The HNF4α-BC200-FMR1-Positive Feedback Loop Promotes Growth and Metastasis in Invasive Mucinous
The HNF4α-BC200-FMR1-Positive Feedback Loop Promotes Growth and Metastasis in Invasive Mucinous
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HNF4a-BC200-FMR1正反馈环促进侵袭性粘液性肺腺癌的生长和转移
DOI：
10.1158/0008-5472.can-21-0980
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发表时间：
2021-12-01
期刊：
影响因子：
11.2
通讯作者：
Zhan, Yan-Yan
中科院分区：
文献类型：
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作者：
Chen, Xiong;Zhao, Yujie;Zhan, Yan-Yan
侵袭性黏液性肺腺癌（Invasive mucinous lung adenocarcinoma，IMA）是肺腺癌的一个亚型，具有较强的侵袭能力. IMA经常携带“不可治疗”的KRAS突变，这突出了对新分子靶点和治疗方法的需求。核受体HNF 4 α在IMA中异常富集，但HNF 4 α作为IMA治疗靶点的潜力仍然未知。在这里，我们报告说，P2启动子驱动的HNF 4 α表达促进IMA的生长和转移。在机制上，HNF 4 α反式激活lncRNA BC 200，其充当mRNA结合蛋白FMR 1的支架。BC 200促进FMR 1结合和调节癌症相关mRNA和HNF 4 α mRNA稳定性的能力，形成正反馈回路。霉酚酸是FDA批准的药物霉酚酸酯的活性代谢产物，被鉴定为HNF 4 α拮抗剂，在体外和体内均表现出抗IMA活性。本研究揭示了HNF 4 α-BC 200-FMR 1-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.Significance提供了靶向治疗策略：侵袭性粘液性肺腺癌的生长和转移进展可以通过靶向HNF 4 α（BC 200-FMR 1-mRNA稳定性轴的关键调节因子）来限制。
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 HNF4 alpha is abnormally enriched in IMA, but the potential of HNF4 alpha to be a therapeutic target for IMA remains unknown. Here, we report that P2 promoter-driven HNF4 alpha expression promotes IMA growth and metastasis. Mechanistically, HNF4 alpha 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 HNF4 alpha mRNA, forming a positive feedback circuit. Mycophenolic acid, the active metabolite of FDA-approved drug mycophenolate mofetil, was identified as an HNF4 alpha antagonist exhibiting anti-IMA activities in vitro and in vivo. This study reveals the role of a HNF4 alpha-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 HNF4 alpha, a critical regulator of a BC200-FMR1-mRNA stability axis.