Affiliations of authors: MRC Cancer Unit, Cambridge, UK (C-AJO, CSR-I, MO, CEW, AN, RCF); Cancer Research UK Cambridge Institute, Cambridge, UK (NBS, OMR, D-eH, MIK, CC, KB); UK Cambridge Esophagogastric Centre, Addenbrooke's Hospital, Cambridge, UK (RHH).
J Natl Cancer Inst. 2014 Apr 28;106(5):dju050. doi: 10.1093/jnci/dju050.
Many prognostic biomarkers have been proposed recently. However, there is a lack of therapeutic strategies exploiting novel prognostic biomarkers. We aimed to propose therapeutic options in patients with overexpression of TRIM44, a recently identified prognostic gene.
Genomic and transcriptomic data of epithelial cancers (n = 1932), breast cancers (BCs; n = 1980) and esophago-gastric cancers (EGCs; n = 163) were used to identify genomic aberrations driving TRIM44 overexpression. The driver gene status of TRIM44 was determined using a small interfering RNA (siRNA) screen of the 11p13 amplicon. Integrative analysis was applied across multiple datasets to identify pathway activation and potential therapeutic strategies. Validation of the in silico findings were performed using in vitro assays, xenografts, and patient samples (n = 160).
TRIM44 overexpression results from genomic amplification in 16.1% of epithelial cancers, including 8.1% of EGCs and 6.1% of BCs. This was confirmed using fluorescent in situ hybridization. The siRNA screen confirmed TRIM44 to be a driver of the amplicon. In silico analysis revealed an association between TRIM44 and mTOR signalling, supported by a decrease in mTOR signalling after siRNA knockdown of TRIM44 in cell lines and colocalization of TRIM44 and p-mTOR in patient samples. In vitro inhibition studies using an mTOR inhibitor (everolimus) decreased cell viability in two TRIM44-amplified cells lines by 88% and 70% compared with 35% in the control cell line. These findings were recapitulated in xenograft models.
Genomic amplification drives TRIM44 overexpression in EGCs and BCs. Targeting the mTOR pathway provides a potential therapeutic option for TRIM44-amplified tumors.
最近提出了许多预后生物标志物，但缺乏利用新型预后生物标志物的治疗策略。我们旨在为 TRIM44 过表达的患者提出治疗选择，TRIM44 是最近发现的一个预后基因。
使用上皮癌（n = 1932）、乳腺癌（BC；n = 1980）和食管胃癌症（EGC；n = 163）的基因组和转录组数据，确定驱动 TRIM44 过表达的基因组异常。使用 11p13 扩增子的小干扰 RNA（siRNA）筛选确定驱动基因状态。对多个数据集进行综合分析，以确定通路激活和潜在的治疗策略。使用体外实验、异种移植和患者样本（n = 160）验证了计算机分析的结果。
TRIM44 过表达是上皮癌中 16.1%的基因组扩增的结果，包括 8.1%的 EGC 和 6.1%的 BC。这一点通过荧光原位杂交得到了证实。siRNA 筛选证实 TRIM44 是扩增子的驱动基因。计算机分析显示 TRIM44 与 mTOR 信号通路之间存在关联，这一关联得到了 siRNA 敲低 TRIM44 后细胞系中 mTOR 信号通路的减少以及患者样本中 TRIM44 和 p-mTOR 的共定位的支持。使用 mTOR 抑制剂（依维莫司）进行体外抑制研究，与对照细胞系相比，两种 TRIM44 扩增细胞系的细胞活力分别降低了 88%和 70%。这些发现在异种移植模型中得到了重现。
EGC 和 BC 中的基因组扩增驱动 TRIM44 过表达。靶向 mTOR 通路为 TRIM44 扩增肿瘤提供了一种潜在的治疗选择。
