The Hippo pathway in colorectal cancer

Abstract

Colorectal cancer (CRC) is one the most frequently diagnosed neoplastic diseases worldwide. Currently, aside from traditional chemotherapy, advanced CRCs are treated with modern drugs targeting cellular components such as epithelial growth factor receptor (EGFR). Since up to 70% of metastasized CRCs are drug resistant, the description of recent progress in cellular homeostasis regulation may shed new light on the development of new molecular targets in cancer treatment. The Hippo pathway has recently become subject of intense investigations since it plays a crucial role in cell proliferation, differentiation, apoptosis and tumourigenesis. Components of the Hippo pathway are deregulated in various human malignancies, and expression levels of its major signal transducers were proposed as prognostic factors in colorectal cancer. In this review we focused on recent data regarding Hippo pathway, its up-stream signals and down-stream effectors. Hippo negatively regulates its major effectors, YAP1 and TAZ kinases, which act as transcriptional co-activators inducing expression of genes involved not only in tissue repair and proliferation but are also oncoproteins involved in tumour development and progression. The deregulation of Hippo pathway components was found in many malignancies. The interactions between Hippo and Wnt/β-catenin signalling, crucial in the maintenance of cell homeostasis, have been described in relation to the control of intestinal stem cell proliferation and CRC development. The recently discovered positive feedback loop between activated YAP1 and increased EGFR/KRAS signalling found in oesophageal, ovarian and hepatocellular cancer has been related to the CRC progression and resistance to EGFR inhibitors during CRC therapy.