Fan Chuifeng, Jiang Guiyang, Zhang Xiupeng, Miao Yuan, Lin Xuyong, Luan Lan, Xu Zhonghai, Zhang Yijun, Zhao Huanyu, Liu Di, Wang Enhua
Department of Pathology, First Affiliated Hospital and College of Basic Medical Sciences of China Medical University, Shenyang, China.
Institute of Pathology and Pathophysiology, China Medical University, Shenyang, China.
Mol Carcinog. 2015 Jun;54 Suppl 1:E138-47. doi: 10.1002/mc.22216. Epub 2014 Sep 27.
Our previous studies indicate that abnormal expression of several Wnt signaling molecules including Axin, Dvl and β-catenin are involved in proliferation, invasion and metastasis of lung cancer. Zbed3 was found to inhibit function of Axin-GSK3β complex and thus lead to accumulation of β-catenin in NIH3T3 and HEK293T cells. However its function in malignant tumors is largely unknown. Here we investigate the clinico-pathological significance of Zbed3 expression and its function in non-small cell lung cancer. We use immunohistochemistry and Western blotting to examine Zbed3 expression in non-small cell lung cancer and lung tissues. Transfection of siRNA and plasmid was used to study the function of Zbed3 in lung cancer cells in vitro. We found Zbed3 expression was elevated in cancer tissues compared to normal lung tissues. Increased Zbed3 expression is significantly associated with lymph node metastasis, advanced TNM stages, higher Ki67 status and patients' poor clinical outcome. Higher Zbed3 expression was also found in lung cancer cell lines compared to bronchial epithelial cell line HBE. Downregulation of Zbed3 by siRNA significantly inhibits cancer cell proliferation and invasion in vitro. Downregulation of Zbed3 also significantly inhibits expression of β-catenin, downstream molecules of Wnt signaling and P120ctn-1 in lung cancer cells. These results suggest that Zbed3 may contribute to lung cancer cell invasion through regulating β-catenin and p120ctn-1 and may be a promissing cancer marker in non-small cell lung cancer.
我们之前的研究表明，包括Axin、Dvl和β-连环蛋白在内的几种Wnt信号分子的异常表达与肺癌的增殖、侵袭和转移有关。研究发现Zbed3可抑制Axin-GSK3β复合物的功能，从而导致NIH3T3和HEK293T细胞中β-连环蛋白的积累。然而，其在恶性肿瘤中的功能尚不清楚。在此，我们研究Zbed3表达在非小细胞肺癌中的临床病理意义及其功能。我们采用免疫组织化学和蛋白质印迹法检测非小细胞肺癌组织和肺组织中Zbed3的表达。利用小干扰RNA（siRNA）和质粒转染来体外研究Zbed3在肺癌细胞中的功能。我们发现，与正常肺组织相比，癌组织中Zbed3表达升高。Zbed3表达增加与淋巴结转移、晚期TNM分期、较高的Ki67状态以及患者较差的临床预后显著相关。与支气管上皮细胞系HBE相比，肺癌细胞系中也发现Zbed3表达较高。通过siRNA下调Zbed3可显著抑制体外癌细胞的增殖和侵袭。下调Zbed3也显著抑制肺癌细胞中β-连环蛋白、Wnt信号下游分子和P120ctn-1的表达。这些结果表明，Zbed3可能通过调节β-连环蛋白和p120ctn-1促进肺癌细胞侵袭，并且可能是一种有前景的非小细胞肺癌肿瘤标志物。
