Abstract 3903: Role of the miR-301a/Fra-2/GLIPR1 axis in lung cancer cisplatin resistance

Abstract

Abstract Lung cancer is the leading cause of cancer-related mortality in both men and women worldwide. Despite the administration of platinum compounds represents the main treatment, the majority of tumors remains intrinsically resistant. In lung cancer, miR-301a exerts a main role by modulating the activity of transcription factors like NF-kB and Stat3. Here, we dissected the contribution of miR-301a in the regulation of its new identified target Fos-related antigen-2 (Fra-2), a transcription factor that belongs to the Fos/AP-1 family. By microarray analysis, we discovered that Fra-2 overexpression increased glioma pathogenesis-related protein 1 (GLIPR1) levels, a mediator of cisplatin resistance in lung cancer. Its mechanism of regulation is still unclear. We demonstrated that GLIPR1 is also a miR-301a target. In vitro, modulation of miR-301a reduced Fra-2 and GLIPR1 levels; conversely, Fra-2 overexpression significantly increased GLIPR1 and miR-301a. Then, by chromatin immunoprecipitation assay, we confirmed that Fra-2 interacts with the promoter regions of both GLIPR1 and MIR301A genes, supporting that miR-301a/Fra-2/GLIPR1 axis could be autoregulated by feedback loop in which Fra-2 promotes the transcription of MIR301A gene. Investigating the effect of this new axis on the response to cisplatin, we observed that both Fra-2/GLIPR1 overexpression and miR-301a silencing induced cisplatin resistance in lung cancer cells. By contrast, silencing of GLIPR1 and combined administration of low doses of Fos/AP-1 inhibitor restored the cisplatin sensitivity in Fra-2 overexpressing cells. In the lung adenocarcinoma samples from the TCGA dataset, miR-301a overexpression inversely correlated with Fra-2 and GLIPR1 expression. Consistently, the overexpression of miR-301a identified a fraction of tumors with low expression of Fra-2 and GLIPR1 in an internal cohort of lung cancer samples. Altogether, our findings identify the miR-301a/Fra-2/GLIPR1 axis that contributes to cisplatin resistance in lung cancer cells and could serve as biomarker to stratify patients who may benefit from cisplatin administration, alone or in combination with Fos/AP-1 inhibitors. Citation Format: Francesca Lovat, Gian Luca Rampioni Vinciguerra, Marina Capece, Rosario Distefano, Giovanni Nigita, Andrea Vecchione, Carlo M. Croce. Role of the miR-301a/Fra-2/GLIPR1 axis in lung cancer cisplatin resistance. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3903.