Abstract
Abstract Lung adenocarcinoma accounts for ~40% of lung cancers and is among the deadliest cancers worldwide. Patients with metastatic lung adenocarcinoma exhibit poor outcome with the average 5-year survival of ~1%. Long non-coding RNAs (lncRNAs) have recently emerged as having critical roles in tumorigenesis. While a subset of lncRNAs have been shown to promote tumor invasion and metastasis, little is known about the role of lncRNAs in metastatic lung adenocarcinoma. Therefore, we analyzed publicly available microarray and RNA-Seq gene expression datasets that include primary and metastatic tissues. Through this meta-analysis we discovered 98 metastasis associated lncRNAs that were dysregulated in metastatic tumors compared to non-metastatic tumors (MALLs). Notably, only two lncRNAs (MALL-2 and MALL-36) were found to be down-regulated in primary tumors, relative to normal tissue, and even further down-regulated in metastatic tumors relative to primary tumors. Gene set enrichment analysis revealed that MALL-2, the most down-regulated lncRNA in metastasis, was coexpressed with protein-coding genes enriched with biological concepts associated with repressing tumor growth and metastasis. Furthermore, we found that FOXA2, a metastasis repressor gene, was highly coexpressed with MALL-2 in lung cancer. A pan-cancer analysis using ~7,000 TCGA RNA-Seq tumor samples across 20 cancer types revealed that MALL-2 was also down-regulated and coexpressed with FOXA2 in multiple cancers suggesting the conserved regulatory relationship between the two genes. We confirmed that FOXA2 expression was decreased upon knock-down of MALL-2 and silencing MALL-2 resulted in a significant increase in cellular migration in lung adenocarcinoma cell lines. Last, we found that low expression of MALL-2 was consistently associated with poor overall survival across multiple independent lung adenocarcinoma cohorts. Taken together, our integrative analysis has revealed MALL-2 that acts as a repressor of lung adenocarcinoma metastasis by regulating FOXA2 and could serve as a biomarker of lung adenocarcinoma patient outcome. Citation Format: Ha X. Dang, Nicole M. White, Emily B. Rozycki, Christopher A. Maher. Down-regulation of long non-coding RNA MALL-2 is associated with metastasis and poor survival in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3447. doi:10.1158/1538-7445.AM2017-3447
Published Version
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