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题名:Granzyme B leakage-induced apoptosis is a crucial mechanism of cell death in nasal-type NK/T-cell lymphoma.
作者:Ko YH, Park S, Jin H, Woo H, Lee H, Park C, Kim K. Related Articles, Links
来源:Lab Invest[IF=3.859]. 2007 Mar;87(3):241-50. Epub 2007 Jan 29.
URL :http://dx.doi.org/10.1038/labinvest.3700517
日期:070415
摘要: This study was presented at the 95th Annual Meeting of the United States and Canadian Academy of Pathology, Atlanta, Georgia, February 11C17, 2006.

Young-Hyeh Ko1,2, Sanghui Park1, Heekyung Jin2, Heesook Woo1, Hyunseop Lee1, Chaewha Park3 and Kihyun Kim3

1Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
2Samsung Biochemical Research Institute, Seoul, Korea
3Division of Hematology-Oncology, Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
Correspondence: Dr Y-H Ko, MD, Department of Pathology, Samsung Medical Center, Sungkyunkwan University, 50 Ilwon-dong, Kangnam-gu, Seoul 135-710, Korea. E-mail: yhko@smc.samsung.co.kr

Received 11 June 2006; Revised 28 October 2006; Accepted 25 November 2006; Published online 29 January 2007.

Abstract

This study aims to investigate the role of granzyme B in the apoptosis of nasal-type NK/T-cell lymphoma. Twenty-four nasal-type NK/T-cell lymphomas were examined by TdT-mediated deoxyuridine triphosphate (dUTP)-biotin nick-end labeling (TUNEL) assay and immunohistochemical staining for active caspase 3, poly(ADP-ribose) polymerase (PARP-1/p85)/p85, and Bcl-2. In addition, HANK-1 and NKL cell lines were analyzed using Western blot analysis. Immunoprecipitation was performed to identify the binding of granzyme B and intrinsic serpin proteinase inhibitor 9 (PI-9). To localize granzyme B, immunogold labeling and immunofluorescence staining were performed. The expression level of granzyme B in tumor tissue was correlated with the apoptosis rate (P=0.015), degree of necrosis (P=0.002), and the levels of active caspase 3 (P=0.036) and poly ADP-ribose polymerase (PARP)-1/p85 (P=0.040). The granzyme B-positive HANK-1 cell line showed increased spontaneous cell death compared to the granzyme B-negative NKL cell line. The untreated HANK-1 cells released cytochrome c into the cytosol with cleavage of caspase 3 and PARP-1. Treatment with granzyme B inhibitor and caspase inhibitor decreased the cleavage of PARP-1. By performing immunogold labeling, granzyme B was identified within the cytolytic granules as well as in the cytosol. Confocal microscopy and immunoprecipitation assays confirmed the colocalization of PI-9 and granzyme B, which formed an SDS-resistant complex. These results suggested that granzyme B leakage induces cell death in NK/T-cell lymphomas via both caspase-dependent and -independent mechanisms, and this leads to the extensive necrosis that is commonly seen in NK/T-cell lymphoma.

Keywords: apoptosis, granzyme B, NK/T-cell lympho

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