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• W2119647155 abstract "See “Pin1 interacts with a specific serine-proline motif of hepatitis B virus X-protein to enhance hepatocarcinogenesis” by Pang R, Lee TKW, Poon RTP, Fan ST, Wong KB, Kwong Y–L, and Tse E, on page 1088. See “Pin1 interacts with a specific serine-proline motif of hepatitis B virus X-protein to enhance hepatocarcinogenesis” by Pang R, Lee TKW, Poon RTP, Fan ST, Wong KB, Kwong Y–L, and Tse E, on page 1088. Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, being responsible for 80% of the primary malignant liver tumors in adults, and also is one of the most deadly with average survival rates after the onset of symptoms being <1 year, accounting for over half a million deaths annually.1Llovet J.M. Burroughs A. Bruix J. Hepatocellular carcinoma.Lancet. 2003; 362: 1907-1917Abstract Full Text Full Text PDF PubMed Scopus (3788) Google Scholar Several reasons may account for this dramatic situation. HCC is frequently diagnosed at an advanced stage, when most potentially curative therapies such as resection, transplantation, or percutaneous and transarterial embolization are not applicable or are of limited efficacy. Besides, HCC is a type of tumour highly resistant to available chemotherapeutic regimens.2Avila M.A. Berasain C. Sangro B. Prieto J. New therapies for hepatocellular carcinoma.Oncogene. 2006; 25: 3866-3884Crossref PubMed Scopus (354) Google Scholar Therefore, understanding the molecular mechanisms of HCC development is essential to providing patients with efficacious therapeutic options. In most cases, HCC develops on a background of repetitive hepatic injury and cirrhosis. The underlying nature of chronic active hepatitis and cirrhosis associated with the development of HCC is well known, and major etiologic factors include chronic alcohol consumption, exposure to hepatotoxins (aflatoxin), genetic conditions (eg, hemochromatosis), and chronic viral infections with hepatitis B virus (HBV) and/or hepatitis C virus (HCV).3Coleman W.B. Mechanisms of human hepatocarcinogenesis.Curr Mol Med. 2003; 3: 573-588Crossref PubMed Scopus (210) Google Scholar, 4McKillop I.H. Moran D.M. Jin X. Koniaris L.G. Molecular pathogenesis of hepatocellular carcinoma.J Surg Res. 2006; 136: 125-135Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar There are differences in the level of associated risk for HCC development among these etiologic factors, as indicated by the fact that approximately 75%–80% of HCC cases worldwide are related to chronic infection with HCV and HBV.4McKillop I.H. Moran D.M. Jin X. Koniaris L.G. Molecular pathogenesis of hepatocellular carcinoma.J Surg Res. 2006; 136: 125-135Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar, 5Bosch F.X. Ribes J. Cleries R. Diaz M. Epidemiology of hepatocellular carcinoma.Clin Liver Dis. 2005; 9: 191-211Abstract Full Text Full Text PDF PubMed Scopus (749) Google Scholar Although the risk of HCC development is higher in HCV infection as compared with HBV infection, HBV is globally the main causal factor for HCC,4McKillop I.H. Moran D.M. Jin X. Koniaris L.G. Molecular pathogenesis of hepatocellular carcinoma.J Surg Res. 2006; 136: 125-135Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar, 6Cougot D. Neveut C. Buendia M. HBV-induced carcinogenesis.J Clin Virol. 2005; 34: S75-S78Abstract Full Text PDF PubMed Scopus (162) Google Scholar and >80% of HCCs are found in HBV-infected people.7Lok A.S. Prevention of hepatitis B virus-related hepatocellular carcinoma.Gastroenterology. 