ADNP Is a Therapeutically Inducible Repressor of WNT Signaling in Colorectal Cancer
ADNP Is a Therapeutically Inducible Repressor of WNT Signaling in Colorectal Cancer
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DOI：
10.1158/1078-0432.ccr-16-1604
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发表时间：
2017-06-01
影响因子：
11.5
通讯作者：
Horst, David
中科院分区：
文献类型：
--
作者：
Blaj, Cristina;Bringmann, Agnes;Horst, David
目的：组成性活跃的WNT信号是结直肠癌的标志，也是恶性肿瘤进展的驱动因素。由于WNT信号通路的高度复杂性及其在组织稳态中的作用，治疗靶向是困难的。在这里，我们发现转录因子ADNP是结肠癌中WNT信号的药理学诱导抑制因子。实验设计：我们使用转录组学、蛋白质组学和原位分析来鉴定ADNP在结直肠癌中的表达，并使用细胞生物学方法来确定其功能。我们在体内用低剂量氯胺酮诱导ADNP在结肠癌异种移植物中的表达。在221例人类结直肠癌病例的队列中确定了临床关联。结果：ADNP在WNT高活性的结肠癌细胞中过表达，起到WNT抑制因子的作用。沉默ADNP表达增加了结肠癌细胞的迁移、侵袭和增殖，并加速了异种移植体内肿瘤的生长。亚麻醉剂量氯胺酮诱导ADNP表达，显著抑制肿瘤生长，延长荷瘤动物存活。在人类结肠癌患者中，高ADNP表达与良好的预后有关。结论：我们的研究结果表明，ADNP是一种肿瘤抑制因子和有希望的预后标志物，氯胺酮治疗ADNP诱导是一种潜在的治疗方法，可能会增加结直肠癌患者当前治疗方案的益处。(c) 2016年aacr。
Purpose: Constitutively active WNT signaling is a hallmark of colorectal cancers and a driver of malignant tumor progression. Therapeutic targeting of WNT signaling is difficult due to high pathway complexity and its role in tissue homeostasis. Here, we identify the transcription factor ADNP as a pharmacologically inducible repressor of WNT signaling in colon cancer.Experimental Design: We used transcriptomic, proteomic, and in situ analyses to identify ADNP expression in colorectal cancer and cell biology approaches to determine its function. We induced ADNP expression in colon cancer xenografts by low-dose ketamine in vivo. Clinical associations were determined in a cohort of 221 human colorectal cancer cases.Results: ADNP was overexpressed in colon cancer cells with high WNT activity, where it acted as a WNT repressor. Silencing ADNP expression increased migration, invasion, and proliferation of colon cancer cells and accelerated tumor growth in xenografts in vivo. Treatment with subnarcotic doses of ketamine induced ADNP expression, significantly inhibited tumor growth, and prolonged survival of tumor-bearing animals. In human patients with colon cancer, high ADNP expression was linked to good prognosis.Conclusions: Our findings indicate that ADNP is a tumor suppressor and promising prognostic marker, and that ketamine treatment with ADNP induction is a potential therapeutic approach that may add benefit to current treatment protocols for patients with colorectal cancer. (C) 2016 AACR.