EIF4A3-induced circTOLLIP promotes the progression of hepatocellular carcinoma via the miR-516a-5p/PBX3/EMT pathway.
Carcinoma, Hepatocellular
/ pathology
Cell Line, Tumor
Cell Proliferation
/ genetics
DEAD-box RNA Helicases
/ genetics
Eukaryotic Initiation Factor-4A
/ genetics
Gene Expression Regulation, Neoplastic
Humans
In Situ Hybridization, Fluorescence
Liver Neoplasms
/ pathology
MicroRNAs
/ genetics
RNA, Circular
/ genetics
EMT
HCC
PBX3
circTOLLIP
Journal
Journal of experimental & clinical cancer research : CR
ISSN: 1756-9966
Titre abrégé: J Exp Clin Cancer Res
Pays: England
ID NLM: 8308647
Informations de publication
Date de publication:
05 May 2022
05 May 2022
Historique:
received:
21
01
2022
accepted:
28
04
2022
entrez:
5
5
2022
pubmed:
6
5
2022
medline:
7
5
2022
Statut:
epublish
Résumé
Circular RNAs (circRNAs) function as crucial regulators in multiple cancers, including hepatocellular carcinoma (HCC). However, the roles of circRNAs in HCC remains largely unknown. circTOLLIP was identified in HCC by screening of two public circRNA microarray datasets and detected in HCC cells and tissues through quantitative real-time PCR (qRT-PCR) and in situ hybridization (ISH). Gain- and loss-of-function assays were performed to confirm the biological effects of circTOLLIP on HCC in vitro and in vivo. Mechanistically, bioinformatics analysis of online databases, MS2-RNA pulldown, biotin-labeled circTOLLIP/miR-516a-5p RNA pulldown, RNA immunoprecipitation (RIP), luciferase reporter assay, fluorescence in situ hybridization assay (FISH) and RNA sequencing were used to confirm the regulation of Eukaryotic initiation factor 4A3 (EIF4A3) on circTOLLIP and the interaction among circTOLLIP, miR-516a-5p and PBX homeobox 3 (PBX3). circTOLLIP was significantly upregulated in HCC cells and tissues. High circTOLLIP expression was correlated with poor overall survival (OS) and disease-free survival (DFS) in patients. circTOLLIP promoted the proliferation and metastasis of HCC cells in vitro and in vivo. Mechanistically, EIF4A3 promoted the biogenesis of circTOLLIP without affecting its stability. Moreover, circTOLLIP sponged miR-516a-5p to elevate the expression of PBX3, thereby activating the epithelial-to-mesenchymal transition (EMT) pathway and facilitating tumor progression in HCC. Our findings indicate that EIF4A3-induced circTOLLIP promotes the progression of HCC through the circTOLLIP/miR-516a-5p/PBX3/EMT axis.
Sections du résumé
BACKGROUND
BACKGROUND
Circular RNAs (circRNAs) function as crucial regulators in multiple cancers, including hepatocellular carcinoma (HCC). However, the roles of circRNAs in HCC remains largely unknown.
METHODS
METHODS
circTOLLIP was identified in HCC by screening of two public circRNA microarray datasets and detected in HCC cells and tissues through quantitative real-time PCR (qRT-PCR) and in situ hybridization (ISH). Gain- and loss-of-function assays were performed to confirm the biological effects of circTOLLIP on HCC in vitro and in vivo. Mechanistically, bioinformatics analysis of online databases, MS2-RNA pulldown, biotin-labeled circTOLLIP/miR-516a-5p RNA pulldown, RNA immunoprecipitation (RIP), luciferase reporter assay, fluorescence in situ hybridization assay (FISH) and RNA sequencing were used to confirm the regulation of Eukaryotic initiation factor 4A3 (EIF4A3) on circTOLLIP and the interaction among circTOLLIP, miR-516a-5p and PBX homeobox 3 (PBX3).
RESULTS
RESULTS
circTOLLIP was significantly upregulated in HCC cells and tissues. High circTOLLIP expression was correlated with poor overall survival (OS) and disease-free survival (DFS) in patients. circTOLLIP promoted the proliferation and metastasis of HCC cells in vitro and in vivo. Mechanistically, EIF4A3 promoted the biogenesis of circTOLLIP without affecting its stability. Moreover, circTOLLIP sponged miR-516a-5p to elevate the expression of PBX3, thereby activating the epithelial-to-mesenchymal transition (EMT) pathway and facilitating tumor progression in HCC.
CONCLUSIONS
CONCLUSIONS
Our findings indicate that EIF4A3-induced circTOLLIP promotes the progression of HCC through the circTOLLIP/miR-516a-5p/PBX3/EMT axis.