2004; 127: S303-S309Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar In this issue of Gastroenterology, Pang et al8Pang R. Lee T.K.W. Poon R.T.P. Fan S.T. Wong K.B. Kwong Y.-L. Tse E. 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 PubMed Scopus (113) Google Scholar identify a possible new mechanism for HBV-induced HCC. The underlying mechanisms in the multistep process of HBV-induced hepatocarcinogenesis are not completely known, but may involve several non–mutually exclusive pathways. Host immune responses to HBV result in chronic inflammation of the liver leading to hepatocyte necrosis, which in turn triggers a potent regenerative response in the parenchyma. Rapid and uncontrolled regeneration in a proinflammatory environment may lead to accumulation of mutations and selection of cells with a malignant phenotype.9Park N.H. Song I.H. Chung Y.-H. Chronic hepatitis B in hepatocarcinogenesis.Postgrad Med J. 2006; 82: 507-515Crossref PubMed Scopus (74) Google Scholar In addition, a growing body of evidence suggests that the HBV can have a direct oncogenic capacity.6Cougot D. Neveut C. Buendia M. HBV-induced carcinogenesis.J Clin Virol. 2005; 34: S75-S78Abstract Full Text PDF PubMed Scopus (162) Google Scholar, 10Kremsdorf D. Soussan P. Paterlini-Brechot P. Brechot C. Hepatitis B virus-related hepatocellular carcinoma: paradigms for viral-related human carcinogenesis.Oncogene. 2006; 25: 3823-3833Crossref PubMed Scopus (235) Google Scholar Mechanistically, the oncogenic potential of HBV has been attributed to its ability to integrate in the hepatocyte’s genome, which can generate chromosomal instability and also modify cellular gene expression (ie, cis-activation).9Park N.H. Song I.H. Chung Y.-H. Chronic hepatitis B in hepatocarcinogenesis.Postgrad Med J. 2006; 82: 507-515Crossref PubMed Scopus (74) Google Scholar, 10Kremsdorf D. Soussan P. Paterlini-Brechot P. Brechot C. Hepatitis B virus-related hepatocellular carcinoma: paradigms for viral-related human carcinogenesis.Oncogene. 2006; 25: 3823-3833Crossref PubMed Scopus (235) Google Scholar Recently, there is also considerable evidence that expression of virally encoded proteins, in particular the HBV X protein (HBx), promote cell growth and tumorigenesis.10Kremsdorf D. Soussan P. Paterlini-Brechot P. Brechot C. Hepatitis B virus-related hepatocellular carcinoma: paradigms for viral-related human carcinogenesis.Oncogene. 2006; 25: 3823-3833Crossref PubMed Scopus (235) Google Scholar, 11Bouchard M.J. Schneider R.J. The enigmatic X gene of hepatitis B virus.J Virol. 2004; 78: 12725-12734Crossref PubMed Scopus (410) Google Scholar, 12Feitelson M.A. Reis H.M.G.P.V. Liu J. Lian Z. Pan J. Hepatitis B virus x antigen (HBxAg) and cell cycle control in chronic infection and hepatocarcinogenesis.Front Biosci. 2005; 10: 1558-1572Crossref PubMed Scopus (25) Google Scholar, 13Tang H. Oishi N. Kaneko S. Murakami S. Molecular functions and biological roles of hepatitis B virus x protein.Cancer Sci. 2006; 97: 977-983Crossref PubMed Scopus (246) Google Scholar HBx is encoded by the smallest open reading frame of the HBV DNA, and its expression is retained when the virus integrates hepatocytes.12Feitelson M.A. Reis H.M.G.P.V. Liu J. Lian Z. Pan J. Hepatitis B virus x antigen (HBxAg) and cell cycle control in chronic infection and hepatocarcinogenesis.Front Biosci. 2005; 10: 1558-1572Crossref PubMed Scopus (25) Google Scholar HBx is one of the most prevalent virus antigens in the liver and tumors of HBV carriers, and can induce humoral and cellular immune responses.10Kremsdorf D. Soussan P. Paterlini-Brechot P. Brechot C. Hepatitis B virus-related hepatocellular carcinoma: paradigms for viral-related human carcinogenesis.Oncogene. 