Polo-like kinase-1 mediates hepatitis C virus-induced cell migration, a drug target for liver cancer.

Polo-like kinase 1 (PLK1) is a regulator of cell mitosis and cytoskeletal dynamics. PLK1 overexpression in liver cancer is associated with tumour progression, metastasis, and vascular invasion. Hepatitis C virus (HCV) NS5A protein stimulates PLK1-mediated phosphorylation of host proteins, so we hypothesised that HCV-PLK1 interactions might be a mechanism for HCV-induced liver cancer. We used a HCV cell-culture model (Jc1) to investigate the effects of virus infection on the cytoskeleton. In HCV-infected cells, a novel posttranslational modification in ß-actin was observed with phosphorylation at Ser239. Using in silico and in vitro approaches, we identified PLK1 as the mediating kinase. In functional experiments with a phosphomimetic mutant form of ß-actin, Ser239 phosphorylation influences ß-actin polymerization and distribution, resulting in increased cell motility. The changes were prevented by treating cells with the PLK1 inhibitor volasertib. In HCV-infected hepatocytes, increased cell motility contributes to cancer cell migration, invasion, and metastasis. PLK1 is an important mediator of these effects and early treatment with PLK1 inhibitors may prevent or reduce HCC progression, particularly in people with HCV-induced HCC.

Updates on Organoid Model for the Study of Liver Cancer.

Liver cancer remains one of the most common cancers worldwide with limited therapy options. The main risk factors for hepatocellular carcinoma (HCC), the most common form of liver cancer, include chronic infection with hepatitis B or hepatitis C viruses, alcohol abuse, and metabolic disease. Current systemic therapies for advanced HCCs have greatly improved in the last decade, but there is still a need to develop more targeted drug therapy for HCCs. The development of liver organoids, a self-organising and self-renewal three-dimensional cell culture model, has greatly improved cancer research, including liver cancer. The generation of liver organoids provides a physiologically relevant model to study cancer drug screening and development, personalized medicine, liver disease modeling, and liver regeneration. However, the advent of organoid development also comes with few shortcomings that must be overcome, including the high cost of the model, the availability of origin tissues, and the need for multilineage liver organoids to replicate the true cellular heterogeneity of the liver. Despite all the limitations, liver organoids provide a reliable in vitro model for translational applications to develop more effective HCC therapy and to understand the underlying pathogenic mechanism in various liver diseases.

Host Factors in the Natural History of Chronic Hepatitis B: Role of Genetic Determinants.

Background: The host immune system plays an important role in hepatitis B virus (HBV) infection manifestation. Genetic polymorphisms of several inflammatory cytokines, including TNF-α and IL-10, have been associated with chronic hepatitis B (CHB) progression, although with contradicting results. CHB progression can be categorized into four phases, immune tolerance (IT), immune clearance (IC), low/no replicative (LR), and e-negative hepatitis (ENH), with HBeAg seroconversion as an important milestone. Here, we determined the association of TNF-α (rs1800629) and IL-10 (rs1800896 and rs1800872) SNPs in the context of CHB natural history progression, particularly to HBeAg seroconversion, in Indonesian CHB patients. Methods: A total of 287 subjects were recruited and categorized into distinct CHB phases based on HBeAg, viral load, and ALT levels. TNF-α and IL-10 SNPs were determined using PCR-RFLP and confirmed with direct sequencing. The association between SNP genotypes with CHB dynamics was determined using logistic regression presented as odds ratio (OR) with 95% CI. Results: No significant association was found between IL-10 -592A/C polymorphism and progression of IT and IC to LR, IT and IC to ENH, and LR to ENH phases in all the gene models. IL-10 rs1800896 and TNF-α rs1800629 could not be analyzed using logistic regression. Subjects' age (≥40 years old) was significantly associated with IT and IC to LR (OR: 2.191, 95% CI 1.067-4.578, P = 0.034), IT and IC to ENH (OR: 7.460, 95% CI 3.316-18.310, P < 0.001), and LR to ENH (OR: 5.252, 95% CI 2.010-14.858, P = 0.001). Male gender was associated with LR to ENH (OR: 4.077, 95% CI 1.605-11.023, P = 0.004). Conclusions: Age and male gender were associated with CHB phase progression instead of the TNF-α and IL-10 polymorphisms. It would be beneficial to study not only the effect of host determinants but also the viral factor to understand the mechanisms of CHB phase progression.