Identifiants
pubmed: 35509064
doi: 10.1186/s13046-022-02378-2
pii: 10.1186/s13046-022-02378-2
pmc: PMC9069765
doi:
Substances chimiques
MicroRNAs
0
RNA, Circular
0
Eukaryotic Initiation Factor-4A
EC 2.7.7.-
EIF4A3 protein, human
EC 3.6.1.-
DEAD-box RNA Helicases
EC 3.6.4.13
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
164Subventions
Organisme : National Natural Science Foundation of China
ID : 81572855
Organisme : National Natural Science Foundation of China
ID : 81572427
Organisme : National Natural Science Foundation of China
ID : 81874189
Organisme : National Natural Science Foundation of China
ID : 82073090
Organisme : National Natural Science Foundation of China
ID : 82172976
Organisme : National Natural Science Foundation of China
ID : 82103597
Organisme : Hepatobiliary and Pancreatic Cancer from Hubei Chen Xiaoping Foundation for Scientific and Technological Development
ID : CXPJJH11900001-2019346
Organisme : Start Up Fund for Returnees from Tongji Hospital
ID : 2019HGRY002
Informations de copyright
© 2022. The Author(s).
Références
Nat Rev Clin Oncol. 2018 Oct;15(10):599-616
pubmed: 30061739
Oncol Lett. 2016 Nov;12(5):3485-3491
pubmed: 27900025
Oncol Lett. 2021 May;21(5):358
pubmed: 33747215
Nat Rev Gastroenterol Hepatol. 2021 May;18(5):293-313
pubmed: 33510460
CA Cancer J Clin. 2021 May;71(3):209-249
pubmed: 33538338
J Exp Clin Cancer Res. 2020 Jun 17;39(1):114
pubmed: 32552766
Semin Cell Dev Biol. 2007 Apr;18(2):186-93
pubmed: 17459736
Nature. 2013 Mar 21;495(7441):333-8
pubmed: 23446348
RNA. 2013 Feb;19(2):141-57
pubmed: 23249747
Nature. 2013 Mar 21;495(7441):384-8
pubmed: 23446346
Brief Bioinform. 2019 Jul 19;20(4):1420-1433
pubmed: 29415187
Int J Mol Sci. 2015 Feb 16;16(2):4209-25
pubmed: 25690035
Nat Commun. 2017 Mar 30;8:14741
pubmed: 28358055
PLoS Genet. 2013;9(9):e1003777
pubmed: 24039610
Clin Cancer Res. 2018 Apr 15;24(8):1974-1986
pubmed: 29391352
RNA. 2014 Dec;20(12):1829-42
pubmed: 25404635
Cell Rep. 2019 Feb 19;26(8):2126-2139.e9
pubmed: 30784594
Cell. 2015 Mar 12;160(6):1125-34
pubmed: 25768908
Int J Immunopathol Pharmacol. 2019 Jan-Dec;33:2058738419841481
pubmed: 30966836
Curr Opin Genet Dev. 2018 Feb;48:121-127
pubmed: 29245064
Hepatology. 2020 Jan;71(1):130-147
pubmed: 31148183
Nat Commun. 2015 Sep 30;6:8271
pubmed: 26420065
Nature. 2017 Apr 6;544(7648):115-119
pubmed: 28355180
Cancers (Basel). 2020 Feb 13;12(2):
pubmed: 32069812
Hepatology. 2017 Oct;66(4):1151-1164
pubmed: 28520103
Mol Cancer. 2011 May 06;10:50
pubmed: 21548940
J Exp Clin Cancer Res. 2018 Jul 17;37(1):158
pubmed: 30016974
J Hepatol. 2018 Jul;69(1):182-236
pubmed: 29628281
Int J Surg. 2020 Oct;82S:70-76
pubmed: 32344023
Clin Transl Med. 2020 Dec;10(8):e263
pubmed: 33377649
Curr Opin Cell Biol. 2003 Jun;15(3):326-31
pubmed: 12787775
PLoS One. 2014 Mar 07;9(6):e90859
pubmed: 24609083
Cell Rep. 2016 Apr 19;15(3):611-624
pubmed: 27068474
Signal Transduct Target Ther. 2021 Jan 27;6(1):30
pubmed: 33500381
Genes Dev. 2015 Oct 15;29(20):2168-82
pubmed: 26450910
Nat Rev Genet. 2019 Nov;20(11):675-691
pubmed: 31395983
Hepatology. 2020 Sep;72(3):906-922
pubmed: 31838741
Nat Commun. 2016 Aug 19;7:12429
pubmed: 27539542
RNA. 2004 Feb;10(2):200-9
pubmed: 14730019
Saudi J Biol Sci. 2020 Aug;27(8):2157-2163
pubmed: 32714042
Nat Rev Dis Primers. 2021 Jan 21;7(1):6
pubmed: 33479224
Neuro Oncol. 2021 Apr 12;23(4):611-624
pubmed: 32926734
Proc Natl Acad Sci U S A. 1976 Nov;73(11):3852-6
pubmed: 1069269
Mol Cancer. 2018 Nov 23;17(1):166
pubmed: 30470262