Division of Medical Biochemistry, Department of Pathophysiological and Therapeutic Science, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, 683-8503, Japan; Division of Surgical Oncology, Department of Surgery, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago, 683-8504, Japan.
Division of Medical Biochemistry, Department of Pathophysiological and Therapeutic Science, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, 683-8503, Japan.
Cancer Lett. 2020 Feb 1;470:149-160. doi: 10.1016/j.canlet.2019.11.028. Epub 2019 Nov 23.
The expression and functions of TYRO3, a member of the TAM receptor tyrosine kinase family, in pancreatic cancer (PC) have not been specifically elucidated. In this study, we confirmed TYRO3 expression in five human PC cell lines (PANC-1, MIA PaCa-2, BxPC-3, AsPC-1, and PK-9) using Western blotting. TYRO3 silencing and overexpression studies have revealed that TYRO3 promotes cell proliferation and invasion in PC via phosphorylation of protein kinase B (Akt) and extracellular signal-regulated kinase (ERK). Using a mouse xenograft model, we showed that tumor growth was significantly suppressed in mice subcutaneously inoculated with TYRO3-knockdown PC cells compared with mice inoculated with control PC cells. Furthermore, TYRO3 expression was examined in PC tissues obtained from 106 patients who underwent pancreatic resection for invasive ductal carcinoma through immunohistochemical staining. TYRO3-positive patients had poor prognoses for overall survival and disease-specific survival compared with TYRO3-negative patients. Multivariate analysis revealed that TYRO3 expression is an independent prognostic factor for overall survival. Our study demonstrates the critical role of TYRO3 in PC progression through Akt and ERK activation and suggests TYRO3 as a novel promising target for therapeutic strategies against PC.
TYRO3 是 TAM 受体酪氨酸激酶家族的成员，其在胰腺癌（PC）中的表达和功能尚未被具体阐明。在这项研究中，我们使用 Western blot 法确认了五种人 PC 细胞系（PANC-1、MIA PaCa-2、BxPC-3、AsPC-1 和 PK-9）中 TYRO3 的表达。通过 TYRO3 沉默和过表达研究表明，TYRO3 通过磷酸化蛋白激酶 B（Akt）和细胞外信号调节激酶（ERK）促进 PC 中的细胞增殖和侵袭。通过小鼠异种移植模型，我们表明与接种对照 PC 细胞的小鼠相比，皮下接种 TYRO3 敲低 PC 细胞的小鼠的肿瘤生长明显受到抑制。此外，通过免疫组织化学染色法检测了 106 例接受胰腺切除术治疗浸润性导管癌的 PC 组织中的 TYRO3 表达。与 TYRO3 阴性患者相比，TYRO3 阳性患者的总生存和疾病特异性生存预后较差。多变量分析显示，TYRO3 表达是总生存的独立预后因素。我们的研究表明，TYRO3 通过激活 Akt 和 ERK 在 PC 进展中起关键作用，并提示 TYRO3 是针对 PC 的治疗策略的一个有前途的新靶点。
