Zhao Huan-Yu, Han Yang, Wang Jian, Yang Lian-He, Zheng Xiao-Ying, Du Jiang, Wu Guang-Ping, Wang En-Hua
Department of Pathology, First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, China.
Tumour Biol. 2017 Jun;39(6):1010428317705769. doi: 10.1177/1010428317705769.
IQ-domain GTPase-activating protein 1 is a scaffolding protein with multidomain which plays a role in modulating dishevelled (Dvl) nuclear translocation in canonical Wnt pathway. However, the biological function and mechanism of IQ-domain GTPase-activating protein 1 in invasive ductal carcinoma (IDC) remain unknown. In this study, we found that IQ-domain GTPase-activating protein 1 expression was elevated in invasive ductal carcinoma, which was positively correlated with tumor grade, lymphatic metastasis, and poor prognosis. Coexpression of IQ-domain GTPase-activating protein 1 and Dvl in the nucleus and cytoplasm of invasive ductal carcinoma was significantly correlated but not in the membrane. Postoperative survival in the patients with their coexpression in the nucleus and cytoplasm was obviously lower than that without coexpression. The positive expression rates of c-myc and cyclin D1 were significantly higher in the patients with nuclear coexpression of Dvl and IQ-domain GTPase-activating protein 1 than that with cytoplasmic coexpression, correlating with poor prognosis. IQ-domain GTPase-activating protein 1 significantly enhanced cell proliferation and invasion in invasive ductal carcinoma cell lines by interacting with Dvl in cytoplasm to promote Dvl nuclear translocation so as to upregulate the expression of c-myc and cyclin D1. Collectively, our data suggest that IQ-domain GTPase-activating protein 1 may promote the malignant phenotype of invasive ductal carcinoma via canonical Wnt signaling, and it could be used as a potential prognostic biomarker for breast cancer patients.
IQ 结构域 GTP 酶激活蛋白 1 是一种具有多结构域的支架蛋白，在经典 Wnt 信号通路中调节散乱蛋白（Dvl）的核转位过程中发挥作用。然而，IQ 结构域 GTP 酶激活蛋白 1 在浸润性导管癌（IDC）中的生物学功能及机制仍不清楚。在本研究中，我们发现 IQ 结构域 GTP 酶激活蛋白 1 在浸润性导管癌中表达升高，且与肿瘤分级、淋巴转移及预后不良呈正相关。IQ 结构域 GTP 酶激活蛋白 1 和 Dvl 在浸润性导管癌细胞核及细胞质中的共表达显著相关，但在细胞膜中无此相关性。细胞核及细胞质中共表达的患者术后生存率明显低于未共表达的患者。Dvl 与 IQ 结构域 GTP 酶激活蛋白 1 在细胞核中共表达的患者中，c-myc 和细胞周期蛋白 D1 的阳性表达率显著高于在细胞质中共表达的患者，与预后不良相关。IQ 结构域 GTP 酶激活蛋白 1 通过与细胞质中的 Dvl 相互作用，促进 Dvl 的核转位，从而上调 c-myc 和细胞周期蛋白 D1 的表达，显著增强浸润性导管癌细胞系的细胞增殖和侵袭能力。总的来说，我们的数据表明 IQ 结构域 GTP 酶激活蛋白 1 可能通过经典 Wnt 信号通路促进浸润性导管癌的恶性表型，并且它可以作为乳腺癌患者潜在的预后生物标志物。
