Guillaume Fallot

Hepatocellular Carcinoma Is Associated With an Increased Risk of Hepatitis B Virus Recurrence After Liver Transplantation

BACKGROUND & AIMS Hepatitis B virus (HBV) recurrence after orthotopic liver transplantation (OLT) is significantly reduced by prophylaxis with hyperimmune antibody to hepatitis B surface antigen (anti-HBs) globulins (HBIG) and antiviral drugs. The role of hepatocellular carcinoma (HCC) in HBV recurrence remains unclear. We investigated the association between HCC pre-OLT and HBV recurrence post-OLT. METHODS We studied 99 hepatitis B surface antigen-positive patients who underwent OLT for cirrhosis. The median follow-up period was 43 months. All patients received HBIG, and 51 also received lamivudine and/or adefovir. Of these 99 patients, 31 had HCC before OLT. Total HBV DNA and covalently closed circular (ccc)-DNA were measured in tumor and nontumor tissues from the explanted livers of 16 of these 31 HCC patients and, also, in a context of tumor recurrence, in 3 patients who developed HBV/HCC recurrence. RESULTS Fourteen patients (14.1%) developed HBV recurrence within a median period of 15 months post-OLT. HCC at OLT, a pre-OLT HBV DNA viral load > or = 100,000 copies/mL, and HBIG monoprophylaxis were independently associated with HBV recurrence post-OLT. Eleven out of the 31 patients with HCC at OLT presented with HBV recurrence and 3 out of the 68 patients without HCC had HBV recurrence (P < .0001). HBV recurrence was more frequent in patients who developed HCC recurrence (7/8 patients, 87.5%) than in those who did not (4/23 patients, 17.4%) (P < .0001). In the 16 explanted livers, cccDNA was detectable in HCC cells in 11 and in nontumor cells in 12. cccDNA was detected in a context of HCC recurrence in 2 of the 3 patients tested who developed HBV/HCC recurrence. CONCLUSIONS The associations of HCC pre-OLT, and HCC recurrence with HBV recurrence post-OLT, and the detection of HBV DNA and cccDNA in HCC suggest that HBV replication in tumor cells may contribute to HBV recurrence post-OLT.

Diverse roles of hepatitis B virus in liver cancer

Hepatitis B virus (HBV) is a widespread human pathogen responsible for acute and chronic liver diseases. The hepatitis B burden is particularly heavy in endemic countries, where liver cirrhosis and hepatocellular carcinoma are leading causes of death. However, the oncogenic role of HBV remains enigmatic. As the virus has no cytopathic effect, liver damage is attributed to immune responses that induce inflammation, apoptosis and regeneration, fostering the accumulation of genetic and epigenetic alterations. In a more direct action, frequent integration of HBV DNA into host chromosomes may lead to insertional mutagenesis of cancer-related genes and chromosomal instability. HBV proteins, notably the HBx transactivator, participate as co-factors in oncogenesis. Better understanding of hepatitis B pathogenesis is mandatory for improving disease management.

Pleiotropic effects of PI-3' kinase/Akt signaling in human hepatoma cell proliferation and drug-induced apoptosis.

Abstract:  IGF‐II and type I‐IGF receptor (IGF‐IR) gene expression is increased in primary liver tumors, and transgenic mice overexpressing IGF‐II in the liver develop hepatocellular carcinoma (HCC) spontaneously, suggesting that alterations of IGF‐IR signaling in vivo may play a role in the auto/paracrine control of hepatocarcinogenesis. We have addressed the contribution of PI‐3′K/Akt signaling on the proliferation of HepG2 human hepatoma cells and on their protection against doxorubicin‐induced apoptosis. Both basal HepG2 cell DNA replication and that stimulated by IGF‐IR signaling were inhibited by the specific PI‐3′K inhibitor Ly294002 (Ly). In the former case, PI‐3′K signaling overcame cell cycle arrest in G1 via increased cyclin D1 protein and decreased p27kip1 gene expression. Doxorubicin treatment induced apoptosis in HepG2 cells and was concomitant with the proteolytic cleavage of Akt‐1 and ‐2. Drug‐induced apoptosis was reversed by IGF‐I and this effect was (i) dependent on Akt‐1 and ‐2 phosphorylation and (ii) accompanied by the inhibition of initiator caspase‐9 activity, suggesting that IGF‐IR signaling interferes with mitochondria‐dependent apoptosis. Accordingly, Ly enhanced doxorubicin‐induced apoptosis and suppressed its reversal by IGF‐I. Altogether, the data emphasize the crucial role of PI‐3′K/Akt signaling (i) in basal as well as IGF‐IR‐stimulated HepG2 cell proliferation and (ii) in controlling both doxorubicin‐induced apoptosis (e.g., drug‐induced cleavage of Akt) and its reversal by IGF‐I (protection against apoptosis parallels the extent of Akt phosphorylation). They suggest that targeting Akt activity or downstream Akt effectors (e.g., GSK3‐beta, FOXO transcription factors) may help define novel therapeutic strategies of increased efficacy in the treatment of HCC‐bearing patients.

