Activation of fetal promoters of insulinlike growth factors II gene in hepatitis C virus-related chronic hepatitis, cirrhosis, and hepatocellular carcinoma

Abstract

Hepatitis C virus (HCV) is a positive-stranded RNA expressed abundantly in most CAH and all cirrhotic pa-virus that plays a major role in the development of tients. Transcripts from fetal P4 promoter were detected chronic liver disease (CLD). 1,2 Acute posttransfusion at high levels in 3 of 9 CAH patients and in the majority hepatitis due to HCV is followed by chronic hepatitis of cirrhotic patients. Increased expression of fetal proin more than 50% of cases, 3,4 and 20% to 50% of these moter-derived transcripts was also found in the liver of patients eventually progress to cirrhosis. 3,5 Mounting HCC patients, although levels were lower than in cirrhoevidence suggests that HCV infection may play a role in the development of hepatocellular carcinoma (HCC) in cirrhotic patients. [5][6][7] Chronic injury of liver cells and Abbreviations: HCV, hepatitis C virus; CLD, chronic liver disease; HCC, the associated inflammatory and regenerative rehepatocellular carcinoma; IGF-II, insulinlike growth factor II; IGF-IR, insusponse that occurs in CLD are known to represent a linlike growth factor type I receptor; RT-PCR, reverse-transcription polymerase chain reaction; CAH, chronic active hepatitis; PCNA, proliferating cell preneoplastic process that may evolve toward malignuclear antigen; PCR, polymerase chain reaction; mRNA, messenger RNA; nancy. [8][9][10] However, the mechanisms responsible for the GAPDH, glyceraldehyde-3-phosphate dehydrogenase.development of HCC in HCV-related CLD are not well Insulinlike growth factor II (IGF-II) is a small pep-2 Cattedra di Gastroenterologia, Facoltà di Medicina e Chirurgia, Università di Napoli ''Federico II''; 3 Dipartimento di Internistica Clinica e Sperimentale, tide that is structurally related to proinsulin and disCattedra di Gastroenterologia; 4 Istituto di Medicina Generale e Metodologia plays multiform effects on cell growth and metaboClinica, Secondo Ateneo di Napoli, Napoli; and the 5 Dipartimento di Fisiopatolism. 11 IGF-II exerts its mitogenic activity through the logia,

Notch Signaling Is Activated in Human Hepatocellular Carcinoma and Induces Tumor Formation in Mice

“…In this regard, we found strong up-regulation of Igf2 in Notch-derived tumors, raising the possibility that Igf2 acts as an oncogenic partner of Notch in this setting. Reactivation of Igf2 fetal promoters and their tight correlation with mRNA levels lends credence to such a cooperative pathogenic role, as both promoter reactivation and IGF2 up-regulation are well recognized features of human HCC 29,30 . Whether there is a functional crosstalk between both cascades in HCC needs further evidence.…”

“…2a). Since previous reports have documented IGF2 overexpression and reactivation of fetal IGF2 promoters in human HCC 29,30 , we tested whether this was also occurring in Notch-induced tumors in mice. Igf2 promoters P1–P3 were strongly induced in tumors (4/5) when compared to control liver, mirroring the Igf2 mRNA array levels (Supplementary Fig.…”

IGF activation in a molecular subclass of hepatocellular carcinoma and pre-clinical efficacy of IGF-1R blockage

“…TaqMan® probes are listed inSupplementary Table 2. Specific IGF2 transcripts derived from adult P1 promoter and fetal P3, P4 promoters were amplified following a modified protocol from a previous report(19) (Supplementary Table 3)…”

The GH-IGF-SST system in hepatocellular carcinoma: biological and molecular pathogenetic mechanisms and therapeutic targets

“…IGF2 messenger has been reported to be overexpressed in human liver with chronic hepatitis, cirrhosis and HCC as compared with normal adult liver [113-116]. Additionally, high IGF2 protein expression has been described in HBV- and HCV-positive HCC tissues, compared with normal and HCC cirrhotic and virus negative tissues [117,118]. The inactivation of adult-specific IGF2 promoter (P1) [119] and the activation of foetal-specific IGF2 promoters (P2-P4) could represent the mechanism underlying IGF2 dysregulation in HCC [120].…”