Ran GTPase-activating protein 1 is a therapeutic target in diffuse large B-cell lymphoma.

Lymphoma-specific biomarkers contribute to therapeutic strategies and the study of tumorigenesis. Diffuse large B-cell lymphoma (DLBCL) is the most common type of malignant lymphoma. However, only 50% of patients experience long-term survival after current treatment; therefore, developing novel ther...

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Autores principales:	Kung-Chao Chang, Wei-Chao Chang, Yao Chang, Liang-Yi Hung, Chien-Hsien Lai, Yu-Min Yeh, Yu-Wei Chou, Chung-Hsuan Chen
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/132c1591d29a4d2797e33f88ef9fba88
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spelling	oai:doaj.org-article:132c1591d29a4d2797e33f88ef9fba882021-11-18T08:48:02ZRan GTPase-activating protein 1 is a therapeutic target in diffuse large B-cell lymphoma.1932-620310.1371/journal.pone.0079863https://doaj.org/article/132c1591d29a4d2797e33f88ef9fba882013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24223200/?tool=EBIhttps://doaj.org/toc/1932-6203Lymphoma-specific biomarkers contribute to therapeutic strategies and the study of tumorigenesis. Diffuse large B-cell lymphoma (DLBCL) is the most common type of malignant lymphoma. However, only 50% of patients experience long-term survival after current treatment; therefore, developing novel therapeutic strategies is warranted. Comparative proteomic analysis of two DLBCL lines with a B-lymphoblastoid cell line (LCL) showed differential expression of Ran GTPase-activating protein 1 (RanGAP1) between them, which was confirmed using immunoblotting. Immunostaining showed that the majority of DLBCLs (92%, 46/50) were RanGAP1(+), while reactive lymphoid hyperplasia (n = 12) was RanGAP1(+) predominantly in germinal centers. RanGAP1 was also highly expressed in other B-cell lymphomas (BCL, n = 180) with brisk mitotic activity (B-lymphoblastic lymphoma/leukemia: 93%, and Burkitt lymphoma: 95%) or cell-cycle dysregulation (mantle cell lymphoma: 83%, and Hodgkin's lymphoma 91%). Interestingly, serum RanGAP1 level was higher in patients with high-grade BCL (1.71 ± 2.28 ng/mL, n = 62) than in low-grade BCL (0.75 ± 2.12 ng/mL, n = 52) and healthy controls (0.55 ± 1.58 ng/mL, n = 75) (high-grade BCL vs. low-grade BCL, p = 0.002; high-grade BCL vs. control, p < 0.001, Mann-Whitney U test). In vitro, RNA interference of RanGAP1 showed no effect on LCL but enhanced DLBCL cell death (41% vs. 60%; p = 0.035) and cell-cycle arrest (G0/G1: 39% vs. 49%, G2/M: 19.0% vs. 7.5%; p = 0.030) along with decreased expression of TPX2 and Aurora kinases, the central regulators of mitotic cell division. Furthermore, ON 01910.Na (Estybon), a multikinase inhibitor induced cell death, mitotic cell arrest, and hyperphosphorylation of RanGAP1 in DLBCL cell lines but no effects in normal B and T cells. Therefore, RanGAP1 is a promising marker and therapeutic target for aggressive B-cell lymphoma, especially DLBCL.Kung-Chao ChangWei-Chao ChangYao ChangLiang-Yi HungChien-Hsien LaiYu-Min YehYu-Wei ChouChung-Hsuan ChenPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 11, p e79863 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Kung-Chao Chang Wei-Chao Chang Yao Chang Liang-Yi Hung Chien-Hsien Lai Yu-Min Yeh Yu-Wei Chou Chung-Hsuan Chen Ran GTPase-activating protein 1 is a therapeutic target in diffuse large B-cell lymphoma.
description	Lymphoma-specific biomarkers contribute to therapeutic strategies and the study of tumorigenesis. Diffuse large B-cell lymphoma (DLBCL) is the most common type of malignant lymphoma. However, only 50% of patients experience long-term survival after current treatment; therefore, developing novel therapeutic strategies is warranted. Comparative proteomic analysis of two DLBCL lines with a B-lymphoblastoid cell line (LCL) showed differential expression of Ran GTPase-activating protein 1 (RanGAP1) between them, which was confirmed using immunoblotting. Immunostaining showed that the majority of DLBCLs (92%, 46/50) were RanGAP1(+), while reactive lymphoid hyperplasia (n = 12) was RanGAP1(+) predominantly in germinal centers. RanGAP1 was also highly expressed in other B-cell lymphomas (BCL, n = 180) with brisk mitotic activity (B-lymphoblastic lymphoma/leukemia: 93%, and Burkitt lymphoma: 95%) or cell-cycle dysregulation (mantle cell lymphoma: 83%, and Hodgkin's lymphoma 91%). Interestingly, serum RanGAP1 level was higher in patients with high-grade BCL (1.71 ± 2.28 ng/mL, n = 62) than in low-grade BCL (0.75 ± 2.12 ng/mL, n = 52) and healthy controls (0.55 ± 1.58 ng/mL, n = 75) (high-grade BCL vs. low-grade BCL, p = 0.002; high-grade BCL vs. control, p < 0.001, Mann-Whitney U test). In vitro, RNA interference of RanGAP1 showed no effect on LCL but enhanced DLBCL cell death (41% vs. 60%; p = 0.035) and cell-cycle arrest (G0/G1: 39% vs. 49%, G2/M: 19.0% vs. 7.5%; p = 0.030) along with decreased expression of TPX2 and Aurora kinases, the central regulators of mitotic cell division. Furthermore, ON 01910.Na (Estybon), a multikinase inhibitor induced cell death, mitotic cell arrest, and hyperphosphorylation of RanGAP1 in DLBCL cell lines but no effects in normal B and T cells. Therefore, RanGAP1 is a promising marker and therapeutic target for aggressive B-cell lymphoma, especially DLBCL.
format	article
author	Kung-Chao Chang Wei-Chao Chang Yao Chang Liang-Yi Hung Chien-Hsien Lai Yu-Min Yeh Yu-Wei Chou Chung-Hsuan Chen
author_facet	Kung-Chao Chang Wei-Chao Chang Yao Chang Liang-Yi Hung Chien-Hsien Lai Yu-Min Yeh Yu-Wei Chou Chung-Hsuan Chen
author_sort	Kung-Chao Chang
title	Ran GTPase-activating protein 1 is a therapeutic target in diffuse large B-cell lymphoma.
title_short	Ran GTPase-activating protein 1 is a therapeutic target in diffuse large B-cell lymphoma.
title_full	Ran GTPase-activating protein 1 is a therapeutic target in diffuse large B-cell lymphoma.
title_fullStr	Ran GTPase-activating protein 1 is a therapeutic target in diffuse large B-cell lymphoma.
title_full_unstemmed	Ran GTPase-activating protein 1 is a therapeutic target in diffuse large B-cell lymphoma.
title_sort	ran gtpase-activating protein 1 is a therapeutic target in diffuse large b-cell lymphoma.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/132c1591d29a4d2797e33f88ef9fba88
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Ran GTPase-activating protein 1 is a therapeutic target in diffuse large B-cell lymphoma.

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