2006; 25: 3823-3833Crossref PubMed Scopus (235) Google Scholar HBx seems to play a regulatory role during viral infection and replication.11Bouchard M.J. Schneider R.J. The enigmatic X gene of hepatitis B virus.J Virol. 2004; 78: 12725-12734Crossref PubMed Scopus (410) Google Scholar, 13Tang H. Oishi N. Kaneko S. Murakami S. Molecular functions and biological roles of hepatitis B virus x protein.Cancer Sci. 2006; 97: 977-983Crossref PubMed Scopus (246) Google Scholar However, numerous studies have also established that HBx can modulate a variety of host functions directly related to the carcinogenic process, including cell proliferation and viability. Work from many laboratories has established that HBx can activate oncogenic signaling pathways14Branda M. Wands J.R. Signal transduction cascades and hepatitis B and C related hepatocellular carcinoma.Hepatology. 2006; 43: 891-902Crossref PubMed Scopus (101) Google Scholar and moderately stimulate transcription from different cellular genes, although HBx does not bind directly to DNA.11Bouchard M.J. Schneider R.J. The enigmatic X gene of hepatitis B virus.J Virol. 2004; 78: 12725-12734Crossref PubMed Scopus (410) Google Scholar, 12Feitelson M.A. Reis H.M.G.P.V. Liu J. Lian Z. Pan J. Hepatitis B virus x antigen (HBxAg) and cell cycle control in chronic infection and hepatocarcinogenesis.Front Biosci. 2005; 10: 1558-1572Crossref PubMed Scopus (25) Google Scholar, 13Tang H. Oishi N. Kaneko S. Murakami S. Molecular functions and biological roles of hepatitis B virus x protein.Cancer Sci. 2006; 97: 977-983Crossref PubMed Scopus (246) Google Scholar Therefore, its ability to activate gene expression likely resides in the direct interaction with basal and regulatory components of the nuclear transcription machinery, and with proteins involved in cytosolic signaling pathways.13Tang H. Oishi N. Kaneko S. Murakami S. Molecular functions and biological roles of hepatitis B virus x protein.Cancer Sci. 2006; 97: 977-983Crossref PubMed Scopus (246) Google Scholar Cellular factors reported to interact with HBx include a multitude of proteins with diverse functions such as proteasome subunits and transcription factors like RPB5, TFIIB, TBP, TFIIH, ATF/CREB, ATF3, c/EBP, NF-IL-6, Ets, Egr, SMAD4, Oct1, RXR receptor, CBP-P300, p53, p55sen, and IκBα, among others.10Kremsdorf D. Soussan P. Paterlini-Brechot P. Brechot C. Hepatitis B virus-related hepatocellular carcinoma: paradigms for viral-related human carcinogenesis.Oncogene. 2006; 25: 3823-3833Crossref PubMed Scopus (235) Google Scholar, 11Bouchard M.J. Schneider R.J. The enigmatic X gene of hepatitis B virus.J Virol. 2004; 78: 12725-12734Crossref PubMed Scopus (410) Google Scholar, 12Feitelson M.A. Reis H.M.G.P.V. Liu J. Lian Z. Pan J. Hepatitis B virus x antigen (HBxAg) and cell cycle control in chronic infection and hepatocarcinogenesis.Front Biosci. 2005; 10: 1558-1572Crossref PubMed Scopus (25) Google Scholar, 13Tang H. Oishi N. Kaneko S. Murakami S. Molecular functions and biological roles of hepatitis B virus x protein.Cancer Sci. 2006; 97: 977-983Crossref PubMed Scopus (246) Google Scholar, 15Cougot D. Wu Y. Cairo S. Caramel J. Renard C.A. Lévy l. Buendia M.A. Neuveut C. The hepatitis B virus X protein functionally interacts with CBP/p300 in the regulation of CREB-mediated transcription.J Biol Chem. 2006; 282: 4277-4287Crossref PubMed Scopus (168) Google Scholar HBx binding is thought to alter the subcellular distribution and/or activity of its target proteins. For example, it has been shown that p53 is retained in the cytoplasm by HBx; therefore, ablating p53 tumor suppressor activities.16Ueda H. Ullrich S.J. Gangemi J.D. Kappel C.A. Ngo L. Feitelson M.A. Jay G. Functional inactivation but not structural mutation of p53 causes liver cancer.Nat Genet. 