Dysbindin promotes progression of pancreatic ductal adenocarcinoma via direct activation of PI3K
Dysbindin promotes progression of pancreatic ductal adenocarcinoma via direct activation of PI3K
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DOI：
10.1093/jmcb/mjx043
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发表时间：
2017-12-01
影响因子：
5.5
通讯作者：
Chen, Yong
中科院分区：
文献类型：
--
作者：
Fang, Cheng;Guo, Xin;Chen, Yong
胰腺导管腺癌（Pancreatic ductal adenocarcinoma，PDAC）由于其侵袭性强，缺乏靶向治疗手段，是临床肿瘤学的一大挑战。我们最近的研究表明，PDAC患者血清中精神分裂症易感因子dysbindin水平显著升高。然而，dysbindin在PDAC中的功能相关性仍不清楚。在这里，我们表明dysbindin通过PI 3 K/AKT信号通路加速细胞周期中的G1/S期转变，在体外和体内促进肿瘤生长。机制上，dysbindin与PI 3 K相互作用并刺激PI 3 K的激酶活性。此外，dysbindin在PDAC中的过表达与临床病理特征显著相关，如组织分化（P = 0.011）和肿瘤大小（P = 0.007）。Kaplan-Meier生存曲线显示，与dysbindin低表达的患者相比，dysbindin高表达的患者表现出较差的总生存期（P < 0.001）。多因素分析显示dysbindin是胰腺导管腺癌的独立预后因素（P = 0.001）。因此，我们的研究结果表明，dysbindin是一种新的PI 3 K激活剂，并通过刺激PI 3 K/AKT促进PDAC进展。因此，Dysbindin代表了PDAC预后和治疗的潜在靶点。
Pancreatic ductal adenocarcinoma (PDAC) represents a biggest challenge in clinic oncology due to its invasiveness and lack of targeted therapeutics. Our recent study showed that schizophrenia susceptibility factor dysbindin exhibited significant higher level in serum of PDAC patients. However, the functional relevance of dysbindin in PDAC is still unclear. Here, we show that dysbindin promotes tumor growth both in vitro and in vivo by accelerating the G1/S phase transition in cell cycle via PI3K/AKT signaling pathway. Mechanistically, dysbindin interacts with PI3K and stimulates the kinase activity of PI3K. Moreover, overexpression of dysbindin in PDAC is correlated with clinicopathological characteristics significantly, such as histological differentiation (P = 0.011) and tumor size (P = 0.007). Kaplan-Meier survival curves show that patients with high dysbindin expression exhibit poorer overall survival, compared to those with low dysbindin expression (P < 0.001). Multivariate analysis reveals that dysbindin is an independent prognostic factor for pancreatic ductal adenocarcinoma (P = 0.001). Thus, our findings reveal that dysbindin is a novel PI3K activator and promotes PDAC progression via stimulation of PI3K/AKT. Dysbindin therefore represents a potential target for prognosis and therapy of PDAC.