Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Clin Cancer Res. 2010 Jan 1;16(1):226-39. doi: 10.1158/1078-0432.CCR-09-1405. Epub 2009 Dec 22.
We attempted to identify novel biomarkers and therapeutic targets for lung and esophageal cancers.
We screened for genes that were overexpressed in a large proportion of lung and esophageal carcinomas using a cDNA microarray representing 27,648 genes or expressed sequence tags. A gene encoding WDHD1, a WD repeat and high-mobility group box DNA binding protein 1, was selected as a candidate. Tumor tissue microarray containing 267 archival non-small cell lung cancers and 283 esophageal squamous cell carcinomas (ESCC) was used to investigate the clinicopathologic significance of WDHD1 expression. The role of WDHD1 in cancer cell growth and/or survival was examined by small interfering RNA experiments and cell growth assays. The mechanism of WDHD1 activation through its phosphorylation in cancer cells was examined by immunoprecipitation and kinase assays.
Positive WDHD1 immunostaining was associated with a poor prognosis for patients with non-small cell lung cancer (P = 0.0403) as well as ESCC (P = 0.0426). Multivariate analysis indicated it to be an independent prognostic factor for ESCC (P = 0.0104). Suppression of WDHD1 expression with small interfering RNAs effectively suppressed lung and esophageal cancer cell growth. In addition, induction of the exogenous expression of WDHD1 promoted the growth of mammalian cells. AKT1 kinase seemed to phosphorylate and stabilize the WDHD1 protein in cancer cells.
WDHD1 expression is likely to play an important role in lung and esophageal carcinogenesis as a cell cycle regulator and a downstream molecule in the phosphoinositide 3-kinase/AKT pathway, and that WDHD1 is a candidate biomarker and a promising therapeutic target for cancer.
我们试图鉴定肺癌和食管癌的新型生物标志物和治疗靶点。
我们使用代表 27648 个基因或表达序列标签的 cDNA 微阵列筛选了大量肺癌和食管癌中过表达的基因。选择编码 WDHD1 的基因作为候选基因，WDHD1 是一种 WD 重复和高迁移率族框 DNA 结合蛋白 1。使用包含 267 例存档非小细胞肺癌和 283 例食管鳞状细胞癌 (ESCC) 的肿瘤组织微阵列来研究 WDHD1 表达的临床病理意义。通过小干扰 RNA 实验和细胞生长测定来研究 WDHD1 在癌细胞生长和/或存活中的作用。通过免疫沉淀和激酶测定来研究 WDHD1 在癌细胞中通过磷酸化激活的机制。
阳性 WDHD1 免疫染色与非小细胞肺癌患者的不良预后相关（P = 0.0403）以及 ESCC（P = 0.0426）。多变量分析表明，它是非小细胞肺癌的独立预后因素（P = 0.0104）。用小干扰 RNA 抑制 WDHD1 表达可有效抑制肺癌和食管癌细胞的生长。此外，诱导外源性表达 WDHD1 可促进哺乳动物细胞的生长。AKT1 激酶似乎在癌细胞中磷酸化并稳定 WDHD1 蛋白。
WDHD1 表达可能作为细胞周期调节剂和磷酸肌醇 3-激酶/AKT 通路下游分子在肺癌和食管癌发生中发挥重要作用，WDHD1 是癌症的候选生物标志物和有前途的治疗靶点。
