Abstract LB259: Distinct microRNA signature and suppression of ZFP36L1 define ASCL1-positive lung adenocarcinoma

Abstract

Background: Achaete-scute family bHLH transcription factor 1 (ASCL1) is a master transcription factor involved in neuroendocrine differentiation. ASCL1 is expressed in approximately 10% of lung adenocarcinomas and exerts tumor-promoting effects. However, microRNA (miRNA) profiles regulated by ASCL1 in lung adenocarcinoma cells remain unexplored. Method: We analyzed public database of gene expression profiling (RNA-sequencing and miRNA expression data). We also studied miRNA profiles in ASCL1-positive lung adenocarcinoma cells and identified a subset of miRNAs downregulated by ASCL1 knockdown. We examined functions of genes suppressed by miRNAs in ASCL1-positive lung adenocarcinoma cell line, VMRC-LCD. Result: We identified miRNA profiles in ASCL1-positive lung adenocarcinomas and found several miRNAs closely associated with ASCL1 expression, including miR-375, miR-95-3p/miR-95-5p, miR-124-3p, and members of the miR-17~92 family. Similar to small cell lung cancer, Yes1 associated transcriptional regulator (YAP1), a representative miR-375 target gene, is suppressed in ASCL1-positive lung adenocarcinomas. ASCL1 knockdown followed by miRNA profiling in a cell culture model further revealed that ASCL1 positively regulates miR-124-3p and members of the miR-17~92 family. Integrative transcriptomic analyses identified the RNA-binding protein zinc finger protein 36 like 1 (ZFP36L1) as a target gene of miR-124-3p, and immunohistochemical studies have demonstrated that ASCL1-positive lung adenocarcinomas are associated with low ZFP36L1 protein levels. Cell culture studies have shown that ectopic ZFP36L1 expression inhibits cell proliferation, survival, and cell cycle progression. Mechanistically, ZFP36L1 negatively regulated tumorigenic genes, including E2F transcription factor 1 (E2F1) and snail family transcriptional repressor 1 (SNAI1), indicating a tumor-suppressing action. Conclusion: Our study revealed that suppression of ZFP36L1 via ASCL1-regulated miR-124-3p could induce tumor-promoting effects, providing evidence that ASCL1-mediated regulation of miRNAs shapes malignant features of ASCL1-positive lung adenocarcinomas. Citation Format: Naoya Miyashita, Takayoshi Enokido, Masafumi Horie, Hiroshi I. Suzuki, Rei Matsuki, Hans Brunnström, Patrick Micke, Takahide Nagase, Akira Saito. Distinct microRNA signature and suppression of ZFP36L1 define ASCL1-positive lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB259.