High YAP and TEAD4 immunolabelings are associated with poor prognosis in patients with gallbladder cancer

Abstract

Yes‐associated protein (YAP) and TEA domain‐containing sequence‐specific transcription factors 4 (TEAD4) are essential components of the Hippo pathway. Abnormal regulation of the Hippo pathway contributes to the progression and metastasis of many cancer types. However, their clinicopathologic and prognostic significances have not been studied in gallbladder cancers. Here, we systematically evaluated the YAP and TEAD4 immunolabelings and their association with clinicopathologic characteristics and survival outcomes using 212 specimens of surgically resected gallbladder cancers. High YAP and TEAD4 immunolabelings were identified in 70 (33%) cases and were associated with infiltrative growth pattern, poor differentiation, perineural invasion, and advanced pT classification and AJCC stage. High YAP immunolabeling was significantly associated with high TEAD4 immunolabeling (p < 0.001). High immunolabeling levels of YAP or TEAD4 alone and the combined YAPhigh TEAD4high group were significantly associated with poor survival in both univariate (p < 0.001) and multivariate analyses (HR = 2.358; 95% CI, 1.369–4.061; p = 0.002). Therefore, the YAP and TEAD4 immunolabelings are associated with aggressive behavior of gallbladder cancers and may be useful as a prognostic indicator in patients with surgically resected gallbladder cancer.

High TEAD4 Expression is Associated With Aggressive Clear Cell Renal Cell Carcinoma, Regardless of YAP1 Expression

“…Immunoreactivity was classified into low ( ≤ 5) and high (6 to 12) expression by multiplying staining intensity by proportion scores. 5 Four phenotypes were classified according to YAP1 and TEAD4 expression: (1) YAP1-low/TEAD4-low, (2) YAP1-low/ TEAD4-high, (3) YAP1-high/TEAD4-low, and (4) YAP1high/TEAD4-high.…”

“…23,24 Most previous studies have suggested the association of YAP1 and TEAD4 expression with aggressive clinicopathologic factors and poor survival in various cancers. 5,9,[16][17][18][19][20][25][26][27][28] In contrast, diminished YAP1 expression is related to short survival in some cancers, such as breast cancer, esophageal squamous cell carcinoma, and colorectal cancer. 22 Regarding RCC, Rybarczyk et al 29 demonstrated that nuclear YAP1 expression was significantly higher in CCRCC than in normal kidney tissue, and its expression was associated with high clinical stage and Fuhrman's grade in 86 CCRCC cases.…”

“…Upregulation of TEAD4 expression has been reported in various cancers, including gastric, colon, breast, gallbladder, RCC, and lung cancers, and is associated with poor prognosis. 4,5,13,18,32,33 TEAD4-induced EMT and metastasis are common in gastric, breast, and colorectal cancers. 18,24,34 In GEPIA and TCGA databases and previous studies, TEAD4 mRNA expression was higher in tumors than in normal tissue.…”

“…2 Moreover, recurrence occurs in ~30% of patients after complete tumor resection. 3 Inactivation of the Hippo signaling pathway (HSP), an important regulator of cell proliferation, tissue homeostasis, organ size, apoptosis, and stem cell functions, 4,5 has a significant impact on the development, progression, metastasis, and outcome of various cancers. 6 Yes-associated protein (YAP), a downstream transcriptional coactivator of HSP, regulates cellular proliferation, epithelial-mesenchymal transition (EMT), cellular invasion, metastasis, and drug resistance.…”

“…14,15 YAP1 and TEAD4 overexpression has been associated with tumorigenesis and tumor progression in various carcinomas and sarcomas. 5,[16][17][18][19][20] However, few studies have evaluated YAP1 and TEAD4 expression and their clinicopathologic significance in CCRCC. We analyzed the expression of YAP1 and TEAD4, their association with clinicopathologic factors, and whether they can be used as prognostic and therapeutic targets in a large cohort of CCRCCs.…”