Journal Article

Long non-coding RNA RAMS11 promotes metastatic colorectal cancer progression

Mardis, Elaine R., Tang, Cynthia, White, Nicole M., Cabanski, Christopher R., Goedegebuure, S. Peter, Jeffers, Gejae G. L., Wilson, Richard K., Eteleeb, Abdallah, Highkin, Maureen K., Silva-Fisher, Jessica M., Maher, Christopher A., Fields, Ryan C., Rozycki, Emily B., Dang, Ha X., Lockhart, Albert C., Mudd, Jacqueline, Luo, Jingqin, Ley, Timothy J., Strand, Matthew S., Grossman, Julie G., Krasnick, Bradley A.

2020

Overview

Colorectal cancer (CRC) is the most common gastrointestinal malignancy in the U.S.A. and approximately 50% of patients develop metastatic disease (mCRC). Despite our understanding of long non-coding RNAs (lncRNAs) in primary colon cancer, their role in mCRC and treatment resistance remains poorly characterized. Therefore, through transcriptome sequencing of normal, primary, and distant mCRC tissues we find 148 differentially expressed RNAs Associated with Metastasis ( RAMS ). We prioritize RAMS11 due to its association with poor disease-free survival and promotion of aggressive phenotypes in vitro and in vivo. A FDA-approved drug high-throughput viability assay shows that elevated RAMS11 expression increases resistance to topoisomerase inhibitors. Subsequent experiments demonstrate RAMS11 -dependent recruitment of Chromobox protein 4 (CBX4) transcriptionally activates Topoisomerase II alpha (TOP2α ) . Overall, recent clinical trials using topoisomerase inhibitors coupled with our findings of RAMS11- dependent regulation of TOP2α supports the potential use of RAMS11 as a biomarker and therapeutic target for mCRC. The role of long non-coding RNAs (lncRNAs) in metastatic colorectal cancer (mCRC) and treatment resistance is unclear. Here, the authors use transcriptome sequencing of matched normal, primary, and metastatic CRC tissues to discover and validate that lncRNA RAMS11 promotes metastasis and resistance to topoisomerase inhibitors in mCRC.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/1 / 13/106 / 13/109 / 13/31 / 13/44 / 13/51 / 13/89 / 13/95 / 14 / 38 / 38/15 / 38/22 / 38/47 / 38/77 / 42 / 45 / 49 / 49/109 / 49/90 / 49/91 / 59 / 59/5 / 631/114 / 631/67 / 631/67/68 / 631/67/68/2486 / 631/67/69 / 64 / 64/60 / 82/80 / 96 / 96/31 / Animals / Biomarkers / Blotting, Western / Caco-2 Cells / Cell Line, Tumor / Chromatin Immunoprecipitation / Clinical trials / Colon / Colon cancer / Colorectal cancer / Colorectal Neoplasms - genetics / Colorectal Neoplasms - pathology / Computational Biology / Disease Progression / DNA topoisomerase (ATP-hydrolysing) / DNA Topoisomerases, Type II - metabolism / Exons - genetics / Gene expression / Gene Expression Regulation, Neoplastic - drug effects / Gene Expression Regulation, Neoplastic - genetics / HCT116 Cells / Health services / HT29 Cells / Humanities and Social Sciences / Humans / Inhibitors / Ligases - metabolism / Malignancy / Metastases / Metastasis / Mice / multidisciplinary / Non-coding RNA / Phenotypes / Polycomb-Group Proteins - metabolism / Real-Time Polymerase Chain Reaction / RNA, Long Noncoding - genetics / RNA, Long Noncoding - metabolism / RNA-Seq / Science / Science (multidisciplinary) / Therapeutic applications / Topoisomerase Inhibitors - pharmacology / Transcription / Treatment resistance