RNF173 suppresses RAF/MEK/ERK signaling to regulate invasion and metastasis via GRB2 ubiquitination in Hepatocellular Carcinoma.
GRB2
Hepatocellular carcinoma
RAF/MEK/ERK signaling pathway
RNF173
Ubiquitination
Journal
Cell communication and signaling : CCS
ISSN: 1478-811X
Titre abrégé: Cell Commun Signal
Pays: England
ID NLM: 101170464
Informations de publication
Date de publication:
25 08 2023
25 08 2023
Historique:
received:
03
04
2023
accepted:
22
07
2023
medline:
28
8
2023
pubmed:
26
8
2023
entrez:
25
8
2023
Statut:
epublish
Résumé
The role of the membrane-associated RING-CH (MARCH) family in carcinogenesis has been widely studied, but the member of this family, RNF173, has not yet been thoroughly explored in the context of hepatocellular carcinoma (HCC). With the use of an HCC tissue microarray and IHC staining, we aim to determine the differential expression of RNF173 in HCC patients and its clinical significance. The biological role of RNF173 is investigated through in vitro and in vivo experiments. RNA sequencing, mass spectrometry, and immunoprecipitation are performed to uncover the underlying mechanism of RNF173's impact on the development of HCC. The mRNA and protein levels of RNF173 were significantly lower in HCC tissues than in normal tissues. HCC patients with low RNF173 expression had shorter overall survival and recurrence-free survival, and RNF173 was significantly correlated with tumor number, tumor capsule, tumor differentiation, and BCLC stage. In addition, in vitro and in vivo experiments showed that RNF173 downregulation exacerbated tumor progression, including migration, invasion, and proliferation. GRB2 is a key molecule in the RAF/MEK/ERK pathway. RNF173 inhibits the RAF/MEK/ERK signaling by ubiquitinating and degrading GRB2, thereby suppressing HCC cell proliferation, invasion and migration. Combining clinical samples, we found that HCC patients with high RNF173 and low GRB2 expression had the best prognosis. RNF173 inhibits the invasion and metastasis of HCC by ubiquitinating and degrading GRB2, thereby suppressing the RAF/MEK/ERK signaling pathway. RNF173 is an independent risk factor for the survival and recurrence of HCC patients. RNF173 may serve as a novel prognostic molecule and potential therapeutic target for HCC. Video Abstract Graphical abstract Model of RNF173 on RAF/MEK/ERK signaling. RNF173 knockdown resulted in impaired ubiquitination and degradation of GRB2, leading to the activation of the RAF/MEK/ERK signaling pathway and promotion of invasion and metastasis in HCC cells.
Sections du résumé
BACKGROUND
The role of the membrane-associated RING-CH (MARCH) family in carcinogenesis has been widely studied, but the member of this family, RNF173, has not yet been thoroughly explored in the context of hepatocellular carcinoma (HCC).
METHODS
With the use of an HCC tissue microarray and IHC staining, we aim to determine the differential expression of RNF173 in HCC patients and its clinical significance. The biological role of RNF173 is investigated through in vitro and in vivo experiments. RNA sequencing, mass spectrometry, and immunoprecipitation are performed to uncover the underlying mechanism of RNF173's impact on the development of HCC.
RESULTS
The mRNA and protein levels of RNF173 were significantly lower in HCC tissues than in normal tissues. HCC patients with low RNF173 expression had shorter overall survival and recurrence-free survival, and RNF173 was significantly correlated with tumor number, tumor capsule, tumor differentiation, and BCLC stage. In addition, in vitro and in vivo experiments showed that RNF173 downregulation exacerbated tumor progression, including migration, invasion, and proliferation. GRB2 is a key molecule in the RAF/MEK/ERK pathway. RNF173 inhibits the RAF/MEK/ERK signaling by ubiquitinating and degrading GRB2, thereby suppressing HCC cell proliferation, invasion and migration. Combining clinical samples, we found that HCC patients with high RNF173 and low GRB2 expression had the best prognosis.
CONCLUSION
RNF173 inhibits the invasion and metastasis of HCC by ubiquitinating and degrading GRB2, thereby suppressing the RAF/MEK/ERK signaling pathway. RNF173 is an independent risk factor for the survival and recurrence of HCC patients. RNF173 may serve as a novel prognostic molecule and potential therapeutic target for HCC. Video Abstract Graphical abstract Model of RNF173 on RAF/MEK/ERK signaling. RNF173 knockdown resulted in impaired ubiquitination and degradation of GRB2, leading to the activation of the RAF/MEK/ERK signaling pathway and promotion of invasion and metastasis in HCC cells.
