Department of Clinical Laboratory Medicine, Shiga University of Medical Science, Shiga, Japan.
Cancer Res. 2011 Jul 1;71(13):4598-607. doi: 10.1158/0008-5472.CAN-11-0320. Epub 2011 May 13.
RECQL1 and WRN proteins are RecQ DNA helicases that participate in suppression of DNA hyper-recombination and repair. In this study, we report evidence supporting their candidacy as cancer therapeutic targets. In hypopharyngeal carcinomas, which have the worst prognosis among head and neck squamous cell carcinomas (HNSCC) that are rapidly rising in incidence, we found that RECQL1 and WRN proteins are highly expressed and that siRNA-mediated silencing of either gene suppressed carcinoma cell growth in vitro. Similarly, siRNA administration in a murine xenograft model of hypopharyngeal carcinoma markedly inhibited tumor growth. Moreover, combining either siRNA with cis-platinum (II) diammine dichloride significantly augmented the in vivo anticancer effects of this drug that is used commonly in HNSCC treatment. Notably, we observed no recurrence of some tumors following siRNA treatment in this model. Our findings offer a preclinical proof of concept for RECQL1 and WRN proteins as novel therapeutic targets to treat aggressive HNSCC and perhaps other cancers.
RECQL1 和 WRN 蛋白是参与抑制 DNA 超重组和修复的 RecQ DNA 解旋酶。在这项研究中，我们提供了支持它们作为癌症治疗靶点候选物的证据。在下咽癌中，其预后是头颈部鳞状细胞癌（HNSCC）中最差的，其发病率正在迅速上升，我们发现 RECQL1 和 WRN 蛋白表达水平较高，siRNA 介导的基因沉默可抑制体外癌细胞生长。同样，在下咽癌的小鼠异种移植模型中，siRNA 给药显著抑制了肿瘤生长。此外，将 siRNA 与顺铂（II）二氨二氯合用，显著增强了该药物在 HNSCC 治疗中常用的体内抗癌作用。值得注意的是，我们在该模型中观察到一些肿瘤在 siRNA 治疗后没有复发。我们的研究结果为 RECQL1 和 WRN 蛋白作为治疗侵袭性 HNSCC 甚至其他癌症的新型治疗靶点提供了临床前概念验证。
