The Long Noncoding RNA Promotes Sarcoma Metastasis by Regulating RNA Splicing Pathways.

TitleThe Long Noncoding RNA Promotes Sarcoma Metastasis by Regulating RNA Splicing Pathways.
Publication TypeJournal Article
Year of Publication2020
AuthorsHuang, Jianguo, Mohit Sachdeva, Eric Xu, Timothy J. Robinson, Lixia Luo, Yan Ma, Nerissa T. Williams, Omar Lopez, Lisa D. Cervia, Fan Yuan, Xiaodi Qin, Dadong Zhang, Kouros Owzar, Nalan Gokgoz, Andrew Seto, Tomoyo Okada, Samuel Singer, Irene L. Andrulis, Jay S. Wunder, Alexander J. Lazar, Brian P. Rubin, Krista Pipho, Stephano S. Mello, Jimena Giudice, and David G. Kirsch
JournalMol Cancer Res
Volume18
Issue10
Pagination1534-1544
Date Published2020 10
ISSN1557-3125
KeywordsHumans, Neoplasm Metastasis, PC-3 Cells, RNA Splicing, RNA, Long Noncoding, Sarcoma, Transfection
Abstract

Soft-tissue sarcomas (STS) are rare malignancies showing lineage differentiation toward diverse mesenchymal tissues. Half of all high-grade STSs develop lung metastasis with a median survival of 15 months. Here, we used a genetically engineered mouse model that mimics undifferentiated pleomorphic sarcoma (UPS) to study the molecular mechanisms driving metastasis. High-grade sarcomas were generated with Cre recombinase technology using mice with conditional mutations in and (KP) genes. After amputation of the limb bearing the primary tumor, mice were followed for the development of lung metastasis. Using RNA-sequencing of matched primary KP tumors and lung metastases, we found that the long noncoding RNA (lncRNA) Nuclear Enriched Abundant Transcript 1 () is significantly upregulated in lung metastases. Furthermore, RNA ISH of human UPS showed that is upregulated within a subset of lung metastases compared with paired primary UPS. Remarkably, CRISPR/Cas9-mediated knockout of suppressed the ability of KP tumor cells to colonize the lungs. To gain insight into the underlying mechanisms by which the lncRNA promotes sarcoma metastasis, we pulled down RNA and used mass spectrometry to identify interacting proteins. Interestingly, most interacting proteins are involved in RNA splicing regulation. In particular, KH-Type Splicing Regulatory Protein (KHSRP) interacts with and is associated with poor prognosis of human STS. Moreover, depletion of KHSRP suppressed the ability of KP tumor cells to colonize the lungs. Collectively, these results suggest that and its interacting proteins, which regulate RNA splicing, are involved in mediating sarcoma metastasis. IMPLICATIONS: Understanding that lncRNA promotes sarcoma metastasis, at least in part, through interacting with the RNA splicing regulator KHSRP may translate into new therapeutic approaches for sarcoma.

DOI10.1158/1541-7786.MCR-19-1170
Alternate JournalMol Cancer Res
Original PublicationThe long noncoding RNA promotes sarcoma metastasis by regulating RNA splicing pathways.
PubMed ID32561656
PubMed Central IDPMC7541426
Grant ListR01 GM130866 / GM / NIGMS NIH HHS / United States
R35 CA197616 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
P30 CA014236 / CA / NCI NIH HHS / United States
P01 CA142538 / CA / NCI NIH HHS / United States