Huo Yinping, Yuan Dongmei, Liu Hongbing, Song Yong
Department of Respiratory Medicine, Jinling Hospital, Nanjing Medical University, Jiangsu Province, China; Department of Respiratory Medicine, Nanjing Pukou People's Hospital, Jiangsu Province, China.
Department of Respiratory Medicine, Jinling Hospital, Nanjing Medical University, Jiangsu Province, China.
Cell Signal. 2025 Mar;127:111571. doi: 10.1016/j.cellsig.2024.111571. Epub 2024 Dec 20.
Circular RNA (circRNA) can sponge miRNA participate in the tumorigenesis and progression of various cancers. We substantiate for the first time that the fusion circular RNA (F-circRNA) F-circEA1 is involved in driving the echinoderm microtubule associated-protein like 4-anaplastic lymphoma kinase variant 1-positive (EML4-ALK1) lung adenocarcinoma (LUAD) progression and the expression of the parental gene EML4-ALK1, molecular mechanisms of F-circEA1 in the EML4-ALK1 LUAD remain unknown. Bioinformatics analysis showed that only miR-4673 can bind to F-circEA1 and bind to EML4-ALK1 3'-UTR to regulate the expression of EML4-ALK1. Notably, high miR-4673 expression exerted an inhibitory impact on the invasion, migration, and proliferation of EML4-ALK1-positive LUAD cells, and partially reversed the invasion, migration, and proliferation of F-cirEA1. F-circEA1 can sponge miR-4673, enhanced the recombinant mothers against decapentaplegic homolog 4 (SMAD4) expression, which is a downstream target of miR-4673. As a transcription factor, SMAD4 exhibits the ability to directly associate with EML4-ALK1 and adenosinedeaminase RNA editingenzyme 1 (ADAR1) promoter regions. Interestingly, it was also observed that the RNA editing enzyme ADAR1 facilitated the expression of F-circEA1, but inhibited the expression of miR-4673. The interplay between F-circEA1, miR-4673, SMAD4, and ADAR1 forms a feedback pathway that aids in regulating the progression of EML4-ALK variant 1-positive LUAD. This novel finding offers promising therapeutic ideas for the EML4-ALK variant 1-positive lung adenocarcinoma.
环状RNA（circRNA）可通过吸附微小RNA（miRNA）参与多种癌症的发生发展。我们首次证实，融合环状RNA（F-circRNA）F-circEA1参与驱动棘皮动物微管相关蛋白样4-间变性淋巴瘤激酶变异体1阳性（EML4-ALK1）肺腺癌（LUAD）的进展及亲本基因EML4-ALK1的表达，F-circEA1在EML4-ALK1 LUAD中的分子机制尚不清楚。生物信息学分析表明，只有miR-4673能与F-circEA1结合并与EML4-ALK1的3'-非翻译区（UTR）结合以调节EML4-ALK1的表达。值得注意的是，高表达的miR-4673对EML4-ALK1阳性LUAD细胞的侵袭、迁移和增殖具有抑制作用，并部分逆转了F-cirEA1的侵袭、迁移和增殖。F-circEA1可吸附miR-4673，增强重组母亲对dpp同源物4（SMAD4）的表达，而SMAD4是miR-4673的下游靶点。作为一种转录因子，SMAD4具有直接与EML4-ALK1和腺苷脱氨酶RNA编辑酶1（ADAR1）启动子区域结合的能力。有趣的是，还观察到RNA编辑酶ADAR1促进F-circEA1的表达，但抑制miR-4673的表达。F-circEA1、miR-4673、SMAD4和ADAR1之间的相互作用形成了一个反馈通路，有助于调节EML4-ALK变异体1阳性LUAD的进展。这一新颖发现为EML4-ALK变异体1阳性肺腺癌提供了有前景的治疗思路。
