The STAT3 pathway is frequently overactive in non–small cell lung cancer (NSCLC), an often fatal disease with known risk factors including tobacco and chemical exposures. Whether STAT3 can be downmodulated to delay or prevent development of lung cancer resulting from an environmental exposure has not been previously tested. A circular oligonucleotide STAT3 decoy (CS3D) was used to treat mice previously exposed to the tobacco carcinogen nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. CS3D contains a double-stranded STAT3 DNA response element sequence and interrupts STAT3 signaling by binding to STAT3 dimers, rendering them unable to initiate transcription at native STAT3 DNA binding sites. An intermittent course of CS3D decreased the development of airway preneoplasias by 42% at 1 week posttreatment, reduced the progression of preneoplasia to adenomas by 54% at 8 weeks posttreatment, and reduced the size and number of resulting lung tumors by 49.7% and 29.5%, respectively, at 20 weeks posttreatment. No toxicity was detected. A mutant cyclic oligonucleotide with no STAT3 binding ability was used as a control. Chemopreventive effects were independent of the KRAS mutational status of the tumors. In lungs harvested during and after the treatment course with CS3D, airway preneoplasias had reduced STAT3 signaling. Chemopreventive effects were accompanied by decreased VEGFA expression, ablated IL6, COX-2, and p-NF-κB, and decreased pulmonary M2 macrophages and myeloid-derived suppressor cells. Thus, downmodulation of STAT3 activity using a decoy molecule both reduced oncogenic signaling in the airway epithelium and favored a lung microenvironment with reduced immunosuppression.

中文翻译：

---

通过新型 STAT3 诱饵抑制剂预防烟草致癌物诱导的肺肿瘤发展

STAT3 通路在非小细胞肺癌 (NSCLC) 中经常过度活跃，非小细胞肺癌 (NSCLC) 是一种通常致命的疾病，已知风险因素包括烟草和化学品暴露。STAT3 是否可以被下调以延迟或预防由环境暴露引起的肺癌的发展，此前尚未进行过测试。环状寡核苷酸 STAT3 诱饵 (CS3D) 用于治疗先前暴露于烟草致癌物亚硝胺 4-(甲基亚硝胺)-1-(3-吡啶基)-1-丁酮的小鼠。CS3D 包含双链 STAT3 DNA 反应元件序列，并通过与 STAT3 二聚体结合来中断 STAT3 信号传导，使它们无法在天然 STAT3 DNA 结合位点启动转录。在治疗后 1 周，间歇性的 CS3D 疗程将气道前瘤形成的发生率降低了 42%，在治疗后 8 周，肿瘤前期向腺瘤的进展减少了 54%，在治疗后 20 周时，导致的肺肿瘤的大小和数量分别减少了 49.7% 和 29.5%。未检测到毒性。不具有STAT3结合能力的突变环状寡核苷酸用作对照。化学预防作用与肿瘤的 KRAS 突变状态无关。在 CS3D 治疗过程中和治疗后采集的肺中，气道肿瘤前期减少了 STAT3 信号传导。化学预防作用伴随着 VEGFA 表达降低、IL6、COX-2 和 p-NF-κB 消融，以及肺 M2 巨噬细胞和髓源性抑制细胞的减少。因此，