Oncogenic targets Mmp7, S100a9, Nppb and Aldh1a3 from transcriptome profiling of FAP and Pirc adenomas are downregulated in response to tumor suppression by Clotam
Oncogenic targets Mmp7, S100a9, Nppb and Aldh1a3 from transcriptome profiling of FAP and Pirc adenomas are downregulated in response to tumor suppression by Clotam
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DOI：
10.1002/ijc.30458
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发表时间：
2017-01-15
影响因子：
6.4
通讯作者：
Dashwood, Roderick H.
中科院分区：
文献类型：
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作者：
Ertem, Furkan U.;Zhang, Wenqian;Dashwood, Roderick H.
家族性腺瘤性息肉病（FAP）患者和其他高危结直肠癌（CRC）人群的干预策略强调了内镜检查与安全有效的预防药物相结合的迫切需求。我们对来自FAP患者的结直肠腺瘤和大鼠结肠息肉病（Pirc）临床前模型进行了转录组分析，并优先考虑了体内预防研究的分子靶点。在Pirc模型中的临床相关剂量下，当单独给药或与舒林酸联合给药时，药物Clotam（托芬那酸，TA）在抑制结肠和小肠中的肿瘤发生方面非常有效。TA显著降低结肠隐窝中的细胞增殖，与增加的裂解半胱天冬酶-3和减少的存活素、β-连环蛋白、细胞周期蛋白D1和基质金属蛋白酶7一致。从转录组分析优先的差异表达基因列表中，Mmp 7、S100 a9、Nppb和Aldh 1a 3被定义为TA治疗后结肠肿瘤中下调的关键癌基因候选者。每月一次的结肠镜检查显示，在Pirc模型中，TA对肿瘤的抑制作用迅速起效，Mmp 7、S100 a9、Nppb和Aldh 1a 3的时间变化突出了它们作为临床预防的潜在早期生物标志物的价值。我们的结论是，TA，一种从偏头痛中重新利用的“老药”，为FAP和其他高危CRC患者人群提供了一种令人兴奋的新治疗途径。
Intervention strategies in familial adenomatous polyposis (FAP) patients and other high-risk colorectal cancer (CRC) populations have highlighted a critical need for endoscopy combined with safe and effective preventive agents. We performed transcriptome profiling of colorectal adenomas from FAP patients and the polyposis in rat colon (Pirc) preclinical model, and prioritized molecular targets for prevention studies in vivo. At clinically relevant doses in the Pirc model, the drug Clotam (tolfenamic acid, TA) was highly effective at suppressing tumorigenesis both in the colon and in the small intestine, when administered alone or in combination with Sulindac. Cell proliferation in the colonic crypts was reduced significantly by TA, coincident with increased cleaved caspase-3 and decreased Survivin, beta-catenin, cyclin D1 and matrix metalloproteinase 7. From the list of differentially expressed genes prioritized by transcriptome profiling, Mmp7, S100a9, Nppb and Aldh1a3 were defined as key oncogene candidates downregulated in colon tumors after TA treatment. Monthly colonoscopies revealed the rapid onset of tumor suppression by TA in the Pirc model, and the temporal changes in Mmp7, S100a9, Nppb and Aldh1a3, highlighting their value as potential early biomarkers for prevention in the clinical setting. We conclude that TA, an "old drug" repurposed from migraine, offers an exciting new therapeutic avenue in FAP and other high-risk CRC patient populations.