Fusion circRNA F-circEA1 facilitates EML4-ALK1 positive lung adenocarcinoma progression through the miR-4673/SMAD4/ADAR1 axis

Abstract

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.