1995; 9: 41-47Crossref PubMed Scopus (328) Google Scholar Direct association of HBx with IκBα17Weil R. Sirma H. Giannini C. Kremsdorf D. Bessia C. Dargemont C. Brechot C. Israël A. Direct association and nuclear import of the hepatitis B virus X protein with the NF-κB inhibitor IκBβ.Mol Cell Biol. 1999; 19: 6345-6354Crossref PubMed Google Scholar might prevent IκBα from interacting with DNA-bound nuclear factor (NF)-κB complexes and lead to sustained NF-κB activation, resulting in enhanced apoptotic resistance and the promotion of cell growth and survival.12Feitelson M.A. Reis H.M.G.P.V. Liu J. Lian Z. Pan J. Hepatitis B virus x antigen (HBxAg) and cell cycle control in chronic infection and hepatocarcinogenesis.Front Biosci. 2005; 10: 1558-1572Crossref PubMed Scopus (25) Google Scholar, 17Weil R. Sirma H. Giannini C. Kremsdorf D. Bessia C. Dargemont C. Brechot C. Israël A. Direct association and nuclear import of the hepatitis B virus X protein with the NF-κB inhibitor IκBβ.Mol Cell Biol. 1999; 19: 6345-6354Crossref PubMed Google Scholar Pang et al8Pang R. Lee T.K.W. Poon R.T.P. Fan S.T. Wong K.B. Kwong Y.-L. Tse E. 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 PubMed Scopus (113) Google Scholar now identify Pin1, a peptidyl-prolyl cis/trans isomerase (PPIase), as a novel binding partner for HBx that appears to have profound effects on the stability and protumorigenic activity of the viral protein. To discuss the potential implications of this interaction, we first put into perspective the recently recognized biological and pathologic functions of Pin1. Pin1 binds to and isomerizes specific phosphorylated Ser/Thr-Pro (pSer/Thr-Pro) motifs in a group of proteins, catalytically inducing conformational changes following phosphorylation.18Yaffe M. Schutkowski M. Shen M. Zhou X.Z. Stukenberg P.T. Rahfeld J.-U. Xu J. Kuang J. Kirschner M.W. Fischer G. et al.Sequence-specific and phosphorylation-dependent proline isomerization: A potential mitotic regulatory mechanism.Science. 1997; 278: 1957-1960Crossref PubMed Scopus (678) Google Scholar, 19Wulf G. Finn G. Suizu F. Lu K.P. Phosphorylation-specific prolyl isomerisation: is there an underlying theme?.Nat Cell Biol. 2005; 7: 435-441Crossref PubMed Scopus (218) Google Scholar Because of the unique 5-carbonyl ring structure of Pro, pSer/Thr-Pro motifs in a native protein can exist in 2 distinct conformations, cis or trans, whose conversions in certain proteins are slowed down upon phosphorylation but accelerated specifically by Pin1.18Yaffe M. Schutkowski M. Shen M. Zhou X.Z. Stukenberg P.T. Rahfeld J.-U. Xu J. Kuang J. Kirschner M.W. Fischer G. et al.Sequence-specific and phosphorylation-dependent proline isomerization: A potential mitotic regulatory mechanism.Science. 1997; 278: 1957-1960Crossref PubMed Scopus (678) Google Scholar, 19Wulf G. Finn G. Suizu F. Lu K.P. Phosphorylation-specific prolyl isomerisation: is there an underlying theme?.Nat Cell Biol. 2005; 7: 435-441Crossref PubMed Scopus (218) Google Scholar This unique phosphorylation-specific activity of Pin1 is rendered by its 2-domain structure, consisting of an N-terminal WW domain and a C-terminal PPIase domain that binds to and isomerizes only specific pSer/Thr-Pro motifs, respectively.18Yaffe M. Schutkowski M. Shen M. Zhou X.Z. Stukenberg P.T. Rahfeld J.