Figure 12. Schematic cartoons showing the proposed mechanism underlying the Hippo signaling pathway regulation of cervical cancer progression.

1. Schematic cartoons showing the proposed positive feedback loop in cervical cancer cells. Data in this study support the existence of an autocrine loop involving EGF-like ligands/EGFR pathway/Hippo pathway/EGF-like ligands in regulating the proliferation and motility of cervical cancer cells, which plays a critical role in cancer progression. Under normal conditions, low levels of EGF-like ligands such as TGF-α and AREG are not sufficient to activate EGFR. The inactive EGFR ensures the activation of Hippo signaling pathway, which in turn results in ubiquitination-dependent degradation of YAP protein. In cervical cancer tissues, especially the advanced-stage cancer tissues, the elevated nuclear YAP protein stimulates the expressions of TGF-α and AREG, which in turn activates the EGFR, leading to suppression of LATS1 and MOB1 phosphorylation. Dephosphorylation of LATS1 and MOB1 results in the dissociation of LATS1/2-MOB1 complex, leading to inactivation of the Hippo pathway and subsequent activation of the growth-promoting co-activator YAP. Activated YAP induces expression of growth factors such as TGF-α and AREG to drive cervical cancer growth. YAP-induced growth factors such as TGF-α and AREG complete the autocrine loop by activating EGFR and YAP to drive the proliferation of cancer cell and the production of growth-promoting factors in cervical cancer cells. HPV E6 protein maintains YAP protein level in the HPV-infected normal and cancerous cervical cells by preventing YAP from proteasome-dependent protein degradation.
2. Schematic cartoons showing the clinical relevance of the proposed positive feedback loop in cervical cancer. Multidimensional cancer genomics data analysis indicates that very high frequency of alterations has been observed in genes involved in the Hippo/YAP/EGFR positive feedback loop in cervical cancer (we acknowledge The Cancer Genome Atlas (TCGA) Data Portal for the datasets and the cBioPortal for Cancer Genomics for the online analysis tools).