Hepatitis B virus P protein initiates glycolytic bypass in HBV-related hepatocellular carcinoma via a FOXO3/miRNA-30b-5p/MINPP1 axis.
Glycolysis
HBV
HBp
HCC
MINPP1
miRNA
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:
04 Jan 2021
04 Jan 2021
Historique:
received:
08
09
2020
accepted:
07
12
2020
entrez:
4
1
2021
pubmed:
5
1
2021
medline:
31
8
2021
Statut:
epublish
Résumé
Hepatitis B virus (HBV) infection is a crucial risk factor for hepatocellular carcinoma (HCC). However, its underlying mechanism remains understudied. Microarray analysis was conducted to compare the genes and miRNAs in liver tissue from HBV-positive and HBV-negative HCC patients. Biological functions of these biomarkers in HBV-related HCC were validated via in vitro and in vivo experiments. Furthermore, we investigated the effect of HBV on the proliferation and migration of tumor cells in HBV-positive HCC tissue. Bioinformatics analysis was then performed to validate the clinical value of the biomarkers in a large HCC cohort. We found that a gene, MINPP1 from the glycolytic bypass metabolic pathway, has an important biological function in the development of HBV-positive HCC. MINPP1 is down-regulated in HBV-positive HCC and could inhibit the proliferation and migration of the tumor cells. Meanwhile, miRNA-30b-5p was found to be a stimulator for the proliferation of tumor cell through glycolytic bypass in HBV-positive HCC. More importantly, miRNA-30b-5p could significantly downregulate MINPP1 expression. Metabolic experiments showed that the miRNA-30b-5p/MINPP1 axis is able to accelerate the conversion of glucose to lactate and 2,3-bisphosphoglycerate (2,3-BPG). In the HBV-negative HCC cells, miRNA-30b-5p/MINPP1 could not regulate the glycolytic bypass to promote the tumorigenesis. However, once HBV was introduced into these cells, miRNA-30b-5p/MINPP1 significantly enhanced the proliferation, migration of tumor cells, and promoted the glycolytic bypass. We further revealed that HBV infection promoted the expression of miRNA-30b-5p through the interaction of HBV protein P (HBp) with FOXO3. Bioinformatics analysis on a large cohort dataset showed that high expression of MINPP1 was associated with favorable survival of HBV-positive HCC patients, which could lead to a slower progress of this disease. Our study found that the HBp/FOXO3/miRNA-30b-5p/MINPP1 axis contributes to the development of HBV-positive HCC cells through the glycolytic bypass. We also presented miRNA-30b-5p/MINPP1 as a novel biomarker for HBV-positive HCC early diagnosis and a potential pharmaceutical target for antitumor therapy.
Sections du résumé
BACKGROUND
BACKGROUND
Hepatitis B virus (HBV) infection is a crucial risk factor for hepatocellular carcinoma (HCC). However, its underlying mechanism remains understudied.
METHODS
METHODS
Microarray analysis was conducted to compare the genes and miRNAs in liver tissue from HBV-positive and HBV-negative HCC patients. Biological functions of these biomarkers in HBV-related HCC were validated via in vitro and in vivo experiments. Furthermore, we investigated the effect of HBV on the proliferation and migration of tumor cells in HBV-positive HCC tissue. Bioinformatics analysis was then performed to validate the clinical value of the biomarkers in a large HCC cohort.
RESULTS
RESULTS
We found that a gene, MINPP1 from the glycolytic bypass metabolic pathway, has an important biological function in the development of HBV-positive HCC. MINPP1 is down-regulated in HBV-positive HCC and could inhibit the proliferation and migration of the tumor cells. Meanwhile, miRNA-30b-5p was found to be a stimulator for the proliferation of tumor cell through glycolytic bypass in HBV-positive HCC. More importantly, miRNA-30b-5p could significantly downregulate MINPP1 expression. Metabolic experiments showed that the miRNA-30b-5p/MINPP1 axis is able to accelerate the conversion of glucose to lactate and 2,3-bisphosphoglycerate (2,3-BPG). In the HBV-negative HCC cells, miRNA-30b-5p/MINPP1 could not regulate the glycolytic bypass to promote the tumorigenesis. However, once HBV was introduced into these cells, miRNA-30b-5p/MINPP1 significantly enhanced the proliferation, migration of tumor cells, and promoted the glycolytic bypass. We further revealed that HBV infection promoted the expression of miRNA-30b-5p through the interaction of HBV protein P (HBp) with FOXO3. Bioinformatics analysis on a large cohort dataset showed that high expression of MINPP1 was associated with favorable survival of HBV-positive HCC patients, which could lead to a slower progress of this disease.