-U. Xu J. Kuang J. Kirschner M.W. Fischer G. et al.Sequence-specific and phosphorylation-dependent proline isomerization: A potential mitotic regulatory mechanism.Science. 1997; 278: 1957-1960Crossref PubMed Scopus (678) Google Scholar, 19Wulf G. Finn G. Suizu F. Lu K.P. Phosphorylation-specific prolyl isomerisation: is there an underlying theme?.Nat Cell Biol. 2005; 7: 435-441Crossref PubMed Scopus (218) Google Scholar Protein phosphorylation on Ser/Thr-Pro motifs is a major regulatory mechanism in the cell under physiologic and pathologic conditions. Many kinases can phosphorylate such motifs, including all cyclin-dependent kinases, and most, if not all, the mitogen-activated protein kinases and glycogen synthase kinase 3β, which play key roles in cell growth and signaling. Isomerization of pSer/Thr-Pro motifs between cis and trans can alter the local, or even the global structure, and has profound effects on the function and regulation of the target molecule.19Wulf G. Finn G. Suizu F. Lu K.P. Phosphorylation-specific prolyl isomerisation: is there an underlying theme?.Nat Cell Biol. 2005; 7: 435-441Crossref PubMed Scopus (218) Google Scholar Indeed, kinases such as MAP kinase, and phosphatases like PP2A, phosphorylate or dephosphorylate only the trans conformation of Ser/Thr-Pro motifs.19Wulf G. Finn G. Suizu F. Lu K.P. Phosphorylation-specific prolyl isomerisation: is there an underlying theme?.Nat Cell Biol. 2005; 7: 435-441Crossref PubMed Scopus (218) Google Scholar Through isomerizing certain pSer/Thr-Pro motifs, Pin1 has been demonstrated to modulate the activity, stability, and subcellular localization of many key regulatory proteins, including cyclin D1, β-catenin, p65 (NF-κB), c-Jun, and p53. It appears that it is Pin1-induced conformational changes after phosphorylation, rather than the initial phosphorylation per se, that regulate protein function.19Wulf G. Finn G. Suizu F. Lu K.P. Phosphorylation-specific prolyl isomerisation: is there an underlying theme?.Nat Cell Biol. 2005; 7: 435-441Crossref PubMed Scopus (218) Google Scholar Pin1 expression and function are tightly regulated in normal cells but are prevalently over expressed in most common cancers, with over expression levels correlating with the poor clinical outcome of some cancers.20Lu K.P. Prolyl isomerase Pin1 as a molecular target for cancer diagnostics and therapeutics.Cancer Cell. 2003; 4: 175-180Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar, 21Bao L. Kimzey A. Sauter G. Sowadski J.M. Lu K.P. Wang D.-G. Prevalent overexpression of prolyl isomerase Pin1 in human cancers.Am J Pathol. 2004; 164: 1727-1737Abstract Full Text Full Text PDF PubMed Scopus (334) Google Scholar, 22Ayala G. Wang D. Wulf G. Kimzey A. Frolov A. Le R. Sowadski J. Wheeler T. Lu K.P. Bao L. Pin1 is a novel prognostic marker in prostate cancer.Cancer Res. 2003; 63: 6244-6251PubMed Google Scholar In human HCC, although Pin1 over expression was found to be at a relatively low frequency (∼20%) in Western patients,21Bao L. Kimzey A. Sauter G. Sowadski J.M. Lu K.P. Wang D.-G. Prevalent overexpression of prolyl isomerase Pin1 in human cancers.Am J Pathol. 2004; 164: 1727-1737Abstract Full Text Full Text PDF PubMed Scopus (334) Google Scholar Pang and et al observed a higher frequency in Chinese patients (>50%).17Weil R. Sirma H. Giannini C. Kremsdorf D. Bessia C. Dargemont C. Brechot C. Israël A. Direct association and nuclear import of the hepatitis B virus X protein with the NF-κB inhibitor IκBβ.Mol Cell Biol. 1999; 19: 6345-6354Crossref PubMed Google Scholar, 23Pang R. Yuen J. Yuen M.F. Lai C.L. Lee T.K.W. Man K. Poon R.T.P. Fan S.T. Wong C.M. Ng I.O.L. et al.Pin1 overexpression and b-catenin gene mutations are distinct oncogenic events in human hepatocellular carcinoma.Oncogene. 