Identifiants
pubmed: 37626338
doi: 10.1186/s12964-023-01241-x
pii: 10.1186/s12964-023-01241-x
pmc: PMC10464048
doi:
Substances chimiques
GRB2 Adaptor Protein
0
GRB2 protein, human
0
Mitogen-Activated Protein Kinase Kinases
EC 2.7.12.2
MARCHF3 protein, human
EC 2.3.2.27
Types de publication
Video-Audio Media
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
224Informations de copyright
© 2023. BioMed Central Ltd., part of Springer Nature.
Références
FEBS J. 2021 Mar;288(5):1447-1456
pubmed: 33070450
Gastroenterology. 2019 Jan;156(2):510-524
pubmed: 30287171
Cell Mol Immunol. 2022 Oct;19(10):1117-1129
pubmed: 35982175
J Med Chem. 2006 Mar 9;49(5):1585-96
pubmed: 16509576
Nat Rev Mol Cell Biol. 2016 Oct;17(10):626-42
pubmed: 27485899
Front Oncol. 2021 Oct 11;11:752725
pubmed: 34707994
Signal Transduct Target Ther. 2022 Jan 24;7(1):21
pubmed: 35075102
Cell Mol Immunol. 2021 Dec;18(12):2648-2659
pubmed: 34785732
Semin Cancer Biol. 2008 Dec;18(6):441-50
pubmed: 18948196
Onco Targets Ther. 2020 Oct 09;13:10129-10141
pubmed: 33116595
Nat Rev Dis Primers. 2021 Jan 21;7(1):6
pubmed: 33479224
Surgery. 2022 Oct;172(4):1147-1155
pubmed: 35868902
JAMA Oncol. 2021 Jan 01;7(1):113-123
pubmed: 33090190
Proc Natl Acad Sci U S A. 2018 Dec 4;115(49):12483-12488
pubmed: 30442668
J Exp Clin Cancer Res. 2020 Oct 21;39(1):222
pubmed: 33087136
J Exp Clin Cancer Res. 2019 Mar 5;38(1):113
pubmed: 30836988
Lancet Oncol. 2016 Dec;17(12):e542-e551
pubmed: 27924752
Onco Targets Ther. 2017 Dec 11;10:5863-5872
pubmed: 29270024
Arch Biochem Biophys. 2008 Nov 1;479(1):52-62
pubmed: 18778683
Mol Cancer. 2014 Apr 29;13:95
pubmed: 24775912
Front Immunol. 2022 Oct 03;13:997265
pubmed: 36263042
J Biochem. 2006 Jan;139(1):137-45
pubmed: 16428329
J Clin Invest. 2003 Mar;111(6):833-41
pubmed: 12639989
Trends Cell Biol. 2019 Mar;29(3):212-226
pubmed: 30594349
Tumour Biol. 2017 May;39(5):1010428317698359
pubmed: 28459363
Cancer Med. 2018 Mar;7(3):796-808
pubmed: 29446253
Cell. 2021 May 13;184(10):2649-2664.e18
pubmed: 33848463
J Cell Biol. 2021 Nov 1;220(11):
pubmed: 34515735
Nat Rev Mol Cell Biol. 2019 Feb;20(2):69-84
pubmed: 30459476
Ann Surg Oncol. 2023 Jan;30(1):346-358
pubmed: 36114441
Mol Cancer Ther. 2015 Feb;14(2):355-63
pubmed: 25504754
Am J Transl Res. 2016 Feb 15;8(2):1208-17
pubmed: 27158407
Nat Rev Gastroenterol Hepatol. 2019 Oct;16(10):589-604
pubmed: 31439937
Cells. 2018 Aug 07;7(8):
pubmed: 30087284
EMBO J. 2001 Dec 3;20(23):6793-804
pubmed: 11726515
Cancers (Basel). 2021 May 06;13(9):
pubmed: 34066546
Immunol Lett. 2006 Apr 15;104(1-2):76-82
pubmed: 16386802
Cancer Lett. 2020 Jan 28;469:22-34
pubmed: 31634528
Lancet. 2022 Oct 15;400(10360):1345-1362
pubmed: 36084663