CONCLUSION
CONCLUSIONS
Our study found that the HBp/FOXO3/miRNA-30b-5p/MINPP1 axis contributes to the development of HBV-positive HCC cells through the glycolytic bypass. We also presented miRNA-30b-5p/MINPP1 as a novel biomarker for HBV-positive HCC early diagnosis and a potential pharmaceutical target for antitumor therapy.
Identifiants
pubmed: 33390177
doi: 10.1186/s13046-020-01803-8
pii: 10.1186/s13046-020-01803-8
pmc: PMC7779247
doi:
Substances chimiques
FOXO3 protein, human
0
Forkhead Box Protein O3
0
MicroRNAs
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1Subventions
Organisme : Key Research & Development Plan of Zhejiang Province
ID : 2019C04005
Organisme : the major national S&T projects for infectious diseases
ID : 2018ZX10301401
Organisme : National Key Research and Development Program of China
ID : 2018YFC2000500
Références
Carcinogenesis. 2017 Jan;38(1):2-11
pubmed: 27838634
Mol Cancer. 2017 Dec 20;16(1):178
pubmed: 29262861
Nat Rev Genet. 2012 Apr 18;13(5):358-69
pubmed: 22510765
PLoS Pathog. 2020 Aug 10;16(8):e1008646
pubmed: 32776974
J Virol. 2019 Sep 30;93(20):
pubmed: 31375584
Immunol Res. 2017 Oct;65(5):1074-1082
pubmed: 28905195
Cancer Metastasis Rev. 2019 Jun;38(1-2):157-164
pubmed: 30997670
Nucleic Acids Res. 2017 Jan 4;45(D1):D353-D361
pubmed: 27899662
Annu Rev Biochem. 2010;79:351-79
pubmed: 20533884
J Hepatol. 2016 Apr;64(1 Suppl):S4-S16
pubmed: 27084035
Proteomics. 2016 Mar;16(5):741-58
pubmed: 26677817
Cancer Res. 2001 Mar 1;61(5):2129-37
pubmed: 11280777
Biochem Soc Trans. 2016 Oct 15;44(5):1499-1505
pubmed: 27911732
World J Gastroenterol. 2016 Jan 7;22(1):126-44
pubmed: 26755865
Proc Natl Acad Sci U S A. 2008 Apr 22;105(16):5998-6003
pubmed: 18413611
Hepatology. 2018 May;67(5):1823-1841
pubmed: 29149457
Blood Transfus. 2019 Jan;17(1):27-52
pubmed: 30653459
Clin Chem. 2019 Sep;65(9):1090-1101
pubmed: 31101638
Theranostics. 2014 Sep 19;4(12):1176-92
pubmed: 25285167
Viruses. 2018 Nov 15;10(11):
pubmed: 30445742
Mol Cancer. 2018 Jul 25;17(1):104
pubmed: 30045773
Cells. 2019 Nov 24;8(12):
pubmed: 31771261
J Hepatol. 2011 Nov;55(5):996-1003
pubmed: 21376091
PLoS One. 2010 Jan 27;5(1):e8694
pubmed: 20111700
Hepatology. 2018 Jan;67(1):188-203
pubmed: 28802060
Hepatology. 2015 Oct;62(4):1132-44
pubmed: 26054020
Semin Cancer Biol. 2018 Jun;50:53-64
pubmed: 29309928
J Hepatol. 2016 Apr;64(1 Suppl):S84-S101
pubmed: 27084040
J Clin Invest. 2013 Feb;123(2):630-45
pubmed: 23321675
Hepatology. 2019 Mar;69(3):974-992
pubmed: 30180281
Eur J Biochem. 1977 Mar 1;73(2):421-7
pubmed: 14829
Cancer Lett. 2018 Apr 10;419:167-174
pubmed: 29366802
Clin Liver Dis. 2018 Nov;22(4):703-722
pubmed: 30266158
Blood. 2005 Dec 15;106(13):4034-42
pubmed: 16051738
World J Gastroenterol. 2014 Oct 7;20(37):13477-92
pubmed: 25309078
Nat Rev Gastroenterol Hepatol. 2019 Jan;16(1):57-73
pubmed: 30158570
Rev Esp Cardiol (Engl Ed). 2017 Sep;70(9):744-753
pubmed: 28623160
Annu Rev Pathol. 2014;9:287-314
pubmed: 24079833
Proc Natl Acad Sci U S A. 2001 Dec 18;98(26):15089-94
pubmed: 11752456
Ann Surg Oncol. 2006 Jul;13(7):947-54
pubmed: 16788756
Biophys J. 2002 Aug;83(2):646-62
pubmed: 12124254
Proc Natl Acad Sci U S A. 1968 Feb;59(2):526-32
pubmed: 5238982
J Exp Clin Cancer Res. 2018 Sep 4;37(1):216
pubmed: 30180863
Adv Exp Med Biol. 2020;1179:39-69
pubmed: 31741333
Sci Adv. 2016 May 27;2(5):e1600200
pubmed: 27386546