2004; 23: 4182-4186Crossref PubMed Scopus (102) Google Scholar As the authors noted here,8Pang R. Lee T.K.W. Poon R.T.P. Fan S.T. Wong K.B. Kwong Y.-L. Tse E. 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 PubMed Scopus (113) Google Scholar the prevalence of Pin1 over expression seems to be associated with the etiology of the tumors, being higher in HBx positive HBV-related HCC. This observation suggests that Pin1 may have a role in HBV-mediated hepatocarcinogenesis. Moreover, it raises the interesting but as yet untested possibility that HBx might contribute to the induction of Pin1 expression, and therefore that the expression of Pin1 could be up-regulated from the early stages of HBV infection, long before HCC develops. The fact that HBx can be phosphorylated in vivo at a potential Pin1 binding motif (Ser-Pro)11Bouchard M.J. Schneider R.J. The enigmatic X gene of hepatitis B virus.J Virol. 2004; 78: 12725-12734Crossref PubMed Scopus (410) Google Scholar led the authors to hypothesize that Pin1 might interact with the viral protein, and to evaluate the consequences of such potential interaction on the neoplastic phenotype of HCC cells. By means of transient transfection experiments, the investigators provide solid evidence demonstrating the interaction between Pin1 and HBx. Furthermore, such interaction was dependent on phosphorylation of HBx, specifically on the pSer41-Pro motif.8Pang R. Lee T.K.W. Poon R.T.P. Fan S.T. Wong K.B. Kwong Y.-L. Tse E. 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 PubMed Scopus (113) Google Scholar Importantly, this interaction was shown to have functional significance. HBx is a protein with a short half-life,11Bouchard M.J. Schneider R.J. The enigmatic X gene of hepatitis B virus.J Virol. 2004; 78: 12725-12734Crossref PubMed Scopus (410) Google Scholar but its steady-state levels were significantly increased by Pin1.8Pang R. Lee T.K.W. Poon R.T.P. Fan S.T. Wong K.B. Kwong Y.-L. Tse E. 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 PubMed Scopus (113) Google Scholar In addition to regulating protein stability, Pin1 can change the distribution of its substrates in the cell.19Wulf G. Finn G. Suizu F. Lu K.P. Phosphorylation-specific prolyl isomerisation: is there an underlying theme?.Nat Cell Biol. 2005; 7: 435-441Crossref PubMed Scopus (218) Google Scholar Therefore, it would be interesting to evaluate if Pin1 could also affect the intracellular distribution of HBx, which can influence its biological effects.9Park N.H. Song I.H. Chung Y.-H. Chronic hepatitis B in hepatocarcinogenesis.Postgrad Med J. 2006; 82: 507-515Crossref PubMed Scopus (74) Google Scholar, 11Bouchard M.J. Schneider R.J. The enigmatic X gene of hepatitis B virus.J Virol. 2004; 78: 12725-12734Crossref PubMed Scopus (410) Google Scholar The functional significance of the HBx/Pin1 interaction is further demonstrated by showing enhanced transactivation activity of HBx on either a transfected reporter construct or on endogenous target genes. Significantly, the synergistic effects were lost when HBx variants unable to bind Pin1, or Pin1 mutated in the WW or isomerase domain were used, indicating that their cooperation depends on the interaction between the 2 proteins and on Pin1 enzymatic activity. In future experiments, it would be interesting to determine if Pin1 could regulate the conformation of phosphorylated HBx and affect its other biological properties. Finally, Pang et al provide convincing evidence of the biological significance of the HBx/Pin1 interaction when they demonstrate that the presence of both proteins increased HCC cell proliferation in vitro, and synergistically stimulated the ability to form tumors in vivo of a nontransformed hepatocyte cell line.8Pang R. Lee T.K.W. Poon R.T.P. Fan S.T. Wong K.B. Kwong Y.