HNF4α-lncRNA BC200正反馈环路促浸润性黏液型肺腺癌生长和转移的作用及机制研究

核受体HNF4α在正常肺组织中不表达，而在近90%浸润性黏液型肺腺癌（IMA）中呈阳性表达，但其作用及机制不清楚。本项目前期发现，HNF4α促进人IMA细胞的增殖、迁移和侵袭。HNF4α能上调lncRNA BC200的表达，且HNF4α促IMA作用依赖于BC200；BC200反过来也能上调HNF4α的表达。基于此，本项目拟深入探讨HNF4α-BC200正反馈环路在IMA生长和转移中的作用及相关分子机制，包括：1）小鼠模型验证HNF4α促IMA生长和转移的作用及BC200的介导作用；2）HNF4α调控BC200表达的分子机制；3）BC200促IMA生长和转移的分子机理；4）BC200调控HNF4α表达的分子机制；5）IMA临床样本HNF4α与BC200表达的相关性；6）从FDA上市药物库中筛选具抗IMA活性的HNF4α拮抗剂。希望通过本项目，为IMA精准治疗提供新策略。

Recent studies revealed that nuclear receptor HNF4α, whose expression was undetectable in human normal lung tissue, was positively expressed in approximately 90% of human invasive mucinous lung adenocarcinoma (IMA). However, the role of HNF4α and the mechanisms involved in IMA progression are still unknown. Initial study of this project found that HNF4α significantly promoted the proliferation, migration and invasion of human IMA cells. HNF4α elevated the expression level of lncRNA BC200, which was essential for HNF4α to regulate the proliferation and metastatic potential of human IMA cells. We also found that BC200 in turn had a positive regulatory effect on the expression of HNF4α. Based on these results, this project intends to comprehensively explore the role of HNF4α-BC200 positive feedback loop in the growth and metastasis of IMA and the related molecular mechanisms, including: 1) verification on the regulatory role of HNF4α on IMA growth and metastasis and the mediating role of BC200 using mouse models; 2) the molecular mechanisms on how HNF4α regulates BC200 expression; 3) the underlying mechanisms of BC200 in promoting IMA growth and metastasis; 4) the molecular mechanisms for BC200 to regulate the expression of HNF4α; 5) the correlation between the expressions of HNF4α and BC200 in IMA clinical samples; 6) screening of HNF4α antagonists with anti-IMA activity from FDA-approved drug library. Through this project, we hope to provide new strategies for IMA precision treatment.