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Pin1–HBx Interaction: A Step Toward Understanding the Significance of Hepatitis B Virus Genotypes in Hepatocarcinogenesis

2007; Elsevier BV; Volume: 133; Issue: 2 Linguagem: Inglês

10.1053/j.gastro.2007.06.033

1528-0012

Sibnarayan Datta, Arup Banerjee, Partha K. Chandra, Runu Chakravarty,

Toxin Mechanisms and Immunotoxins

We found the article by Pang et al1Pang P. Lee T.K.W. Poon R.T.P. et al.Pin1 interacts with a specific serine-proline motif of hepatitis B virus X-protein to enhance hepatocarcinogenesis.Gastroenterology. 2007; 132: 1088-1103Abstract Full Text Full Text PDF Scopus (113) Google Scholar and editorial commentary by Avila and Lu,2Avila M.A. Lu K.P. Hepatitis B virus X protein and Pin1 in liver cancer: "les liaisons dangereuses.".Gastroenterology. 2007; 132: 1180-1183Abstract Full Text Full Text PDF Scopus (11) Google Scholar published in the March 2007 issue of Gastroenterology to be of great interest as a novel mechanism of hepatitis B virus X protein (HBx)-associated hepatocarcinogenesis with promising implications in therapeutics.2Avila M.A. Lu K.P. Hepatitis B virus X protein and Pin1 in liver cancer: "les liaisons dangereuses.".Gastroenterology. 2007; 132: 1180-1183Abstract Full Text Full Text PDF Scopus (11) Google Scholar Hepatitis B virus (HBV) infection is a global health problem, with >350 million persistently infected people.3Tanaka Y. Mizokami M. Genetic diversity of hepatitis B virus as an important factor associated with differences in clinical outcomes.J Infect Dis. 2007; 195: 1-4Google Scholar, 4Schaefer S. Hepatitis B virus: significance of genotypes.J Viral Hepatol. 2005; 12: 111-124Google Scholar Based on molecular evolutionary analyses, HBV has been classified into genotypes and subgenotypes, with distinct geographic distribution.3Tanaka Y. Mizokami M. Genetic diversity of hepatitis B virus as an important factor associated with differences in clinical outcomes.J Infect Dis. 2007; 195: 1-4Google Scholar, 4Schaefer S. Hepatitis B virus: significance of genotypes.J Viral Hepatol. 2005; 12: 111-124Google Scholar HBV genotypes are genetically stable variants, evolved through selection pressures, in specific ethnic populations and in specific geographic regions. HBV genetic heterogeneity is reflected in the ORF length, specific substitutions, and even in the emergence of clinically significant mutations.3Tanaka Y. Mizokami M. Genetic diversity of hepatitis B virus as an important factor associated with differences in clinical outcomes.J Infect Dis. 2007; 195: 1-4Google Scholar, 4Schaefer S. Hepatitis B virus: significance of genotypes.J Viral Hepatol. 2005; 12: 111-124Google Scholar Population-based studies have clearly shown that HBV genotypes are significantly associated with clinical outcomes, suggesting the existence of genotype-dependent mechanisms of pathogenesis.3Tanaka Y. Mizokami M. Genetic diversity of hepatitis B virus as an important factor associated with differences in clinical outcomes.J Infect Dis. 2007; 195: 1-4Google Scholar, 4Schaefer S. Hepatitis B virus: significance of genotypes.J Viral Hepatol. 2005; 12: 111-124Google Scholar Although different mechanisms for HBV-induced carcinogenesis have been suggested, the exact mechanism remained uncertain until now.5Pang R. Tse E. Poon R.T.P. Molecular pathways in hepatocellular carcinoma.Cancer Lett. 2006; 240: 157-169Google Scholar Most of the studies concerning this area have targeted HBx because it can modulate the expression and function of a variety of important cellular factors involved in maintaining the balance between cell proliferation and apoptosis.2Avila M.A. Lu K.P. Hepatitis B virus X protein and Pin1 in liver cancer: "les liaisons dangereuses.".Gastroenterology. 2007; 132: 1180-1183Abstract Full Text Full Text PDF Scopus (11) Google Scholar, 5Pang R. Tse E. Poon R.T.P. Molecular pathways in hepatocellular carcinoma.Cancer Lett. 2006; 240: 157-169Google Scholar However, unlike other ORFs of HBV, only a few studies on HBx variability have been reported, to date.6Elmore L.W. Hancock A.R. Chang S.F. et al.Hepatitis B virus X protein and p53 tumor suppressor interactions in the modulation of apoptosis.Proc Natl Acad Sci U S A. 1997; 94: 14707-14712Google Scholar, 7Lin X. Xu X. Huang Q.L. et al.Biological impacts of "hot-spot" mutations of hepatitis B virus proteins are genotype differentiated.World J Gastroenterol. 