Risk factors for hepatocellular carcinoma in Caucasian patients with non‐viral cirrhosis: the importance of prior obesity

In patients with cirrhosis, the risk of hepatocellular carcinoma (HCC) depends upon age, gender and the etiology of liver disease. Few studies are available in Caucasian patients with alcoholic or metabolic cirrhosis without viral hepatitis.

The cAMP-Responsive Unit of the Human Insulin-Like Growth Factor–Binding Protein-1 Coinstitutes a Functional Insulin-Response Element

Abstract:  Insulin‐like growth factor–binding protein‐1 (IGFBP‐1) is one of the genes involved in glucose homeostasis. In vivo, its level is increased by counter‐regulatory hormones (glucocorticoids and glucagon via its second messenger cAMP) and decreased by insulin, these variations being primarily correlated with IGFBP‐1 gene transcription. Previous reports described a functional insulin response element (IRE), immediately 5′‐ to the glucocorticoid response element (GRE). This IRE has been shown to mediate partial inhibition (1) of basal IGFBP‐1 promoter activity and (2) of glucocorticoid‐induced stimulation of gene transcription by insulin. In this work, using human HepG2 hepatoma cells as a model system, we showed: (1) that insulin inhibited both basal and cAMP‐induced hIGFBP‐1 promoter (nt‐1 to ‐341) activity; (2) that in the absence of insulin, forkhead box class O (FOXO) transcription factors enhance constitutive hIGFBP‐1 promoter activity without interfering with the stimulatory effect of cAMP; (3) that PI‐3′ kinase signaling is involved in the inhibition of constitutive and cAMP‐induced promoter activities by insulin; (4) that wild‐type FOXO‐1 mediates the inhibitory effect of insulin on the promoter, although FOXO‐1Ala3, a nonphosphorylatable mutant of FOXO‐1, does not; (5) that the cAMP‐responsive unit (CRU), that includes a putative IRE (nt‐265 to ‐282) and a cAMP responsive element (CRE; nt‐258 to ‐263), is sufficient per se to mediate both cAMP stimulation of a heterologous promoter, and inhibition of both basal and cAMP‐induced promoter activities by insulin; and (6) that the inhibitory effects of insulin on the isolated CRU are mediated by the FOXOs. This study is the first evidence for the occurrence of a second IRE within hIGFBP‐1 promoter sequences, IRECRU, located 5′‐ to the CRE.

Hepatitis B virus pregenomic RNA in hepatocellular carcinoma: A nosological and prognostic determinant.

Hepatitis B virus (HBV) is a major cause of hepatocellular carcinoma (HCC). However, very little is known about the replication of HBV in HCC tissues. We analyzed viral and cellular parameters in HCC (T) and nontumor liver (NT) samples from 99 hepatitis B surface antigen (HBsAg)‐positive, virologically suppressed patients treated by tumor resection or liver transplantation. We examined total HBV DNA and RNA as well as covalently closed circular DNA (cccDNA) and pregenomic RNA (pgRNA), which are considered as markers of active HBV replication. Total HBV DNA and RNA were detected in both T and NT samples in a majority of cases, but only a subset of tumors harbored detectable levels of HBV cccDNA and pgRNA (39% and 67%) compared to NT livers (66% and 90%; P < 0.01). Further evidence for HBV replication in tumor tissues was provided by sequencing of the X gene derived from episomal forms, showing that HBV genotypes differed between T and matched NT samples in 11 cases. The detection of pgRNA and cccDNA in tumors was correlated to the absence of tumorous microvascular invasion and to better patient survival. Analysis of gene expression profiles by Agilent microarrays revealed that pgRNA‐positive HCCs were characterized by low levels of cell cycle and DNA repair markers and expression of the HBV receptor, sodium taurocholate cotransporting polypeptide, indicating well‐differentiated tumors. Conclusion: HCC replicating HBV represents a subtype of weakly invasive HCC with a transcriptomic signature. pgRNA originating from nonintegrated, complete HBV genomes is a sensitive marker for viral replication and prognosis. (Hepatology 2018;67:86‐96).