Arl4c expression in colorectal and lung cancers promotes tumorigenesis and may represent a novel therapeutic target
Arl4c expression in colorectal and lung cancers promotes tumorigenesis and may represent a novel therapeutic target
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DOI：
10.1038/onc.2014.402
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发表时间：
2015-09-10
期刊：
影响因子：
8
通讯作者：
Kikuchi, A.
中科院分区：
文献类型：
--
作者：
Fujii, S.;Matsumoto, S.;Kikuchi, A.
我们最近证明，在三维培养的正常上皮细胞中，由Wnt/ β -连环蛋白和表皮生长因子/Ras信号联合诱导的adp -核糖基化因子（ARF）样4c （Arl4c）的表达促进了细胞的迁移和增殖，导致管状结构的形成，表明Arl4c参与了上皮细胞的形态发生。可以想象，在上皮细胞形态发生和癌变之间可能存在一个共同的机制。因此，本研究旨在探讨Arl4c是否可能参与肿瘤发生。对结直肠癌和肺癌患者组织标本的免疫组化分析显示，Arl4c在非肿瘤区域未观察到，但在肿瘤病变中以高频率强烈表达。抑制Wnt/ β -连环蛋白或Ras/丝裂原激活的蛋白激酶信号可降低HCT116结直肠癌细胞和A549肺癌细胞中Arl4c mRNA水平。在这些癌细胞中，Arl4c的敲低抑制了Rac活性，也阻止了yes相关蛋白(YAP)/具有pdz结合基序（TAZ）的转录共激活子的核定位。arl4c缺失的癌细胞在体外和体内均表现出迁移、侵袭和增殖能力的下降。此外，在HCT116细胞源性肿瘤中直接注射Arl4c小干扰RNA (siRNA)（体内用siRNA处理）可抑制免疫缺陷小鼠的肿瘤生长。这些结果表明，Arl4c参与肿瘤发生，可能是抑制结直肠癌和肺癌细胞增殖和侵袭的新治疗靶点。
We recently demonstrated that expression of ADP-ribosylation factor (ARF)-like 4c (Arl4c) induced by a combination of Wnt/beta-catenin and epidermal growth factor/Ras signaling in normal epithelial cells grown in three-dimensional culture promotes cellular migration and proliferation, resulting in formation of tube-like structures, suggesting the involvement of Arl4c in epithelial morphogenesis. It is conceivable that there could be a common mechanism between epithelial morphogenesis and carcinogenesis. Therefore the current study was conducted to investigate whether Arl4c might be involved in tumorigenesis. Immunohistochemical analyses of tissue specimens obtained from colorectal and lung cancer patients revealed that Arl4c was not observed in non-tumor regions but was strongly expressed at high frequencies in tumor lesions. Inhibition of Wnt/beta-catenin or Ras/mitogen-activated protein kinase signaling reduced Arl4c mRNA levels in HCT116 colorectal cancer cells and A549 lung cancer cells. Knockdown of Arl4c inhibited Rac activity and also prevented nuclear localization of yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) in these cancer cells. Arl4c-depleted cancer cells consistently showed decreased migration, invasion and proliferation capabilities both in vitro and in vivo. Furthermore, direct injection of Arl4c small interfering RNA (siRNA) into HCT116 cell-derived tumors (in vivo treatment with siRNA) inhibited tumor growth in immunodeficient mice. These results suggest that Arl4c is involved in tumorigenesis and might represent a novel therapeutic target for suppressing proliferation and invasion of colorectal and lung cancer cells.