Oncogenic role of TYRO3 receptor tyrosine kinase in the progression of pancreatic cancer
Oncogenic role of TYRO3 receptor tyrosine kinase in the progression of pancreatic cancer
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DOI：
10.1016/j.canlet.2019.11.028
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发表时间：
2020-01-01
期刊：
影响因子：
9.7
通讯作者：
Matsura, Tatsuya
中科院分区：
文献类型：
--
作者：
Morimoto, Masaki;Horikoshi, Yosuke;Matsura, Tatsuya
作为TAM受体酪氨酸激酶家族的一员，TYRO3在胰腺癌（PC）中的表达和功能尚未明确。在本研究中，我们使用Western blotting证实了TYRO3在5个人PC细胞系（PANC-1、MIA PaCa-2、BxPC-3、AsPC-1和PK-9）中的表达。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细胞增殖和侵袭。通过小鼠异种移植模型，我们发现皮下接种tyro3敲除的PC细胞的小鼠与接种对照PC细胞的小鼠相比，肿瘤生长明显受到抑制。此外，通过免疫组化染色检测106例行胰腺切除术的浸润性导管癌患者PC组织中TYRO3的表达。与tyro3阴性患者相比，tyro3阳性患者的总生存期和疾病特异性生存期预后较差。多因素分析显示TYRO3表达是影响总生存的独立预后因素。我们的研究证明了TYRO3通过Akt和ERK激活在PC进展中的关键作用，并表明TYRO3是针对PC治疗策略的一个新的有希望的靶点。
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.