Xie Chengyao, Jiang Guiyang, Fan Chuifeng, Zhang Xiupeng, Zhang Yong, Miao Yuan, Lin Xuyong, Wu Junhua, Wang Liang, Liu Yang, Yu Juanhan, Yang Lianhe, Zhang Di, Xu Ke, Wang Enhua
Department of Pathology, First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, China.
Tumour Biol. 2014 Sep;35(9):8903-11. doi: 10.1007/s13277-014-2162-z. Epub 2014 Jun 4.
ARMC8 proteins are novel armadillo repeat containing proteins, which are well conserved in eukaryotes and are involved in a variety of processes such as cell migration, proliferation, tissue maintenance, signal transduction, and tumorigenesis. Armadillo repeat proteins include well-known proteins such as β-catenin and p120ctn. Our current knowledge of ARMC8, especially its role in cancer, is limited. In this study, we quantified ARMC8 expression in 112 non-small cell lung cancer (NSCLC) tissues and adjacent non-cancerous tissues, and seven lung cancer cell lines using immunohistochemistry staining and Western blotting. ARMC8 level was significantly higher in NSCLC tissues than in the adjacent normal tissues (67.9 % versus 5.4 %, p < 0.05) and was significantly associated with TNM stage (p = 0.022), lymph node metastasis (p = 0.001), and poor prognosis (p < 0.001) in NSCLC patients. Cox regression analysis demonstrated that ARMC8 was an independent prognostic factor for NSCLC. Consistent with this, ARMC8α downregulation by siRNA knockdown inhibited growth, colony formation, and invasion in A549 lung cancer cells, while ARMC8α overexpression promoted growth, colony formation, and invasion in H1299 lung cancer cells. In addition, ARMC8α knockdown downregulated canonical Wnt-signaling pathway activity and cyclin D1 and matrix metalloproteinase (MMP)-7 expression. Consistent with this, ARMC8α overexpression upregulated canonical Wnt-signaling pathway activity and cyclin D1 and MMP-7 expression. These results indicate that ARMC8α upregulates cyclin D1 and MMP7 expression by activating the canonical Wnt-signaling pathway and thereby promoting lung cancer cell proliferation and invasion. Therefore, ARMC8 might serve as a novel therapeutic target in NSCLC.
ARMC8蛋白是一类新型的含犰狳重复序列蛋白，在真核生物中高度保守，参与细胞迁移、增殖、组织维持、信号转导和肿瘤发生等多种过程。犰狳重复序列蛋白包括如β-连环蛋白和p120ctn等知名蛋白。我们目前对ARMC8的了解，尤其是其在癌症中的作用，还很有限。在本研究中，我们采用免疫组织化学染色和蛋白质印迹法，对112例非小细胞肺癌（NSCLC）组织及癌旁非癌组织以及7种肺癌细胞系中的ARMC8表达进行了定量分析。NSCLC组织中ARMC8水平显著高于癌旁正常组织（67.9%对5.4%，p<0.05），且与NSCLC患者的TNM分期（p=0.022）、淋巴结转移（p=0.001）及预后不良（p<0.001）显著相关。Cox回归分析表明，ARMC8是NSCLC的独立预后因素。与此一致，通过小干扰RNA敲低ARMC8α可抑制A549肺癌细胞的生长、集落形成和侵袭，而ARMC8α过表达则促进H1299肺癌细胞的生长、集落形成和侵袭。此外，敲低ARMC8α可下调经典Wnt信号通路活性以及细胞周期蛋白D1和基质金属蛋白酶（MMP）-7的表达。与此一致，ARMC8α过表达可上调经典Wnt信号通路活性以及细胞周期蛋白D1和MMP-7的表达。这些结果表明，ARMC8α通过激活经典Wnt信号通路上调细胞周期蛋白D1和MMP7的表达，从而促进肺癌细胞的增殖和侵袭。因此，ARMC8可能是NSCLC的一个新的治疗靶点。
