TY - JOUR

T1 - Reconstruction of the regulatory hypermethylation network controlling hepatocellular carcinoma development during hepatitis C viral infection

AU - Antropova, Evgeniya A

AU - Khlebodarova, Tamara M

AU - Demenkov, Pavel S

AU - Volianskaia, Anastasiia R

AU - Venzel, Artur S

AU - Ivanisenko, Nikita V

AU - Gavrilenko, Alexandr D

AU - Ivanisenko, Timofey V

AU - Adamovskaya, Anna V

AU - Revva, Polina M

AU - Kolchanov, Nikolay A

AU - Lavrik, Inna N

AU - Ivanisenko, Vladimir A

N1 - This research was funded by project No 075-15-2021-944 of the Ministry of Science and Higher Education of the Russian Federation within the ERA-NET “Target identification and drug development in liver cancer (TAIGA)”. © 2023 the author(s), published by De Gruyter, Berlin/Boston.

PY - 2023/9/1

Y1 - 2023/9/1

N2 - Hepatocellular carcinoma (HCC) has been associated with hepatitis C viral (HCV) infection as a potential risk factor. Nonetheless, the precise genetic regulatory mechanisms triggered by the virus, leading to virus-induced hepatocarcinogenesis, remain unclear. We hypothesized that HCV proteins might modulate the activity of aberrantly methylated HCC genes through regulatory pathways. Virus-host regulatory pathways, interactions between proteins, gene expression, transport, and stability regulation, were reconstructed using the ANDSystem. Gene expression regulation was statistically significant. Gene network analysis identified four out of 70 HCC marker genes whose expression regulation by viral proteins may be associated with HCC: DNA-binding protein inhibitor ID - 1 (ID1), flap endonuclease 1 (FEN1), cyclin-dependent kinase inhibitor 2A (CDKN2A), and telomerase reverse transcriptase (TERT). It suggested the following viral protein effects in HCV/human protein heterocomplexes: HCV NS3(p70) protein activates human STAT3 and NOTC1; NS2-3(p23), NS5B(p68), NS1(E2), and core(p21) activate SETD2; NS5A inhibits SMYD3; and NS3 inhibits CCN2. Interestingly, NS3 and E1(gp32) activate c-Jun when it positively regulates CDKN2A and inhibit it when it represses TERT. The discovered regulatory mechanisms might be key areas of focus for creating medications and preventative therapies to decrease the likelihood of HCC development during HCV infection.

AB - Hepatocellular carcinoma (HCC) has been associated with hepatitis C viral (HCV) infection as a potential risk factor. Nonetheless, the precise genetic regulatory mechanisms triggered by the virus, leading to virus-induced hepatocarcinogenesis, remain unclear. We hypothesized that HCV proteins might modulate the activity of aberrantly methylated HCC genes through regulatory pathways. Virus-host regulatory pathways, interactions between proteins, gene expression, transport, and stability regulation, were reconstructed using the ANDSystem. Gene expression regulation was statistically significant. Gene network analysis identified four out of 70 HCC marker genes whose expression regulation by viral proteins may be associated with HCC: DNA-binding protein inhibitor ID - 1 (ID1), flap endonuclease 1 (FEN1), cyclin-dependent kinase inhibitor 2A (CDKN2A), and telomerase reverse transcriptase (TERT). It suggested the following viral protein effects in HCV/human protein heterocomplexes: HCV NS3(p70) protein activates human STAT3 and NOTC1; NS2-3(p23), NS5B(p68), NS1(E2), and core(p21) activate SETD2; NS5A inhibits SMYD3; and NS3 inhibits CCN2. Interestingly, NS3 and E1(gp32) activate c-Jun when it positively regulates CDKN2A and inhibit it when it represses TERT. The discovered regulatory mechanisms might be key areas of focus for creating medications and preventative therapies to decrease the likelihood of HCC development during HCV infection.

KW - Carcinoma, Hepatocellular/genetics

KW - Hepacivirus/genetics

KW - Hepatitis C/complications

KW - Histone-Lysine N-Methyltransferase

KW - Humans

KW - Liver Neoplasms/genetics

KW - Viral Nonstructural Proteins/genetics

KW - Virus Diseases

UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-85181395876&origin=inward&txGid=7edc8e24607c0d54d679ba08ac6756f5

UR - https://www.mendeley.com/catalogue/87f20c9b-5c56-3160-ad4a-87dd498884b3/

U2 - 10.1515/jib-2023-0013

DO - 10.1515/jib-2023-0013

M3 - Article

C2 - 37978846

VL - 20

JO - Journal of integrative bioinformatics

JF - Journal of integrative bioinformatics

SN - 1613-4516

IS - 3

ER -