathway (Kim
The Notch signaling pathway is also critically important in both liver development and tumor formation. Notch signaling promotes formation of the oval cell, which is the liver stem cell (Tanimizu and Mitaka,
In the current study, we found that the loss of Mst1/2 in hepatocytes led to the activation of Notch signaling, which forms a positive feedback loop with Yap/Taz. This positive feedback loop resulted in severe liver enlargement and rapid HCC formation. Furthermore, we uncovered a surprising inhibitory role of Wnt/β-catenin signaling to Yap/Taz activities that is important in tumor initiation. Genetic removal of β-catenin in the liver of the Mst1/2 null mutants significantly increased the number of tumor nodules, that also appeared at younger ages. Mechanistically, we have identified that increased generation of the Notch intracellular domain (NICD) by Yap/Taz activation also stabilized Taz by inhibiting its binding to β-TrCP. Wnt/β-catenin signaling suppressed the positive feedback loop between Notch and Taz through promoting the nuclear localization of DP1 (the dimerization partner of E2F transcriptional factors) which subsequently inhibits Notch activity. Breaking down the Yap/Taz-Notch positive feedback loop by Notch inhibition
This study is supported by the intramural research program of National Human Genome Research Institute (NHGRI) and Harvard School of Dental Medicine. WK (HI13C1274) is supported by the Korean Visiting Scientist Training Award (KVSTA) fellowship from Korea Health Industry Development Institute (KHIDI).