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Translation of circHGF RNA encodes an HGF protein variant promoting glioblastoma growth through stimulation of c-MET

INTRODUCTION: HGF/c-MET signaling is a significant driver of glioblastoma (GBM) growth and disease progression. Unfortunately, c-MET targeted therapies have been found to be largely ineffective suggesting additional redundant mechanisms of c-MET activation. METHODS: Utilizing RNA-sequencing (RNA-seq...

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Autores principales: Saunders, Jacquelyn T., Kumar, Sunil, Benavides-Serrato, Angelica, Holmes, Brent, Benavides, Kennedy E., Bashir, Muhammad T., Nishimura, Robert N., Gera, Joseph
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10232650/
https://www.ncbi.nlm.nih.gov/pubmed/37162666
http://dx.doi.org/10.1007/s11060-023-04331-5
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author Saunders, Jacquelyn T.
Kumar, Sunil
Benavides-Serrato, Angelica
Holmes, Brent
Benavides, Kennedy E.
Bashir, Muhammad T.
Nishimura, Robert N.
Gera, Joseph
author_facet Saunders, Jacquelyn T.
Kumar, Sunil
Benavides-Serrato, Angelica
Holmes, Brent
Benavides, Kennedy E.
Bashir, Muhammad T.
Nishimura, Robert N.
Gera, Joseph
author_sort Saunders, Jacquelyn T.
collection PubMed
description INTRODUCTION: HGF/c-MET signaling is a significant driver of glioblastoma (GBM) growth and disease progression. Unfortunately, c-MET targeted therapies have been found to be largely ineffective suggesting additional redundant mechanisms of c-MET activation. METHODS: Utilizing RNA-sequencing (RNA-seq) and ribosome profiling analyses of circular RNAs, circ-HGF (hsa_circ_0080914) was identified as markedly upregulated in primary GBM and found to potentially encode an HGF protein variant (C-HGF) 119 amino acids in length. This candidate HGF variant was characterized and evaluated for its ability to mediate c-MET activation and regulate PDX GBM cell growth, motility and invasive potential in vitro and tumor burden in intracranial xenografts in mice. RESULTS: An internal ribosome entry site (IRES) was identified within the circ-HGF RNA which mediated translation of the cross-junctional ORF encoding C-HGF and was observed to be highly expressed in GBM relative to normal brain tissue. C-HGF was also found to be secreted from GBM cells and concentrated cell culture supernatants or recombinant C-HGF activated known signaling cascades downstream of c-MET. C-HGF was shown to interact directly with the c-MET receptor resulting in its autophosphorylation and activation in PDX GBM lines. Knockdown of C-HGF resulted in suppression of c-MET signaling and marked inhibition of cell growth, motility and invasiveness, whereas overexpression of C-HGF displayed the opposite effects. Additionally, modulation of C-HGF expression regulated tumor growth in intracranial xenografted PDX GBM models. CONCLUSIONS: These results reveal an alternative mechanism of c-MET activation via a circular RNA encoded HGF protein variant which is relevant in GBM biology. Targeting C-HGF may offer a promising approach for GBM clinical management. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11060-023-04331-5.
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spelling pubmed-102326502023-06-02 Translation of circHGF RNA encodes an HGF protein variant promoting glioblastoma growth through stimulation of c-MET Saunders, Jacquelyn T. Kumar, Sunil Benavides-Serrato, Angelica Holmes, Brent Benavides, Kennedy E. Bashir, Muhammad T. Nishimura, Robert N. Gera, Joseph J Neurooncol Research INTRODUCTION: HGF/c-MET signaling is a significant driver of glioblastoma (GBM) growth and disease progression. Unfortunately, c-MET targeted therapies have been found to be largely ineffective suggesting additional redundant mechanisms of c-MET activation. METHODS: Utilizing RNA-sequencing (RNA-seq) and ribosome profiling analyses of circular RNAs, circ-HGF (hsa_circ_0080914) was identified as markedly upregulated in primary GBM and found to potentially encode an HGF protein variant (C-HGF) 119 amino acids in length. This candidate HGF variant was characterized and evaluated for its ability to mediate c-MET activation and regulate PDX GBM cell growth, motility and invasive potential in vitro and tumor burden in intracranial xenografts in mice. RESULTS: An internal ribosome entry site (IRES) was identified within the circ-HGF RNA which mediated translation of the cross-junctional ORF encoding C-HGF and was observed to be highly expressed in GBM relative to normal brain tissue. C-HGF was also found to be secreted from GBM cells and concentrated cell culture supernatants or recombinant C-HGF activated known signaling cascades downstream of c-MET. C-HGF was shown to interact directly with the c-MET receptor resulting in its autophosphorylation and activation in PDX GBM lines. Knockdown of C-HGF resulted in suppression of c-MET signaling and marked inhibition of cell growth, motility and invasiveness, whereas overexpression of C-HGF displayed the opposite effects. Additionally, modulation of C-HGF expression regulated tumor growth in intracranial xenografted PDX GBM models. CONCLUSIONS: These results reveal an alternative mechanism of c-MET activation via a circular RNA encoded HGF protein variant which is relevant in GBM biology. Targeting C-HGF may offer a promising approach for GBM clinical management. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11060-023-04331-5. Springer US 2023-05-10 2023 /pmc/articles/PMC10232650/ /pubmed/37162666 http://dx.doi.org/10.1007/s11060-023-04331-5 Text en © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research
Saunders, Jacquelyn T.
Kumar, Sunil
Benavides-Serrato, Angelica
Holmes, Brent
Benavides, Kennedy E.
Bashir, Muhammad T.
Nishimura, Robert N.
Gera, Joseph
Translation of circHGF RNA encodes an HGF protein variant promoting glioblastoma growth through stimulation of c-MET
title Translation of circHGF RNA encodes an HGF protein variant promoting glioblastoma growth through stimulation of c-MET
title_full Translation of circHGF RNA encodes an HGF protein variant promoting glioblastoma growth through stimulation of c-MET
title_fullStr Translation of circHGF RNA encodes an HGF protein variant promoting glioblastoma growth through stimulation of c-MET
title_full_unstemmed Translation of circHGF RNA encodes an HGF protein variant promoting glioblastoma growth through stimulation of c-MET
title_short Translation of circHGF RNA encodes an HGF protein variant promoting glioblastoma growth through stimulation of c-MET
title_sort translation of circhgf rna encodes an hgf protein variant promoting glioblastoma growth through stimulation of c-met
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10232650/
https://www.ncbi.nlm.nih.gov/pubmed/37162666
http://dx.doi.org/10.1007/s11060-023-04331-5
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