-L. Tse E. 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 PubMed Scopus (113) Google Scholar Again, using a combination of HBx and Pin1 mutants, these effects were shown to depend on the direct interaction between the 2 proteins and on the preservation of Pin1 catalytic activity. Although these studies cogently demonstrate the physical and functional interaction between the two proteins, it would be important to reevaluate such interaction under conditions that recapitulate HBV infection in hepatocytes. Taken together, the observations presented in this article are of special relevance for the biology of HBV-induced HCC (Figure 1). Both HBx and Pin1 were previously identified as important players in the development of liver cancer, capable of acting on many common molecular targets that regulate cell growth, survival, and tumorigenesis.12Feitelson M.A. Reis H.M.G.P.V. Liu J. Lian Z. Pan J. Hepatitis B virus x antigen (HBxAg) and cell cycle control in chronic infection and hepatocarcinogenesis.Front Biosci. 2005; 10: 1558-1572Crossref PubMed Scopus (25) Google Scholar, 14Branda M. Wands J.R. Signal transduction cascades and hepatitis B and C related hepatocellular carcinoma.Hepatology. 2006; 43: 891-902Crossref PubMed Scopus (101) Google Scholar, 24Pang R.W. Lee T.K. Man K. Poon R.T. Fan S.-T. Kwong Y.-L. Tse E. Pin1 expression contributes to hepatic carcinogenesis.J Pathol. 2006; 210: 19-25Crossref PubMed Scopus (57) Google Scholar, 25Lu K.P. Suizu F. Zhou X.Z. Finn G. Lam P. Wulf G. Targeting carcinogenesis: a role for the prolyl isomerase Pin1?.Mol Carcinog. 2006; 45: 397-402Crossref PubMed Scopus (46) Google Scholar Although both proteins can contribute to hepatocarcinogenesis independently, the present findings expose a synergistic and potentially deadly interaction that may accelerate the progression of the disease. In this regard, it would be worthwhile to examine whether the expression of Pin1 can influence the clinical outcome of HBV-infected patients. Another novel and relevant aspect of this work is the finding that Pin1 activity is not only restricted to cellular proteins, but also can target a virally encoded protein and potentially participate in the pathogenesis of HBV-induced HCC. Likewise, it would be important to test if Pin1 could also have some bearing on the role that HBx may play on viral infection and replication and to examine if Pin1 could regulate other foreign proteins. Finally, these observations may also have therapeutic implications. With specific Pin1 inhibitors being developed,25Lu K.P. Suizu F. Zhou X.Z. Finn G. Lam P. Wulf G. Targeting carcinogenesis: a role for the prolyl isomerase Pin1?.Mol Carcinog. 2006; 45: 397-402Crossref PubMed Scopus (46) Google Scholar the application of such molecules in combination with current antiviral therapies could change the course of chronic HBV infection, prevent the development of HCC, or even quell tumor growth. 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" @default.
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• W2119647155 title "Hepatitis B Virus X Protein and Pin1 in Liver Cancer: “Les Liaisons Dangereuses”" @default.
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