Hasebe Keiji, Yamaguchi Junpei, Kokuryo Toshio, Yokoyama Yukihiro, Ochiai Yosuke, Nagino Masato, Ebata Tomoki
Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Carcinogenesis. 2021 Dec 31;42(12):1496-1505. doi: 10.1093/carcin/bgab093.
Trefoil factor family 2 (TFF2) is one of three trefoil factor family proteins and is expressed abundantly in the gastrointestinal epithelium. Recent studies have shown that TFF2 acts as a tumor suppressor in gastric and pancreatic carcinogenesis; however, little is known about its function in cholangiocarcinogenesis. To investigate the function of TFF2 in cholangiocellular carcinoma (CCC), immunohistochemistry of surgically resected human CCC samples was performed. TFF2 expression was upregulated in the early stage and lost in the late stage of cholangiocarcinogenesis, suggesting the association of TFF2 and CCC. A TFF2 expression vector was then transfected into a CCC cell line (HuCCT1) in vitro, revealing that TFF2 functions as a tumor suppressor not only by inhibiting proliferation and invasion but also by promoting the apoptosis of cancer cells. In addition, PTEN signaling activity was downregulated by TFF2, suggesting an association between TFF2 and PTEN. Next, hepatic carcinogenesis model mice (KC; albumin-Cre/Lox-Stop-Lox KRASG12D) were bred with TFF2-knockout mice to generate a TFF2-deficient mouse model (KC/TFF2-/-). Although the incidence of hepatocellular carcinoma was not different between KC/TFF2-/- mice and control mice, biliary intraepithelial neoplasm (BilIN), the precursor of CCC, was frequently found in the biliary epithelium of KC/TFF2-/- mice. Immunohistochemistry revealed that BilIN samples from these mice did not express PTEN. In addition, two KC/TFF2-/- mice developed CCC adjacent to BilIN, suggesting that TFF2 functions to inhibit the development of CCC in vivo. These results indicate that TFF2 acts as a tumor suppressor to inhibit the development of CCC by regulating PTEN activity.
三叶因子家族2（TFF2）是三叶因子家族的三种蛋白质之一，在胃肠道上皮中大量表达。最近的研究表明，TFF2在胃癌和胰腺癌发生过程中起到肿瘤抑制作用；然而，其在胆管癌发生中的功能却知之甚少。为了研究TFF2在胆管细胞癌（CCC）中的功能，对手术切除的人CCC样本进行了免疫组织化学检测。TFF2表达在胆管癌发生的早期上调，而在晚期消失，提示TFF2与CCC有关联。随后将TFF2表达载体体外转染至CCC细胞系（HuCCT1），结果显示TFF2不仅通过抑制增殖和侵袭，还通过促进癌细胞凋亡发挥肿瘤抑制作用。此外，TFF2下调了PTEN信号活性，提示TFF2与PTEN之间存在关联。接下来，将肝癌发生模型小鼠（KC；白蛋白-Cre/Lox-Stop-Lox KRASG12D）与TFF2基因敲除小鼠杂交，构建TFF2缺陷小鼠模型（KC/TFF2-/-）。尽管KC/TFF2-/-小鼠和对照小鼠的肝细胞癌发生率没有差异，但CCC的前体胆管上皮内瘤变（BilIN）在KC/TFF2-/-小鼠的胆管上皮中经常被发现。免疫组织化学显示，这些小鼠的BilIN样本不表达PTEN。此外，两只KC/TFF2-/-小鼠在BilIN附近发生了CCC，提示TFF2在体内具有抑制CCC发生发展的作用。这些结果表明，TFF2通过调节PTEN活性发挥肿瘤抑制作用，抑制CCC的发生发展。
