Long non-coding RNAs CCAT1 and CCAT2 in colorectal liver metastases are tumor-suppressive via MYC interaction and might predict patient outcomes

Clemens Franz; Michael Wuehrl; Sibylle Hartmann; Fee Klupp; Thomas Schmidt; Martin Schneider

doi:10.1371/journal.pone.0286486

Long non-coding RNAs CCAT1 and CCAT2 in colorectal liver metastases are tumor-suppressive via MYC interaction and might predict patient outcomes

PLoS One. 2023 Jun 22;18(6):e0286486. doi: 10.1371/journal.pone.0286486. eCollection 2023.

Authors

Clemens Franz¹, Michael Wuehrl¹, Sibylle Hartmann¹, Fee Klupp¹, Thomas Schmidt¹, Martin Schneider¹

Affiliation

¹ Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.

Abstract

Background: Liver metastases severely reduce the long term survival of colorectal cancer patients. Long non-coding RNAs (lncRNAs) CCAT1 and CCAT2 have previously been found to be associated with impaired patient outcomes in primary colorectal cancer. We aimed to elucidate the role of CCAT1 and CCAT2 in colorectal liver metastases.

Methods: Total RNA was isolated from 97 human tissue samples of colorectal liver metastases and adjacent normal liver tissue. Gene expression analysis was performed by RT-qPCR and Multiplex ELISA and correlated with patient characteristics and survival. Gene expression, cancer cell migration, invasion, and proliferation were studied after siRNA-mediated knockdown of CCAT1, CCAT2, and MYC in metastatic colorectal cancer cell lines Colo205 and HROC277Met2.

Results: Elevated expression levels of lncRNAs CCAT1 and CCAT2, and their common target MYC in colorectal liver metastases were associated with prolonged progression-free survival after liver resection. High expression of CCAT1 was likewise associated with prolonged overall survival. Knockdown of CCAT1, CCAT2, and MYC resulted in increased migratory and invasive potential in metastatic colorectal cancer cell lines. Gene expression analysis revealed alterations in constituents of Wnt signaling following knockdown.

Conclusion: Our findings demonstrate tumor-suppressive functions of lncRNAs CCAT1 and CCAT2 in colorectal liver metastases. They suppress Wnt signaling directly and indirectly through target gene MYC and might prevent further metastatic spread from colorectal liver metastases.

Copyright: © 2023 Franz et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Proliferation / genetics
Colonic Neoplasms* / genetics
Gene Expression Regulation, Neoplastic
Humans
Liver Neoplasms* / genetics
RNA, Long Noncoding* / genetics
RNA, Small Interfering
Rectal Neoplasms* / genetics
Wnt Signaling Pathway / genetics

Substances

RNA, Long Noncoding
RNA, Small Interfering
MYC protein, human

Grants and funding

CF was supported for this study by the Heidelberger Stiftung Chirurgie, project “non-coding RNAs in colorectal cancer” and by the Deutsche Krebs- und Scharlachstiftung, project “Signalwege nicht kodierender RNAs beim metastasierten kolorektalen Karzinom”. We acknowledge financial support by Deutsche Forschungs-gemeinschaft (DFG) within the funding programme „Open Access Publication“ as well as by Heidelberg University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.