Invasive mucinous lung adenocarcinoma (IMA) is a subtype of lung adenocarcinoma with a strong invasive ability. IMA frequently carries "undruggable" KRAS mutations, highlighting the need for new molecular targets and therapies. Nuclear receptor HNF4α is abnormally enriched in IMA, but the potential of HNF4α to be a therapeutic target for IMA remains unknown. Here, we report that P2 promoter-driven HNF4α expression promotes IMA growth and metastasis. Mechanistically, HNF4α transactivated lncRNA BC200, which acted as a scaffold for mRNA binding protein FMR1. BC200 promoted the ability of FMR1 to bind and regulate stability of cancer-related mRNAs and HNF4α mRNA, forming a positive feedback circuit. Mycophenolic acid, the active metabolite of FDA-approved drug mycophenolate mofetil, was identified as an HNF4α antagonist exhibiting anti-IMA activities in vitro and in vivo . This study reveals the role of a HNF4α-BC200-FMR1–positive feedback loop in promoting mRNA stability during IMA progression and metastasis, providing a targeted therapeutic strategy for IMA. Significance: Growth and metastatic progression of invasive mucinous lung adenocarcinoma can be restricted by targeting HNF4α, a critical regulator of a BC200-FMR1-mRNA stability axis.

中文翻译：

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HNF4{alpha}-BC200-FMR1-正反馈回路促进侵袭性粘液性肺腺癌的生长和转移

侵袭性粘液性肺腺癌（IMA）是肺腺癌的一种亚型，具有很强的侵袭能力。IMA 经常携带“无法治疗”的 KRAS 突变，突出了对新分子靶点和疗法的需求。核受体 HNF4α 在 IMA 中异常富集，但 HNF4α 作为 IMA 治疗靶点的潜力仍然未知。在这里，我们报告 P2 启动子驱动的 HNF4α 表达促进 IMA 生长和转移。从机制上讲，HNF4α 反式激活了 lncRNA BC200，它充当了 mRNA 结合蛋白 FMR1 的支架。BC200促进FMR1结合和调节癌症相关mRNAs和HNF4αmRNA稳定性的能力，形成正反馈回路。霉酚酸，FDA 批准的药物霉酚酸酯的活性代谢物，被鉴定为在体外和体内表现出抗 IMA 活性的 HNF4α 拮抗剂。本研究揭示了 HNF4α-BC200-FMR1-正反馈环在 IMA 进展和转移过程中促进 mRNA 稳定性的作用，为 IMA 提供了靶向治疗策略。意义：侵袭性粘液性肺腺癌的生长和转移进展可以通过靶向 HNF4α 来限制，HNF4α 是 BC200-FMR1-mRNA 稳定性轴的关键调节因子。