Takasawa Kumi, Takasawa Akira, Osanai Makoto, Aoyama Tomoyuki, Ono Yusuke, Kono Tsuyoshi, Hirohashi Yoshihiko, Murata Masaki, Sawada Norimasa
Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
Cancer Lett. 2017 Sep 10;403:66-73. doi: 10.1016/j.canlet.2017.05.033. Epub 2017 Jun 15.
Our recent work revealed that elevated expression of claudin-18 is involved in bile duct neoplasia. In the present study, we found that wound generation of a cell sheet de novo induced claudin-18 expression in its leading edge, coincident with high mitotic activity. We also found that the suppression of claudin-18 expression significantly reduced cell growth and invasiveness of bile duct cancer cell lines and tumorigenicity in vivo. In addition, an antibody specific to an extracellular loop of claudin-18 showed similar effects on the cells such as cell proliferation. Interestingly, treatment with epidermal growth factor (EGF) and overexpression of RAS oncogene induced claudin-18 expression by activation of extracellular signal-related kinase (ERK)1/2. Furthermore, enhanced claudin-18 expression activated ERK1/2. These findings provide evidence for an oncogenic property of claudin-18 in bile duct carcinoma cells via modulation of EGFR/ERK signaling, indicating that claudin-18 is a possible therapeutic target for this malignancy.
我们最近的研究表明，紧密连接蛋白-18（claudin-18）表达升高与胆管肿瘤形成有关。在本研究中，我们发现细胞片层的新生伤口可在其前沿诱导紧密连接蛋白-18表达，这与高有丝分裂活性同时出现。我们还发现，抑制紧密连接蛋白-18表达可显著降低胆管癌细胞系的细胞生长和侵袭能力以及体内致瘤性。此外，一种针对紧密连接蛋白-18细胞外环的特异性抗体对细胞增殖等方面表现出类似作用。有趣的是，表皮生长因子（EGF）处理和RAS癌基因过表达通过激活细胞外信号调节激酶（ERK）1/2诱导紧密连接蛋白-18表达。此外，增强的紧密连接蛋白-18表达激活了ERK1/2。这些发现为紧密连接蛋白-18通过调节表皮生长因子受体（EGFR）/ERK信号通路在胆管癌细胞中的致癌特性提供了证据，表明紧密连接蛋白-18可能是这种恶性肿瘤的治疗靶点。
