FOXA1通过激活Wnt通路驱动小细胞肺癌化疗耐药
FOXA1 drives chemoresistance through activating Wnt pathway in small cell lung cancer.
作者
作者单位
- Department of Thoracic Surgery, Institute of Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
摘要
中文
小细胞肺癌（SCLC）是一种侵袭性神经内分泌肿瘤。尽管化疗是一线治疗的基石，但大多数SCLC患者初治有效后很快出现化疗耐药，其分子基础尚不清楚。本研究旨在识别SCLC化疗耐药的新驱动因素。通过公共数据库分析FOXA1拷贝数变异和表达模式，并用免疫印迹和免疫组化进行验证。通过体外和体内功能获得/缺失实验确定FOXA1在化疗耐药中的功能作用。进行RNA测序和染色质免疫沉淀测序以研究潜在机制。通过遗传扰动和药理学抑制测试FOXA1-WNT5A-Wnt轴的功能意义。结果显示FOXA1是SCLC中频繁扩增和上调的基因。FOXA1过表达促进化疗耐药。机制上，WNT5A被鉴定为FOXA1的直接下游靶标，通过激活Wnt/β-catenin通路介导化疗耐药。FOXA1还诱导SCLC细胞发生上皮间质转化（EMT）。一致地，FOXA1高表达的人SCLC肿瘤表现出富集的EMT和Wnt/β-catenin通路特征。重要的是，Wnt通路的药理学抑制选择性抑制FOXA1过表达SCLC细胞的生长。本研究确定FOXA1是SCLC化疗耐药的关键驱动因素，并强调Wnt通路抑制是克服FOXA1驱动化疗耐药的有前景的治疗策略。
English
Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor. While chemotherapy has been the cornerstone of first-line treatment, most SCLC patients develop chemoresistance shortly after an initial response, and the molecular basis of this resistance remains poorly understood. This study aims to identify novel drivers of SCLC chemoresistance. FOXA1 copy number alterations and expression patterns were analyzed using public databases and validated by immunoblotting and immunohistochemistry. The functional role of FOXA1 in chemoresistance was determined through in vitro and in vivo gain- and loss-of-function assays. RNA sequencing and chromatin immunoprecipitation sequencing were performed to investigate underlying mechanisms. The functional significance of FOXA1-WNT5A-Wnt axis was tested using genetic perturbations and pharmacological inhibition. FOXA1 was a frequently amplified and upregulated gene in SCLC. FOXA1 overexpression promoted resistance to chemotherapy. Mechanistically, WNT5A was identified as a direct downstream target of FOXA1, mediating chemoresistance through activation of the Wnt/β-catenin pathway. FOXA1 also induced epithelial-mesenchymal transition (EMT) in SCLC cells. Consistently, human SCLC tumors with elevated FOXA1 expression exhibited enriched EMT and Wnt/β-catenin pathway signatures. Importantly, pharmacological inhibition of the Wnt pathway selectively suppressed the growth of FOXA1-overexpressing SCLC cells. This study identifies FOXA1 as a key driver of chemoresistance in SCLC and highlights Wnt pathway inhibition as a promising therapeutic strategy to overcome FOXA1-driven chemoresistance.
分类与指标
- 研究类型
- 基础研究
- 病种
- 肺癌
- JCR 分区
- Q2
- 影响因子
- 3.4
- 新锐分区
- 3区