Abstract
The epidermal growth factor receptor (EGFR) pathway and Hippo signaling play an important role in the carcinogenesis of hepatocellular carcinoma (HCC). However, the crosstalk between these two pathways and its implications in targeted therapy remains unclear. We found that the activated EGFR signaling could bypass RhoA to promote the expression of YAP(Yes-associated protein), the core effector of the Hippo signaling, and its downstream target Cyr61. Further studies indicated that EGFR signaling mainly acted through the PI3K-PDK1 (Phosphoinositide 3-kinase-Phosphoinositide-dependent kinase-1) pathway to activate YAP, but not the AKT and MAPK pathways. While YAP knockdown hardly affected the EGFR signaling. In addition, EGF could promote the proliferation of HCC cells in a YAP-independent manner. Combined targeting of YAP and EGFR signaling by simvastatin and the EGFR signaling inhibitors, including the EGFR tyrosine kinase inhibitor (TKI) gefitinib, the RAF inhibitor sorafenib and the MEK inhibitor trametinib, presented strong synergistic cytotoxicities in HCC cells. Therefore, the EGFR-PI3K-PDK1 pathway could activate the YAP signaling, and the activated EGFR signaling could promote the HCC cell growth in a YAP-independent manner. Combined use of FDA-approved inhibitors to simultaneously target YAP and EGFR signaling presented several promising therapeutic approaches for HCC treatment.
Highlights
Hepatocellular carcinoma (HCC), a major malignancy of the liver, is the fifth most common cancer and the third leading cause of cancer-related mortality worldwide
Previous data suggested a critical role of RhoA in EGFmediated carcinogenesis[27], so we investigated whether the epidermal growth factor receptor (EGFR) signaling could act via RhoA to promote the malignant phenotype of HCC cells
Since YAP plays an important role in the carcinogenesis of HCC5, we examined whether activated EGFR signaling could act through YAP to regulate the malignant phenotype of HCC cells
Summary
Hepatocellular carcinoma (HCC), a major malignancy of the liver, is the fifth most common cancer and the third leading cause of cancer-related mortality worldwide. Many studies have implicated that Hippo signaling pathway played a vital role in the tumorigenesis of HCC5,6. Conditional over-expression of YAP in transgenic mice or the liver-specific knockout of Mst1/2 or Sav[1] could lead to expanded liver size and induce HCC, and these are the direct evidences for the importance of the Hippo pathway in regulating organ size and liver tumorigenesis[7,8,9,10,11]. Many clinical studies have illustrated that over-expression and nuclear accumulation of YAP could act as an independent prognostic marker for the overall survival and disease-free survival in HCC patients, as well as in several other tumor types[12,13,14]. Several recent studies indicated that RhoA participated in the activation of YAP through inducing stress fiber formation, and the G-proteincoupled receptor (GPCR) signaling could act through RhoA to regulate the Hippo-YAP pathway[16,17]
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