2005; 11: 4703-4708Google Scholar, 8Kidd-Ljunggren K. Oberg M. Kidd A.H. The hepatitis B virus X gene: analysis of functional domain variation and gene phylogeny using multiple sequences.J Gen Virol. 1995; 76: 2119-2130Google Scholar In their study, Pang et al1Pang P. Lee T.K.W. Poon R.T.P. et al.Pin1 interacts with a specific serine-proline motif of hepatitis B virus X-protein to enhance hepatocarcinogenesis.Gastroenterology. 2007; 132: 1088-1103Abstract Full Text Full Text PDF Scopus (113) Google Scholar demonstrate that interaction and binding of Pin1 to phosphorylated HBx, followed by cis–trans isomerization and stabilization, significantly augmented the expression of HBx downstream target genes, leading to oncogenesis. At the initial and most imperative step, this interaction specifically required phosphorylated Ser41-Pro motif of HBx and any alteration in this motif abrogated the Pin1–HBx binding and subsequent events.1Pang P. Lee T.K.W. Poon R.T.P. et al.Pin1 interacts with a specific serine-proline motif of hepatitis B virus X-protein to enhance hepatocarcinogenesis.Gastroenterology. 2007; 132: 1088-1103Abstract Full Text Full Text PDF Scopus (113) Google Scholar Phylogenetic analyses have revealed that residues 26–52 of HBx constitute a hypervariable region8Kidd-Ljunggren K. Oberg M. Kidd A.H. The hepatitis B virus X gene: analysis of functional domain variation and gene phylogeny using multiple sequences.J Gen Virol. 1995; 76: 2119-2130Google Scholar where the putative Pin1–HBx interaction motif (Ser41-Pro) resides. Nevertheless, this motif was found to be conserved (Ser41-Pro) in all but genotype C and some genotype F sequences.8Kidd-Ljunggren K. Oberg M. Kidd A.H. The hepatitis B virus X gene: analysis of functional domain variation and gene phylogeny using multiple sequences.J Gen Virol. 1995; 76: 2119-2130Google Scholar To examine the occurrence of this motif in hepatocellular carcinoma (HCC) patients, we retrieved 63 HBV sequences from the GenBank, for which the genotype and clinical information were available, either in the GenBank entries or in literature. Deduced amino acid sequences of HBx revealed that Ser41-Pro motif was conserved in all genotype A and B sequences. Remarkably, this motif was altered in most (∼90%, 44/49) of the genotype C sequences. This observation is in line with the earlier study,8Kidd-Ljunggren K. Oberg M. Kidd A.H. The hepatitis B virus X gene: analysis of functional domain variation and gene phylogeny using multiple sequences.J Gen Virol. 1995; 76: 2119-2130Google Scholar suggesting that presence or absence of this motif is genotype dependent. To investigate whether this particular motif is subgenotype dependent (as most but not all of the genotype C HCC sequences had altered motif), we analyzed HBx sequences from 70 HBV subgenotype reference sequences (complete genome) retrieved from the GenBank. We found that this motif was preserved in HBx sequences from subgenotypes of A (Aa/A1, Ae/A2, Ac/A3), B (Bj/B1, Ba/B2, B3, B4, B5), C (only in C5, recently reported from Philippines), D (D1-D5), E, F (only in F1), G (no subgenotype reported), and H (no subgenotype reported). On the other hand, 4 subgenotypes of C (Cs/C1, Ce/C2, C3, C4) and 1 subgenotype of F (F2) had altered motif at this position, confirming the earlier findings.8Kidd-Ljunggren K. Oberg M. Kidd A.H. The hepatitis B virus X gene: analysis of functional domain variation and gene phylogeny using multiple sequences.J Gen Virol. 1995; 76: 2119-2130Google Scholar It is notable that HBV-related HCC is prevalent in specific geographic areas, with specific prevalence of HBV genotypes, such as genotype A (subgenotype Aa/A1) in South Africa, genotype B (subgenotypes Bj/B1, Ba/B2) and C (subgenotypes Cs/C1 and Ce/C2) in East Asia, and genotype F in Alaska (subgenotype F1, based on our phylogenetic analyses of 38 defined genotype F surface gene sequences submitted to GenBank).3Tanaka Y. Mizokami M. Genetic diversity of hepatitis B virus as an important factor associated with differences in clinical outcomes.J Infect Dis. 2007; 195: 1-4Google Scholar Interestingly, in South Africa, India, and Alaska, genotypes/subgenotypes Aa/A1, D, and F1, respectively (all 3 genotypes/subgenotypes had Ser41-Pro motif) are prevalent and reported to be significantly associated with young HCC patients.3Tanaka Y. Mizokami M. Genetic diversity of hepatitis B virus as an important factor associated with differences in clinical outcomes.J Infect Dis. 2007; 195: 1-4Google Scholar, 4Schaefer S. Hepatitis B virus: significance of genotypes.J Viral Hepatol. 