Sugimachi Keishi, Nishio Miki, Aishima Shinichi, Kuroda Yosuke, Iguchi Tomohiro, Komatsu Hisateru, Hirata Hidenari, Sakimura Shotaro, Eguchi Hidetoshi, Bekki Yuki, Takenaka Kenji, Maehara Yoshihiko, Suzuki Akira, Mimori Koshi
Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.
Oncology. 2017;93(1):67-74. doi: 10.1159/000463390. Epub 2017 Apr 28.
MOB1, a core component of the Hippo signaling pathway, suppresses cell proliferation, and MOB1 liver conditional knockout mice develop intrahepatic cholangiocarcinoma (ICC). However, its clinical significance in human ICC has not been established. The aim of this study was to characterize protein levels and the role of Hippo and TGF pathways in ICCs.
The protein levels of yes-associated protein 1 (YAP1), MOB1, Smad2, and TGFβ2 in 88 ICC cases were analyzed. Protein level was graded by a scoring system; then, the clinicopathological factors, including prognosis, were analyzed based on protein level.
Nuclear overexpression of YAP1 was seen in 28 cases (31.8%), and it was significantly associated with a poor overall survival rate (p = 0.01). MOB1 expression decreased in 42 cases (47.7%) and was associated with a poor overall survival rate (p = 0.02). SMAD2 nuclear localization was significantly correlated with a high YAP1 level independent of TGFβ2. Multivariate analysis revealed that a high YAP1 level, a low MOB1 level, and lymphatic permeation were independent risk factors for overall survival.
These results showed that key components of the Hippo signaling pathway are aberrantly expressed and associated with the malignant potential of human ICC.
MOB1是Hippo信号通路的核心组成部分，可抑制细胞增殖，MOB1肝脏条件性敲除小鼠会发生肝内胆管癌（ICC）。然而，其在人类ICC中的临床意义尚未明确。本研究旨在明确Hippo和TGF通路在ICC中的蛋白水平及作用。
分析88例ICC病例中Yes相关蛋白1（YAP1）、MOB1、Smad2和TGFβ2的蛋白水平。通过评分系统对蛋白水平进行分级；然后，根据蛋白水平分析包括预后在内的临床病理因素。
28例（31.8%）出现YAP1核过表达，且与总体生存率低显著相关（p = 0.01）。42例（47.7%）MOB1表达降低，且与总体生存率低相关（p = 0.02）。SMAD2核定位与高YAP1水平显著相关，且独立于TGFβ2。多因素分析显示，高YAP1水平、低MOB1水平和淋巴浸润是总体生存的独立危险因素。
这些结果表明，Hippo信号通路的关键成分表达异常，并与人类ICC的恶性潜能相关。
