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RNA editing enzyme ADAR2 regulates P-glycoprotein expression in murine breast cancer cells via the circRNA-miRNA pathway

ABSTRACT: Among the various modifications of RNA, adenosine-to-inosine RNA editing, catalyzed by adenosine deaminase acting on RNA (ADAR) family, ADAR1 and ADAR2, is the most common nucleotide conversion in mammalian cells. The pathological relevance of ADARs expression has been highlighted in recent human genetic studies. Low expression of the ADAR2 gene is correlated with poor prognosis in breast cancer patients, but the underlying mechanism remains unclear. In this study, we constructed ADAR2-knockdown (ADAR2-KD) murine breast cancer 4T1 cells and found their reduced susceptibility to chemotherapeutic drug doxorubicin. Downregulation of ADAR2 induced the expression of P-glycoprotein (P-gp), resulting in a reduction of intracellular accumulation of doxorubicin. The upregulation of P-gp occurred at the post-transcriptional level due to the decreased miR-195a-3p function. The search for the underlying cause of the induction of P-gp expression in ADAR2-KD 4T1 cells led to the identification of circular RNA (circRNA) circHif1a as a sponge for miR-195a-3p. Indeed, overexpression of circHif1a inhibited miR-195a-3p function, resulting in the upregulation of P-gp expression. Taken together, the decreased expression of ADAR2 in breast cancer plays a critical role in cellular susceptibility to doxorubicin through the regulation of circRNA/miRNA/P-gp pathway. Our findings may contribute to the elucidation of the mechanism of anticancer drug resistance in breast cancer, leading to the overcoming of chemo-resistance.

ORGANISM(S): Mus musculus synthetic construct

PROVIDER: GSE245962 | GEO | 2026/01/01

REPOSITORIES: GEO

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