Activation of an Oncogenic TBC1D7 (TBC1 Domain Family, Member 7) Protein in Pulmonary Carcinogenesis
Activation of an Oncogenic TBC1D7 (TBC1 Domain Family, Member 7) Protein in Pulmonary Carcinogenesis
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DOI：
10.1002/gcc.20747
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发表时间：
2010-04-01
影响因子：
3.7
通讯作者：
Daigo, Yataro
中科院分区：
文献类型：
--
作者：
Sato, Nagato;Koinuma, Junkichi;Daigo, Yataro
为了开发新的肺癌生物标志物和治疗药物，我们通过cDNA微阵列分析筛选了在肺癌中高表达的分子，发现TBC 1结构域家族成员7（TBC 1D 7）在大多数肺癌中表达升高。Northern-blot分析16例正常组织中的mRNA，仅在睾丸中有表达。使用由261个存档的非小细胞肺癌（NSCLC）标本组成的肿瘤组织微阵列进行的免疫组化染色表明，TBC 1D 7表达与NSCLC患者的不良预后相关（P = 0.0063）。使用针对TBC 1DT的siRNA处理肺癌细胞抑制其表达并导致细胞生长的抑制。此外，诱导TBC 1D 7的外源表达在体外和体内条件下赋予生长促进活性。我们还鉴定了TBC 1D 7与肺癌细胞中的TSC 1蛋白相互作用。将TSC 1引入细胞增加了TBC 1D 7蛋白的水平，而敲低TSC 1表达降低了TBC 1D 7蛋白的水平，表明TBC 1D 7可能通过与TSC 1的相互作用而稳定。此外，通过TBC 1D 7衍生的20个氨基酸的细胞渗透肽（11 R-TBCID 7（152-171））（对应于TSC 1的结合结构域）抑制TBC 1D 7和TSC 1之间的结合，有效抑制了肺癌细胞的生长。选择性抑制TBC 1D 7和/或抑制TBC 1D 7-TSC 1复合物形成可能是肺癌治疗的有前途的治疗策略。(C)2010 Wiley-Liss，Inc.
To develop novel biomarkers and therapeutic agents for lung cancers, we screened molecules that were highly expressed in lung cancers by means of cDNA microarray analysis and found an elevated expression of TBC1 domain family, member 7 (TBC1D7) in the majority of lung cancers. Northern-blot analysis using mRNAs from 16 normal tissues detected its expression only in testis. Immunohistochemical staining using tumor tissue microarrays consisting of 261 archived non-small cell lung cancer (NSCLC) specimens suggested an association of TBC1D7 expression with poor prognosis for NSCLC patients (P = 0.0063). Treatment of lung cancer cells using siRNA against TBC1DT suppressed its expression and resulted in inhibition of the cell growth. Furthermore, the induction of exogenous expression of TBC1D7 conferred growth-promoting activity at in vitro and in vivo conditions. We also identified TBC1D7 to interact with TSC1 protein in lung cancer cells. TSC1 introduction into cells increased the level of TBC1D7 protein, whereas knockdown of TSC1 expression decreased the level of TBC1D7 protein, suggesting that TBC1D7 is stabilized probably through interaction with TSC1. In addition, inhibition of the binding between TBC1D7 and TSC1 by a TBC1D7-derived 20-amino acid cell-permeable peptide (11R-TBCID7(152-171)), which corresponded to the binding domain to TSC1, effectively suppressed growth of lung cancer cells. Selective suppression of TBC1D7 and/or inhibition of the TBC1D7-TSC1 complex formation could be promising therapeutic strategies for lung cancer therapy. (C) 2010 Wiley-Liss, Inc.