The kinesin motor protein KIF4A as a potential therapeutic target in renal cell carcinoma
The kinesin motor protein KIF4A as a potential therapeutic target in renal cell carcinoma
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驱动蛋白运动蛋白 KIF4A 作为肾细胞癌的潜在治疗靶点
DOI：
10.1007/s10637-020-00961-y
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发表时间：
2020-06-12
影响因子：
3.4
通讯作者：
Chen, Ming
中科院分区：
文献类型：
--
作者：
Liu, Guihong;Lu, Yachun;Chen, Ming
驱动蛋白家族成员 4A (KIF4A) 位于人类染色体带 Xq13.1 中。它的 N 末端有一个高度保守的驱动蛋白运动区域，后面是一个中央卷曲螺旋区域和一个包含富含半胱氨酸基序的 C 末端货物结合结构域。它在多种癌症中异常表达。我们的研究旨在确定 KIF4A 在肾细胞癌 (RCC) 中的表达，并获得对该疾病潜在分子机制的新见解。在这里，我们发现 RCC 标本中 KIF4A 的表达相对于正常肾组织中有所增加。 KIF4A的表达与肾细胞癌的临床病理特征存在显着相关性。 KIF4A 表达升高与总生存期和无病生存期较差相关。单变量和多变量 Cox 回归分析显示，KIF4A 是人类 RCC 患者生存不良的独立预后因素。 CCK-8增殖实验、细胞周期分析和裸鼠皮下肿瘤形成分析一致表明KIF4A促进RCC增殖。我们的研究结果还表明，KIF4A 可作为 RCC 转移的加速器，这一点已通过 Transwell 小室分析、伤口愈合测定和血管生成测定证实。 KIF4A敲低组中cyclin D1、cyclin E2、基质金属蛋白酶-2、基质金属蛋白酶-9、缺氧诱导因子1α、血管内皮生长因子的表达水平低于对照组，且与经典致癌途径一致。这些发现提示KIF4A的表达与RCC患者的肿瘤发生、转移和预后显着相关。我们的工作为RCC的诊断和治疗提供了新的突破。
Kinesin family member 4A (KIF4A) is located in the human chromosome band Xq13.1. It has a highly conserved kinesin motor region at its N-terminus, which is followed by a central coiled-coil region and a C-terminus cargo-binding domain that contains a cysteine-rich motif. It is aberrantly expressed in a variety of cancers. Our study aimed to determine the expression of KIF4A in renal cell carcinoma (RCC) and to gain new insights into the underlying molecular mechanisms of this disease. Here, we found that KIF4A expression in RCC specimens increased relative to that in normal renal tissues. A significant correlation existed between the expression of KIF4A and the clinicopathologic features of RCC. Elevated KIF4A expression was associated with poor overall survival and disease-free survival. Univariate and multivariate Cox regression analysis revealed that KIF4A was an independent prognostic factor for poor survival in human patients with RCC. CCK-8 proliferation assay, cell cycle analysis, and subcutaneous tumor formation analysis in nude mice consistently showed that KIF4A promoted RCC proliferation. Our findings also indicated that KIF4A functions as an accelerator of RCC metastasis as certified through transwell chamber analysis, wound healing assay, and angiogenesis assay. The expression levels of cyclin D1, cyclin E2, matrix metalloproteinase-2, matrix metalloproteinase-9, hypoxia-inducible factor 1α, and vascular endothelial growth factor in the KIF4A knockdown group were lower than those in the control group and were consistent with those in classic oncogenic pathways. These findings implied that the expression of KIF4A was significantly related to the tumor incidence, metastasis, and prognosis of patients with RCC. Our work provides new breakthroughs for the diagnosis and treatment of RCC.