Understanding the role of RAMS11 in non small cell lung cancer

Washington University, Saint Louis MO

Investigators

Abstract

Our research focuses on understanding how long noncoding RNAs (lncRNAs) promote non-small cell lung cancer (NSCLC) to address the critical need for improved biomarkers and targeted therapies. Lung cancer is currently the leading cause of death worldwide, accounting for more than 150,000 deaths a year in just the United States. Approximately 85% of lung cancer patients have NSCLC and over 50% of these patients present with metastasis at their initial diagnosis. Historically, NSCLC research has primarily focused on the deregulation of protein-coding genes to identify oncogenes and tumor suppressors as potential diagnostic and therapeutic targets, thereby under-representing the emerging roles of long non-coding RNAs (lncRNAs). To address this critical knowledge gap, we focused on the discovery and functional characterization of novel lncRNAs that promote tumorigenesis and aggressive phenotypes in NSCLC patients. Through a pan-cancer computational analysis we discovered that the expression of our recently discovered oncogenic lncRNA, RNA associated with metastasis 11 (RAMS11), was elevated in NSCLC patients harboring mutations in the NRF2 signaling pathway (NRF2 activating mutations and KEAP1 inactivating mutations). Our preliminary data shows: (1) RAMS11 promotes aggressive phenotypes, (2) NRF2 transcriptionally activates RAMS11 by binding to its promoter region, (3) RNA-Seq analysis of models manipulating NRF2 and/or RAMS11 revealed overlapping downstream regulatory programs, (4) NRF2 and RAMS11 interact, and (5) NRF2 transcriptional regulation of canonical targets was dependent on RAMS11 expression. Notably, while NRF2 is dependent on RAMS11 to transcriptionally regulate canonical target genes activated in lung epithelial cells and NSCLC cells, we also demonstrated that RAMS11 may mediate a cancer specific NRF2 regulatory program. Collectively, this serves as a strong rationale for our hypothesis that RAMS11 is necessary to confer NRF2-dependent oncogenic phenotypes in NRF2/KEAP1 mutant NSCLC lung cancer patients. Here we will determine the role of RAMS11 dependent NRF2 transcriptional regulation of cancer-specific, non-canonical target genes and evaluate how RAMS11 interacts with NRF2. Our proposal will significantly advance the lncRNA tumor biology field by providing the first evidence of RAMS11-dependent NRF2 regulation to confer oncogenic phenotypes in vitro and in vivo.