TAZ promotes vasculogenic mimicry in gastric cancer through the upregulation of TEAD4

Abstract

Background and Aim: Vasculogenic mimicry (VM) is a unique blood supply pattern in malignant tumors that is closely associated with metastasis and poor prognosis. The Hippo signaling effector TAZ is upregulated in several cancers, promoting cancer proliferation and metastasis. This study aimed to identify the function of TAZ and its regulatory mechanism in promoting VM in gastric cancer (GC). Methods: The expression of TAZ and TEAD4 and their correlations with overall survival and VM-related markers were analyzed in 228 cases of GC. The regulatory mechanism of TAZ and its interaction with TEAD4 in epithelial-mesenchymal transition (EMT) and VM were investigated in vitro and in vivo. Results: TAZ was highly expressed in GC samples and was associated with shorter patient survival time. TAZ expression was positively correlated with TEAD4 and VM in patients with GC. TAZ enhanced the migration and invasion capacity of GC cells through EMT in vitro and upregulated the expression of VM-associated proteins, including VEcadherin, MMP2, and MMP9, thus promoting VM formation. Overexpression of TAZ accelerated the growth of subcutaneous xenograft and promoted VM formation in vivo. Co-immunoprecipitation assays showed that TAZ can directly bind to TEAD4, and in vitro experiments showed that this binding mediates the function of TAZ in regulating EMT and VM formation in GC. Conclusions: TAZ promotes GC metastasis and VM by upregulating TEAD4 expression. Our findings expand the role of TAZ in VM and provide new theoretical support for the use of antiangiogenic therapy in the treatment of advanced GC.experiments. N. Z., X. L., and X. L. assisted in conducting the experiments and collecting data. X. Z. and B. S. designed the study and helped draft and edit the manuscript. R. C., F. L., and Y. L conducted and completed animal experiments.

GPR137 inactivates Hippo signaling to promote gastric cancer cell malignancy

“…Consistently, immunohistochemistry staining data showed that the localization of TAZ, a key transcriptional co-activator in Hippo signaling, was mainly distributed in nucleus in GC tissues while in cytoplasm in normal gastric epithelial tissues (Fig. 3 E), which was in agreement with a previous report [ 23 ]. Thus, GPR137 may affect Hippo signaling in GC.…”

Tumor-Suppressor Gene Transmembrane Protein 98 Promotes Proliferation and Inhibits Apoptosis in Ovarian Cancer

“…Antiangiogenic drug with bevacizumab promotes a hypoxic response and vasculogenic mimicry [24], which may be related to limited efficacy and poor response to antiangiogenic therapy in OC. Angiogenesis mimicry has recently been demonstrated in a variety of human malignancies such as hepatocellular carcinoma [25], gastric cancer [26], glioblastoma [27], breast cancer [28], and head and neck cancers [29]. Vasculogenic mimicry also exists in OC, which is closely related to tumor progression and poor survival outcomes [30,31].…”

Targeting the Hippo Pathway in Gastric Cancer and Other Malignancies in the Digestive System: From Bench to Bedside

“…High YAP1-expressing peritoneal carcinomatosis cell subset was also prone to develop PDX tumors, while genetic knockout or pharmacological inhibition of YAP1 abolished its tumorigenicity [ 31 ]. Furthermore, TAZ directly interacted with TEAD4 to augment the TAZ-dependent formation of vasculogenic mimicry and EMT in GC cells [ 32 ]. However, it is worth noting that despite YAP1 and TAZ having functional overlaps, integrative transcriptome analysis on GC cells identified the more dominant role of YAP1 in cell-substrate junction [ 33 ].…”