2005; 12: 111-124Google Scholar The age-specific HBV genotype distribution was more prominent in Taiwan, where genotype B infection was significantly prevalent among young HCC patients, in comparison with genotype C.9Kao J.H. Chen P.J. Lai M.Y. et al.Hepatitis B genotypes correlate with clinical outcomes in patients with chronic hepatitis B.Gastroenterology. 2000; 118: 554-559Google Scholar Interestingly, in Taiwan, the prevalent subgenotypes of genotypes B and C are Ba/B2 (having the Ser41-Pro motif) and Ce/C2 (not having the Ser41-Pro motif), respectively. This reinforces the assumption of possible association between early HCC development and presence of Ser41-Pro motif in the infecting HBx. It kindles interest to know whether the above associations are mere coincidences or they imply that HBV genotypes/subgenotypes expressing HBx with Ser41-Pro motif (capable of interacting with Pin1) are accountable for early HCC development. This information would be of potential importance in prediction of disease progression. The results of Pang et al1Pang P. Lee T.K.W. Poon R.T.P. et al.Pin1 interacts with a specific serine-proline motif of hepatitis B virus X-protein to enhance hepatocarcinogenesis.Gastroenterology. 2007; 132: 1088-1103Abstract Full Text Full Text PDF Scopus (113) Google Scholar thus provide an important evidence for HBV genotype- and subgenotype-dependent mechanism of oncogenesis. Further studies on the association of HBV genotypes with age, HBx, and Pin1 expression patterns might provide interesting data. Additionally, in Asian cohorts, frequent association of cirrhosis-related HCC with genotype C signifies a different mechanism, in which Pin1 and HBx (without isomerization by Pin1) presumably follow different pathways. The observation that the same cells respond differently by expressing specific cellular proteins, when infected with HBx of different genotypes,10Tan T.L. Chen W.N. A proteomics analysis of cellular proteins associated with HBV genotype-specific HBX: potential in identification of early diagnostic markers for HCC.J Clin Virol. 2005; 33: 293-298Google Scholar further authenticates that HBx is the key determinant molecule in deciding the clinical outcome of infection. In conclusion, studies involving HBx from different genotypes of HBV, under similar assay conditions, will further enrich our understanding of HBV genotype-related pathogenesis and will help in designing genotype-specific therapeutic regimens to combat HBV more effectively. Pin1 Interacts With a Specific Serine-Proline Motif of Hepatitis B Virus X-Protein to Enhance HepatocarcinogenesisGastroenterologyVol. 132Issue 3PreviewBackground & Aims: The peptidyl prolyl isomerase Pin1 frequently is overexpressed in hepatocellular carcinoma (HCC). Hepatitis B virus (HBV) is the most common etiologic agent in HCC, and its encoded X-protein (HBx) is oncogenic and possesses a serine-proline motif that may bind Pin1. The role of Pin1 in hepatocarcinogenesis, particularly in HBV-related HCC, was investigated. Methods: Immunohistochemical staining was performed to evaluate the prevalence of Pin1 overexpression in HCCs of different etiologies. Full-Text PDF ReplyGastroenterologyVol. 133Issue 2PreviewWe welcome this follow-up study based on our recently published data.1 In our original report, we showed that the interaction between Pin1 and hepatitis B virus X protein (HBx) enhanced hepatocarcinogenesis, and this interaction required the phosphorylated Ser41-Pro motif of HBx. This motif may not be conserved in certain genotypes of hepatitis B virus (HBV),2 implying that the potentiating effect of Pin1 on the oncogenic functions of HBx may vary in hepatocellular carcinoma (HCC) related to different HBV genotypes. Full-Text PDF