Activation of KIF4A as a prognostic biomarker and therapeutic target for lung cancer
Activation of KIF4A as a prognostic biomarker and therapeutic target for lung cancer
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DOI：
10.1158/1078-0432.ccr-07-1328
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发表时间：
2007-11-15
影响因子：
11.5
通讯作者：
Daigo, Yataro
中科院分区：
文献类型：
--
作者：
Taniwaki, Masaya;Takano, Atsushi;Daigo, Yataro
目的和实验设计：为了确定可能作为诊断/预后生物标志物和开发新的分子疗法的靶点的分子，我们通过代表27,648个基因的cDNA微阵列的方法，在很大一部分101例肺癌中筛选出高度反式激活的基因。我们发现了一个编码KIF4A的基因，KIF4A是Kinesin家族成员4A，作为候选基因之一。应用肿瘤组织芯片技术检测357例非小细胞肺癌(NSCLC)标本中KIF4A蛋白的表达及其临床病理意义。通过小干扰RNA实验检测KIF4A在癌细胞生长和/或存活中的作用。用Matrigel比色法检测KIF4A对哺乳动物细胞的侵袭活性。结果：357例非小细胞肺癌中127例(36%)KIF4A阳性，29例小细胞肺癌中19例(66%)KIF4A阳性。KIF4A蛋白阳性表达与患者性别(P=0.0287)、非腺癌组织学类型(P=0.0097)、生存期短(P=0.0005)相关，多因素分析证实其独立预后价值(P=0.0012)。KIF4A小干扰RNA治疗肺癌细胞可抑制癌细胞的生长。此外，我们还发现，诱导外源表达KIF4A可以赋予哺乳动物细胞侵袭活性。结论：这些数据强烈暗示靶向KIF4A分子可能为抗癌药物和癌症疫苗的开发以及临床预后生物标志物的开发提供了希望。
Purpose and Experimental Design: To identify molecules that might be useful as diagnostic/ prognostic biomarkers and as targets for the development of new molecular therapies, we screened genesthat were highly transactivated in a large proportion of 101 lung cancers by means of a cDNA microarray representing 27,648 genes. We found a gene encoding KIF4A, a kinesin family member 4A, as one of such candidates. Tumor tissue microarray was applied to examine the expression of KIF4A protein and its clinicopathologic significance in archival non-small cell lung cancer (NSCLC) samples from 357 patients. A role of KIF4A in cancer cell growth and/or survival was examined by small interfering RNA experiments. Cellular invasive activity of KIF4A on mammalian cells was examined using Matrigel assays. Results: Immunohistochemical staining detected positive KIF4A staining in 127 (36%) of 357 NSCLCs and 19 (66%) of 29 small-cell lung cancers examined. Positive immunostaining of KIF4A protein was associated with male gender (P = 0.0287), nonadenocarcinoma histology (P = 0.0097), and shorter survival for patients with NSCLC (P = 0.0005), and multivariate analysis confirmed its independent prognostic value (P = 0.0012). Treatment of lung cancer cells with small interfering RNAs for KIF4A suppressed growth of the cancer cells. Furthermore, we found that induction of exogenous expression of KIF4A conferred cellular invasive activity on mammalian cells. Conclusions: These data strongly implied that targeting the KIF4A molecule might hold a promise for the development of anticancer drugs and cancer vaccines as well as a prognostic biomarker in clinic.