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 (TAZS89A), BRAF (BRAFV600E), and PIK3CA (PI3KE545K) 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, TAZS89A was simultaneously expressed in murine adult livers with BRAFV600E or PI3KE545K, activated forms of effector molecules downstream of EGFR/HER2 signaling pathways. Expression of TAZS89A plus BRAFV600E induced HCC, whereas TAZS89A and PI3KE545K 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.

Surface roughness modulates EGFR signaling and stemness of triple-negative breast cancer cells

“…The results showed that the nuclear to total ratio of YAP/TAZ was not significantly affected by the surface roughness, but total YAP/TAZ levels were significantly altered for both cells ( Figures 6D–H ). This finding is in agreement with previous studies demonstrating an interplay between EGFR and YAP/TAZ in several cancers including TNBC, and their effect in tumorigenic properties ( Cancer Discov, 2020 ; Ando et al, 2021 ; Moon et al, 2022 ; Soyama et al, 2022 ; Zhang and Li, 2022 ). Overall, this data confirms a mechanosensing effect in a roughness-dependent manner and suggests that changes in the EGF/EGFR signaling pathway are a result of altered YAP/TAZ levels driven by changes in surface roughness.…”

Hepatocyte-specific miR-33 deletion attenuates NAFLD-NASH-HCC progression

“…TAZ upregulation in NASH and HCC has been associated with both increased cholesterol levels and decreased AMPKα activity and it has been described to participate in the transcriptional regulation of several genes involved in fibrosis, proliferation, superoxide formation and regulation of metabolism. Its upregulation has been described in pre-tumor NASH stage (50, 67, 71). In accordance with these studies, we also found a marked upregulation of TAZ levels in NASH livers that was partially abrogated in mice lacking miR-33 in hepatocytes (Fig.…”

“…10E). Recent studies have highlighted the role of the gene regulator TAZ in NASH worsening and progression to HCC (46,47,50,67,68). YAP/TAZ are transcriptional coactivators of the Hippo pathway that participate in the initiation and progression of different cancers (68)(69)(70).…”

“…YAP/TAZ are transcriptional coactivators of the Hippo pathway that participate in the initiation and progression of different cancers (68)(69)(70). Specifically, TAZ levels in HCC have been associated with its initiation and prognosis (50,67,71). TAZ upregulation in NASH and HCC has been associated with both increased cholesterol levels and decreased AMPKa activity and it has been described to participate in the transcriptional regulation of several genes involved in fibrosis, proliferation, superoxide formation and regulation of metabolism.…”

HBx and YAP expression could promote tumor development and progression in HBV-related hepatocellular carcinoma

“…Once it moves out to the cytoplasm and is phosphorylated, its activity is suppressed. The Hippo signaling pathway manages its activity and when the pathway is inhibited, YAP continuously remains in the nucleus and shows oncogenic activity [ [13] , [14] , [15] , [16] , [17] ].…”