Activated TAZ induces liver cancer in collaboration with EGFR/HER2 signaling pathways

Abstract

Background: Liver cancer is a major global health concern due to the steady increases in its incidence and mortality. Transcription factors, yes-associated protein (YAP) and WW domain-containing transcription regulator protein 1 (WWTR1, also known as TAZ) have emerged as critical regulators in human hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC), the two major types of primary liver cancer. However, our study as well as other previous reports have shown that activation of YAP and TAZ (YAP/TAZ) in adult murine livers is insufficient for the development of liver cancer, suggesting a requirement for an additional oncogenic collaborator for liver carcinogenesis in adulthood. Therefore, we sought to identify the oncogenic partners of YAP/TAZ that promote hepatocarcinogenesis in adults.

Methods: Data analysis of the transcriptome of patients with liver cancer was performed using the national center for biotechnology information (NCBI) gene expression omnibus (GEO) database and the cancer genome atlas (TCGA). The cancer therapeutics response portal (CTRP) was used to investigate the correlation between sensitivity to chemicals and the copy number of TAZ in human cancer cell lines. Transposons encoding constitutively activated forms of TAZ (TAZ^S89A), BRAF (BRAF^V600E), and PIK3CA (PI3K^E545K) were used for hydrodynamic tail vein injection. Mice were monitored at least twice per week and sacrificed when moribund. Tumor-bearing livers were formalin fixed for hematoxylin-eosin staining and immunohistochemistry.

Results: Through database analyses, we identified EGFR/HER2 signaling to be essential in human cancers with high TAZ activity. Furthermore, immunohistochemical analyses showed that human HCC and CC tissues with high YAP/TAZ activities exhibited concomitant activation of EGFR/HER2 signaling pathways. To demonstrate that EGFR/HER2 signaling promotes YAP/TAZ-mediated hepatocarcinogenesis, TAZ^S89A was simultaneously expressed in murine adult livers with BRAF^V600E or PI3K^E545K, activated forms of effector molecules downstream of EGFR/HER2 signaling pathways. Expression of TAZ^S89A plus BRAF^V600E induced HCC, whereas TAZ^S89A and PI3K^E545K led to the development of CC-like cancer.

Conclusions: Our study demonstrates that TAZ collaborates with EGFR/HER2 signaling pathways to induce both HCC and CC.

Keywords: Cholangiocarcinoma; EGFR/HER2; Hepatocellular carcinoma; Hydrodynamic transfection; TAZ.