TAZ sensitizes EGFR wild-type non-small-cell lung cancer to gefitinib by promoting amphiregulin transcription

Abstract

Comparatively less toxic and more tolerated, epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are recommendable for advanced non-small-cell lung cancer (NSCLC) patients with EGFR-sensitive mutations. Some EGFR wild-type patients with specific biomarkers also show a response to the drug. TAZ is an oncogene closely associated with the therapeutic effect of EGFR-TKIs. However, this association remains to be clarified. This study aimed to clarify the mechanism through which TAZ sensitizes EGFR wild-type NSCLC to gefitinib. We used CCK-8 assays and in vivo experiments to investigate the influence of TAZ on gefitinib in EGFR wild-type NSCLC. To further validate the tumorigenic role of TAZ, we performed Human umbilical vein endothelial cell (HUVEC) tube formation and migration assays. Luciferase reporter assays, quantitative real-time PCR (qPCR), immunoblotting and Chromatin immunoprecipitation collaborated with qPCR illuminated the mechanism through which TAZ caused those phenotypes. The results showed TAZ promoted the angiogenesis of NSCLC cell lines and improved gefitinib sensitivity in EGFR wild-type NSCLC in vitro and in vivo. Luciferase reporter assays and ChIP-qPCR experiments showed TAZ upregulated AREG by promoting its transcription. EGFR signaling pathway was activated as TAZ was highly expressed. Rescue experiments were conducted to confirm the indispensable role of AREG in tumorigenesis and gefitinib sensitivity regulated by TAZ. Our study concluded that TAZ sensitized EGFR wild-type NSCLC to gefitinib through promoting amphiregulin transcription.

YAP manipulates proliferation via PTEN/AKT/mTOR-mediated autophagy in lung adenocarcinomas

“…Recently, a systematic profiling of 9,125 tumor samples revealed a widespread dysregulation of Hippo pathway components in multiple human cancer types [ 31 ] The Hippo pathway integrates multiple signals to regulate the activity of core transcriptional coactivators YAP/TAZ, which directly or indirectly control multiple cancer hallmarks, including proliferation, survival, evading growth suppressors, reprogramming energy metabolism, angiogenesis, invasion and metastasis, and cancer stem cells, as well as inflammation and immunosuppression [ 31 ]. Our previous research found that TAZ was an oncogene closely associated with the therapeutic effect of cisplatin [ 32 ] and EGFR-TKIs [ 33 , 34 ] in lung adenocarcinoma. However, the role of YAP in lung adenocarcinoma remains unclear.…”

YAP Manipulates Proliferation Via PTEN/AKT/mTOR-mediated Autophagy in Lung Adenocarcinomas

“…The immunosuppression [30]. Our previous research found that TAZ was an oncogene closely associated with the therapeutic effect of cisplatin [31] and EGFR-TKIs [32,33] in lung adenocarcinoma. However, the role of YAP in lung adenocarcinoma remains unclear.…”

A positive feedback loop between TAZ and miR-942-3p modulates proliferation, angiogenesis, epithelial-mesenchymal transition process, glycometabolism and ROS homeostasis in human bladder cancer

“…In detail, TAZ has been reported to be involved in VEGF-induced endothelial cell sprouting [ 54 ]. In addition, TAZ also enhances angiogenesis in EGFR wild-type non-small cell lung cancer cells [ 55 ]. According to these findings, we further evaluated the angiogenesis-inducing ability of conditioned medium acquired from control or TAZ-depleted cancer cells, and the results indicated TAZ has a key role in angiogenesis.…”