Activation of hepatic stem cells compartment during hepatocarcinogenesis in a HBsAg HBV-transgenic mouse model.

Chronic infection of Hepatitis B Virus (HBV) is one of the highest risk factors of hepatocellular carcinoma (HCC). The accumulation of HBV surface antigen (HBsAg) into hepatocytes induces inflammation and oxidative stress, impairing their replicative ability and allowing the activation of the hepatic stem cells (SC) compartment. This study aimed to understand the involvement of SC during hepatocarcinogenesis in HBsAg-related liver damage, from early injury until HCC. HBsAg-transgenic (TG) and wild type (WT) mouse were followed at several stages of the liver damage: inflammation, early hepatocytes damage, dysplasia, and HCC. Serum transaminases, liver histology, and diagnostic data were collected. The expressions of SC and cancer stem cells (CSC) markers was analyzed by RT-qPCR, immunohistochemistry and Western blot. Starting from 3 months, TG animals showed a progressive liver damage characterized by transaminases increase. The up-regulations of SCs markers Cd34 and Sca-1 started from the beginning of the inflammatory stage while progressive increase of Krt19 and Sox9 and CSCs markers Epcam and Cd133 from early hepatic injury. The expressions of Cd133, Cd34, and Afp were significantly higher in HCC compared to paired non-HCC tissue, in contrast to Epcam and Krt19. Western blot and IHC confirmed the positivity of Cd34 and Cd133 in small cells subpopulation.

Significance of hepatitis virus infection in the oncogenic initiation of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) 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 HCC, 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, and DNA damage, that may lead to subsequent hepatic injuries such as chronic hepatitis, fibrosis, cirrhosis, and finally HCC. 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 HCC.

The multiple origin of cancer stem cells in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) accounts for approximately 6% of all new cancer cases diagnosed, and due to its aggressiveness, it is the second most common cause of cancer mortality worldwide. Based on different etiological factors, genetic backgrounds, and longtime development of the disease, HCC is characterized by a high phenotypic and functional heterogeneity. Tumor variability occurs both among patients (intertumoral heterogeneity) and within a single tumor (intratumoral heterogeneity). The intratumoral heterogeneity, in particular the variability of the markers of cancer stem cells (CSC) population may determine specific behavior and prognosis of the tumor. Understanding the cellular mechanisms originating CSC will provide an important hint in the management of HCC. The characterization of the cells of origin of cancer can have significant implication in early diagnosis, in the development of appropriate therapies and in the prevention of relapse. Here, we review recent evidences on the possible cellular origin of CSC that play a role in the heterogeneity of the HCC.

Seroepidemiology and occult hepatitis B virus infection in young adults in Banjarmasin, Indonesia.

Hepatitis B virus (HBV) infection remains a public health problem in Indonesia. There has been limited data regarding HBV infection in young adult population. This study aimed to evaluate the seroepidemiology of HBV infection and characterize occult HBV variants in healthy young adults in Banjarmasin, Indonesia, who were born before the implementation of the universal infant hepatitis B vaccination. Serum samples of 195 healthy young adults were tested for HBsAg, anti-HBc, and anti-HBs. The prevalence of HBsAg, anti-HBc, and anti-HBs was 9 (4.6%), 62 (31.8%), and 96 (49.2%), respectively. Seventy four (37.9%) samples were seronegative for all three parameters, indicating the susceptibility to HBV infection. Among 66 samples positive for HBsAg and/or anti-HBc, 13 (19.7%) were HBV DNA positive; of these, four were HBsAg positive and nine were HBsAg negative, and categorized as occult HBV infection. Most occult HBV cases had high-level anti-HBs (>100 IU/l), suggesting that blood with positive anti-HBs and anti-HBc could not be regarded as noninfectious. Thirteen amino acid substitutions were identified: T126S, P127S, Q129R, T131N, M133T, and Y161S in the HBsAg-positive group; P120T, T126I, G145S, Y161F, E164V, and V168F in the occult-HBV group; and T143S in both groups. More studies are required to provide data on the prevalence and characteristics of mutants to ensure reliable diagnosis. The occult HBV infection, combined with the HBsAg prevalence, could indicate the high HBV carriage among young adults in this area. The high percentage of individuals susceptible to HBV infection reiterates the need for catch-up immunization strategies targeted at young adults.