TY - JOUR
T1 - Long non-coding RNA RAMS11 promotes metastatic colorectal cancer progression
AU - Silva-Fisher, Jessica M.
AU - Dang, Ha X.
AU - White, Nicole M.
AU - Strand, Matthew S.
AU - Krasnick, Bradley A.
AU - Rozycki, Emily B.
AU - Jeffers, Gejae G.L.
AU - Grossman, Julie G.
AU - Highkin, Maureen K.
AU - Tang, Cynthia
AU - Cabanski, Christopher R.
AU - Eteleeb, Abdallah
AU - Mudd, Jacqueline
AU - Goedegebuure, S. Peter
AU - Luo, Jingqin
AU - Mardis, Elaine R.
AU - Wilson, Richard K.
AU - Ley, Timothy J.
AU - Lockhart, Albert C.
AU - Fields, Ryan C.
AU - Maher, Christopher A.
N1 - Funding Information:
J.S.F. received funding from the Washington University School of Medicine Molecular Oncology Training Grant (T32CA113275). B.A.K., M.K.H., and J.G.G. received funding from the Washington University School of Medicine Surgical Oncology Basic Science and Translational Research Training Program (T32CA009621). R.C.F. and C.A.M. received funding from The Alvin J. Siteman Cancer Center Siteman Investment Program, The Foundation for Barnes-Jewish Hospital Cancer Frontier Fund, the National Cancer Institute Cancer Center Support Grant P30 CA091842, and the Barnard Trust. R.C.F. also received funding from the American Surgical Association Foundation Fellowship, American Cancer Society Institutional Review Grant, the Society of Surgical Oncology James Ewing Foundation Clinical Investigator Award, the Sidney Kimmel Translational Science Scholar Award, and the David Riebel Cancer Research Fund. Funding was also provided for C.A.M. by a Research Scholar Grant (130878-RSG-17-058-01-RMC) from the American Cancer Society and the NIH CTSA Grant #UL1 TR002345. We would like to thank the Washington University’s Genome Engineering and iPSC Center for help in the development of the CRISPR cell lines. We thank the Alvin J. Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital in St. Louis, MO., for the use of the Siteman Flow Cytometry, which provided flow cytometry service. The Siteman Cancer Center is supported in part by an NCI Cancer Center Support Grant #P30 CA091842. We would also like to thank the SAIC at Washington University for help with imaging mouse models and the Department of Medicine Pulmonary Morphology Core Division of Pulmonary and Critical Care Medicine for histology preparation. We also thank Jacqueline Payton, MD, PhD, for critically reviewing this manuscript.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85084156227&partnerID=8YFLogxK
U2 - 10.1038/s41467-020-15547-8
DO - 10.1038/s41467-020-15547-8
M3 - Article
C2 - 32358485
AN - SCOPUS:85084156227
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 2156
ER -