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Role of hepatitis B virus in development of hepatocellular carcinoma:Focus on covalently closed circular DNA

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World Journal of hepatology 2022年第5期14卷 866-884页

作者： claryssa Bianca Elizabeth Sidhartha claudio Tiribelli Korri Elvanita El-Khobar caecilia h.c sukowati Department of Biomedicine Indonesia International Institute for Life SciencesJakarta 13210Indonesia centro Studi Fegato Fondazione Italiana Fegato ONLUSTrieste 34149Italy Eijkman center for Molecular Biology National Research and Innovation Agency(BRIN)Jakarta 10340Indonesia

chronic infection with hepatitis B virus(hBV)remains a major global health problem,especially in developing *** may lead to prolonged liver damage,fibrosis,cirrhosis,and hepatocellular *** chronic hBV infection is related to host immune response and the stability of the covalently closed circular DNA(cccDNA)in human *** addition to being essential for viral transcription and replication,cccDNA is also suspected to play a role in persistent hBV infections or hepatitis relapses since cccDNA is very stable in non-dividing human *** the pathogenicity and oncogenicity of hBV components would be essential in the development of new diagnostic tools and treatment *** review summarizes the role and molecular mechanisms of hBV cccDNA in hepatocyte transformation and hepatocarcinogenesis and current efforts to its detection and targeting.

关键词： hepatitis B virus covalently closed circular DNA hepatocellular carcinoma hepatocarcinogenesis

Immunotherapy against programmed death-1/programmed death ligand 1 in hepatocellular carcinoma: Importance of molecular variations, cellular heterogeneity, and cancer stem cells

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World Journal of Stem cells 2021年第7期13卷 795-824页

作者： caecilia h.c sukowati Korri Elvanita El-Khobar claudio Tiribelli centro Studi Fegato Fondazione Italiana Fegato ONLUSTrieste 34149Italy hepatitis Unit Eijkman Institute for Molecular BiologyJakarta 10430Indonesia

hepatocellular carcinoma(h.c)is a heterogeneous malignancy related to diverse etiological *** oncogenic mechanisms and genetic variations lead to multiple h.c molecular ***,an immune-based strategy using immune ch.ckpoint inhibitors(IcIs)was presented in h.c therapy,especially with IcIs against the programmed death-1(PD-1)and its ligand ***,despite the success of anti-PD-1/PD-L1 in other cancers,a substantial proportion of h.c patients fail to *** this review,we gather current information on biomarkers of anti-PD-1/PD-L1 treatment and the contribution of h.c heterogeneity and hepatic cancer stem cells(cScs).Genetic variations of PD-1 and PD-L1 are associated with.chronic liver disease and progression to ***-L1 expression in tumoral tissues is differentially expressed in cScs,particularly in those with a close association with the tumor *** information will be beneficial for the selection of patients and the management of the IcIs against PD-1/PD-L1.

关键词： hepatocellular carcinoma Programmed death-1 Programmed death ligand 1 cancer stem cells cancer heterogeneity Genetic variants

Oncogenicity of viral hepatitis B and c in the initiation of hepatic cancer stem cells

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hepatoma Research 2019年第1期5卷 17-25页

作者： caecilia h.c.sukowati Peter A.c.Reyes Gianluca Tell claudio Tiribelli Fondazione Italiana Fegato Trieste 34149Italy Dipartimento di Area Medica University of UdineUdine 33100Italy hepatology Society of the Philippines Loyola Heights Quezon City 1108Philippines

chronic infection of hepatitis B virus(hBV)or/and hepatitis c virus(hcV)is one of major risk factors in the development of the hepatocellular *** studies had shown the capacity of viral proteins in inducing the presence of the population of so-called the cancer stem cells(cSc).The integration of hBV S and X gene in the host genome indicates its direct *** addition,the presence hBV and hcV proteins were shown to modulate intracellular molecular pathways and epigenetic *** review summarizes current literature regarding direct oncogenic properties of hBV and hcV in the initiation of cSc both in in vitro and in vivo studies.

