Lee Ki Rim, Hong Soon Auck, Hong Mineui, Kim Joo Young
Department of Pathology, College of Medicine, Chung-Ang University, Chung-Ang University Hospital, Seoul, South Korea.
Appl Immunohistochem Mol Morphol. 2025 Sep 1;33(5):330-338. doi: 10.1097/PAI.0000000000001268. Epub 2025 May 29.
The Hippo pathway is a tumor-suppressive pathway. Hippo pathway dysregulation correlates with cancer progression, metastasis, and a poor prognosis. Large tumor suppressor homolog 1/2 (LATS1/2), Yes-associated protein (YAP), and TEA domain-containing sequence-specific transcription factor 4 (TEAD4) are primary Hippo pathway components. We evaluated LATS1/2, YAP, and TEAD4 expression and their correlation with clinicopathological behavior and prognostic significance in 67 distal bile duct cancer (DBDC) cases. LATS1/2 expression was observed in 20 (29.9%) DBDC cases and correlated significantly with low pT classification, absence of lymphovascular invasion, and low American Joint Committee on Cancer (AJCC) stage. High YAP expression was identified in 35 (52.2%) cases and correlated with high pT classification, AJCC stage, and TEAD4 expression. High TEAD4 expression was observed in 13 (19.4%) cases and correlated significantly with lymph node metastasis, involved resection margins, and high AJCC stage. Overall survival was significantly better in patients with DBDC with than in those without LATS1/2 expression ( P < 0.001), and significantly worse in patients with high than in those with low YAP and TEAD4 expression ( P = 0.014, 0.037, respectively). The overall survival of patients with combined LATS1/2 + YAP or TEAD4 low expression was significantly better than that of other groups [hazard ratio (HR) 5.809; 95% CI, 1.770-19.065; P = 0.001]. This combination was an independent good prognostic factor (HR 4.399; 95% CI, 1.313-14.743; P = 0.016) in patients with DBDC. LATS1/2, YAP, and TEAD4 expression correlates with DBDC clinicopathological behavior and may be useful prognostic markers in patients with DBDC.
Hippo信号通路是一条肿瘤抑制通路。Hippo信号通路失调与癌症进展、转移及不良预后相关。大肿瘤抑制因子同源物1/2（LATS1/2）、Yes相关蛋白（YAP）和含TEA结构域的序列特异性转录因子4（TEAD4）是Hippo信号通路的主要组成部分。我们评估了67例远端胆管癌（DBDC）病例中LATS1/2、YAP和TEAD4的表达及其与临床病理行为的相关性和预后意义。在20例（29.9%）DBDC病例中观察到LATS1/2表达，其与低pT分级、无淋巴管侵犯及低美国癌症联合委员会（AJCC）分期显著相关。在35例（52.2%）病例中发现高YAP表达，其与高pT分级、AJCC分期及TEAD4表达相关。在13例（19.4%）病例中观察到高TEAD4表达，其与淋巴结转移、切缘受累及高AJCC分期显著相关。LATS1/2表达阳性的DBDC患者总生存期显著优于无LATS1/2表达者（P<0.001），YAP和TEAD4高表达患者的总生存期显著差于低表达者（分别为P = 0.014、0.037）。LATS1/2+YAP或TEAD4低表达联合组患者的总生存期显著优于其他组[风险比（HR）5.809；95%置信区间（CI），1.770 - 19.065；P = 0.001]。这种联合是DBDC患者独立的良好预后因素（HR 4.399；95% CI，1.313 - 14.743；P = 0.016）。LATS1/2、YAP和TEAD4表达与DBDC临床病理行为相关，可能是DBDC患者有用的预后标志物。
