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Pin1 interacts with a specific serine-proline motif of hepatitis B virus X-protein to enhance hepatocarcinogenesis.
Gastroenterology 2007; 132(3):1088-103G

Abstract

BACKGROUND AND 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. Glutathione S-transferase pull-down and co-immunoprecipitation experiments were used to validate the physical interaction between Pin1 and HBx. Reporter assay, cell proliferation assay, and xenotransplantation experiments were used to show the functional consequence and importance of Pin1-HBx interaction in hepatocarcinogenesis.

RESULTS

We showed preferential Pin1 overexpression in HBV-related tumors and confirmed the interaction between Pin1 and HBx at the specific serine-proline motif. Pin1 overexpression increased the protein stability of HBx. Furthermore, HBx-mediated transactivation was enhanced by co-expression of Pin1. HepG2 expressing Pin1 and HBx showed a synergistic increase in cellular proliferation, as compared with cells expressing Pin1 or HBx alone. Furthermore, concomitant expression of Pin1 and HBx in the nontumorigenic human hepatocyte cell line MIHA led to a synergistic increase in tumor growth. Finally, in Hep3B cells with suppressed Pin1 expression, HBx-enhanced tumor growth in nude mice was abrogated.

CONCLUSIONS

Pin1 binds HBx to enhance hepatocarcinogenesis in HBV-infected hepatocytes. The discovery of an interaction between Pin1 and HBx will further our understanding of the molecular pathogenic mechanism of HBV-related HCC in human beings.

Authors+Show Affiliations

Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17383430

Citation

Pang, Roberta, et al. "Pin1 Interacts With a Specific Serine-proline Motif of Hepatitis B Virus X-protein to Enhance Hepatocarcinogenesis." Gastroenterology, vol. 132, no. 3, 2007, pp. 1088-103.
Pang R, Lee TK, Poon RT, et al. Pin1 interacts with a specific serine-proline motif of hepatitis B virus X-protein to enhance hepatocarcinogenesis. Gastroenterology. 2007;132(3):1088-103.
Pang, R., Lee, T. K., Poon, R. T., Fan, S. T., Wong, K. B., Kwong, Y. L., & Tse, E. (2007). Pin1 interacts with a specific serine-proline motif of hepatitis B virus X-protein to enhance hepatocarcinogenesis. Gastroenterology, 132(3), pp. 1088-103.
Pang R, et al. Pin1 Interacts With a Specific Serine-proline Motif of Hepatitis B Virus X-protein to Enhance Hepatocarcinogenesis. Gastroenterology. 2007;132(3):1088-103. PubMed PMID: 17383430.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pin1 interacts with a specific serine-proline motif of hepatitis B virus X-protein to enhance hepatocarcinogenesis. AU - Pang,Roberta, AU - Lee,Terence K W, AU - Poon,Ronnie T P, AU - Fan,Sheung T, AU - Wong,Kam B, AU - Kwong,Yok-Lam, AU - Tse,Eric, Y1 - 2006/12/19/ PY - 2006/08/04/received PY - 2006/11/30/accepted PY - 2007/3/27/pubmed PY - 2007/4/27/medline PY - 2007/3/27/entrez SP - 1088 EP - 103 JF - Gastroenterology JO - Gastroenterology VL - 132 IS - 3 N2 - BACKGROUND AND 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. Glutathione S-transferase pull-down and co-immunoprecipitation experiments were used to validate the physical interaction between Pin1 and HBx. Reporter assay, cell proliferation assay, and xenotransplantation experiments were used to show the functional consequence and importance of Pin1-HBx interaction in hepatocarcinogenesis. RESULTS: We showed preferential Pin1 overexpression in HBV-related tumors and confirmed the interaction between Pin1 and HBx at the specific serine-proline motif. Pin1 overexpression increased the protein stability of HBx. Furthermore, HBx-mediated transactivation was enhanced by co-expression of Pin1. HepG2 expressing Pin1 and HBx showed a synergistic increase in cellular proliferation, as compared with cells expressing Pin1 or HBx alone. Furthermore, concomitant expression of Pin1 and HBx in the nontumorigenic human hepatocyte cell line MIHA led to a synergistic increase in tumor growth. Finally, in Hep3B cells with suppressed Pin1 expression, HBx-enhanced tumor growth in nude mice was abrogated. CONCLUSIONS: Pin1 binds HBx to enhance hepatocarcinogenesis in HBV-infected hepatocytes. The discovery of an interaction between Pin1 and HBx will further our understanding of the molecular pathogenic mechanism of HBV-related HCC in human beings. SN - 0016-5085 UR - https://www.unboundmedicine.com/medline/citation/17383430/Pin1_interacts_with_a_specific_serine_proline_motif_of_hepatitis_B_virus_X_protein_to_enhance_hepatocarcinogenesis_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0016-5085(06)02680-1 DB - PRIME DP - Unbound Medicine ER -