关键词： cancer stem cells hepatocellular carcinoma hepatitis B virus hepatitis c virus

MutL homolog 1 methylation and microsatellite instability in sporadic colorectal tumors among Filipinos

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World Journal of Gastrointestinal Oncology 2021年第12期13卷 2101-2113页

作者： Loraine Kay D cabral cynthia A Mapua Filipinas F Natividad caecilia h.c sukowati Edgardo R cortez Ma Luisa D Enriquez Research and Biotechnology Group St.Luke's Medical CenterQuezon City 1112Philippines centro Studi Fegato Fondazione Italiana Fegato ONLUSTrieste 34149Italy Department of Surgery St.Luke's Medical CenterQuezon City 1112Philippines center for Natural Science and Environmental Research De La Salle UniversityManila 1004Philippines

BAcKGROUND colorectal cancer(cRc)ranks third in terms of incidence and second in mortality *** cRc,the silencing of mismatch repair genes,including the mutL homolog 1(hMLh1)has been linked to microsatellite instability(MSI),the lengthening or shortening of microsatellite *** limited data have been presented so far on the link of hMLh1 methylation and MSI in Southeast Asia populations with sporadic cRc,and on its clinical *** To investigate the significance of the MSI status and hMLh1 methylation in cRc Filipino *** Fifty-four sporadic cRc patients with.complete clinical data were included in this *** DNA from cRc tumor biopsies and their normal tissue counterparts were profiled for MSI by high resolution melting(hRM)analysis using the Bethesda Panel of Markers(BAT25,BAT26,D2S123,D5S346,and D17S250).hMLh1 methylation screening was performed using bisulfite conversion and methylation specific polymerase chain *** analysis was conducted to calculate their associations to clinicopathological characteristics and survival relevance(Kaplan-Meier curves and the log-rank test).RESULTS hMLh1 methylation was observed in 9%and 35%of cRc and normal samples,*** incidence of consistently methylated hMLh1 found in both normal and cRc was noticed for relation to location of tumor(Phe most common unstable microsatellite and MSI-high(MSIh)was the most common MSI profile,counted for 46%and 50%of normal and cRc tissues,*** presence of MSI-low(MSI-L)and microsatellite stable(MSS)was 43%and 11%for normal,and 31%and 19%for cRc *** mean month of patients’survival was shorter in patients whose normal and tumor tissues had methylated compared to those with unmethylated hMLh1 and with MSI-h.compared to those with MSI-L/MSS(Phis was supported by significant difference in Kaplan-Meier with log-rank *** data indicated that hMLh1 methylation

关键词： Sporadic colorectal cancer DNA methylation Microsatellite instability Population genetic colorectal cancer

Significance of hepatitis virus infection in the oncogenicinitiation of hepatocellular carcinoma

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World Journal of Gastroenterology 2016年第4期22卷 1497-1512页

作者： caecilia hc sukowati Korri E El-Khobar Susan I Ie Beatrice Anfuso David h Muljono claudio Tiribelli Fondazione Italiana Fegato ONLUS AREA Science Park Basovizza34149 TriesteItaly Department of Medicine Surgeryand Health SciencesUniversity of TriesteTeaching Hospital Cattinara34149 TriesteItaly Laboratory of hepatitis and Emerging Disease Eijkman Institute for Molecular BiologyJakarta 10430Indonesia Storr Liver centre The Westmead Institute for Medical ResearchThe University of Sydney at Westmead HospitalWestmead NSW 2145Australia

hepatocellular carcinoma(h.c) is one of the most common causes of cancer-related death worldwide. chronic infection of hepatitis B virus(hBV) and/or hepatitis c virus(hcV) is a major risk factor in the development of the h.c, independently from excessive alcohol abuse and metabolic disease. Since the biology of hBV and hcV is different, their oncogenic effect may go through different mechanisms, direct and/or indirect. Viral hepatitis infection is associated with.cellular inflammation, oxidative stress, DNA damage, that may lead to subsequent hepatic injuries such as chronic hepatitis, fibrosis, cirrhosis, and finally h.c. Direct oncogenic properties of these viruses are related with their genotypic characteristics and the ability of viral proteins to interact with host proteins, thus altering the molecular pathways balance of the cells. In addition, the integration of hBV DNA, especially the gene S and X, in a particular site of the host genome can disrupt chromosomal stability and may activate various oncogenic mechanisms, including those in hematopoietic cells. Recently, several studies also had demonstrated that viral hepatitis could trigger the population of hepatic cancer stem cells. This review summarize available pre-clinical and clinical data in literature regarding oncogenic properties of hBV and hcV in the early initiation of h.c.

关键词： hepatocellular carcinoma hepatitis B virus hepatitis c virus Oncogenicity Viral pathogenicity