Granulysin expressed in a humanized mouse model induces apoptotic cell death and suppresses tumorigenicity

Ya Wen Hsiao, Tsung Ching Lai, Yu Hsiang Lin, Chia Yi Su, Jih Jong Lee, Albert Taiching Liao, Yuan Feng Lin, Shu Chen Hsieh, Alexander T.H. Wu, Michael Hsiao

Research output: Contribution to journalArticle

Abstract

Granulysin (GNLY) is a cytolytic and proinflammatory protein expressed in activated human cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. Conventional mouse models cannot adequately address the triggering mechanism and immunopathological pathways in GNLY-associated diseases due to lack of the GNLY gene in the mouse genome. Therefore, we generated a humanized immune system (HIS) mouse model by transplanting human umbilical cord blood mononuclear cells into NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice after sublethally irradiation. We examined the GNLY expression and its effects on tumor growth using this system. Our HIS mice expressed human CD45+, CD4+, CD8+ and CD56+ cells in the peripheral blood and spleen. A high expression level of human Th1/Th2 and NK cytokines was detected, indicating the activation of both T and NK cells. Importantly, we found an elevated level of GNLY in the serum and it was produced by human CTLs and NK cells obtained from the peripheral blood mononuclear cells and spleen cells in the HIS mice. The serum level of GNLY was negatively correlated with the proliferation of transplanted tumor cells in HIS mice. Collectively, our findings strongly supported that HIS mouse as a valuable model for studying human cancer under an intact immune system and the role of GNLY in tumorigenesis.

Original languageEnglish
Pages (from-to)83495-83508
Number of pages14
JournalOncotarget
Volume8
Issue number48
DOIs
Publication statusPublished - 2017

Fingerprint

Cell Death
Immune System
Cytotoxic T-Lymphocytes
Natural Killer Cells
Blood Cells
Spleen
Neoplasms
Natural Killer T-Cells
Serum
Fetal Blood
Carcinogenesis
Genome
Cytokines
Growth
Genes
Proteins

Keywords

  • Apoptosis
  • Granulysin
  • Humanized mouse model
  • Tumorigenicity

ASJC Scopus subject areas

  • Oncology

Cite this

Hsiao, Y. W., Lai, T. C., Lin, Y. H., Su, C. Y., Lee, J. J., Liao, A. T., ... Hsiao, M. (2017). Granulysin expressed in a humanized mouse model induces apoptotic cell death and suppresses tumorigenicity. Oncotarget, 8(48), 83495-83508. https://doi.org/10.18632/oncotarget.11473

Granulysin expressed in a humanized mouse model induces apoptotic cell death and suppresses tumorigenicity. / Hsiao, Ya Wen; Lai, Tsung Ching; Lin, Yu Hsiang; Su, Chia Yi; Lee, Jih Jong; Liao, Albert Taiching; Lin, Yuan Feng; Hsieh, Shu Chen; Wu, Alexander T.H.; Hsiao, Michael.

In: Oncotarget, Vol. 8, No. 48, 2017, p. 83495-83508.

Research output: Contribution to journalArticle

Hsiao, YW, Lai, TC, Lin, YH, Su, CY, Lee, JJ, Liao, AT, Lin, YF, Hsieh, SC, Wu, ATH & Hsiao, M 2017, 'Granulysin expressed in a humanized mouse model induces apoptotic cell death and suppresses tumorigenicity', Oncotarget, vol. 8, no. 48, pp. 83495-83508. https://doi.org/10.18632/oncotarget.11473
Hsiao, Ya Wen ; Lai, Tsung Ching ; Lin, Yu Hsiang ; Su, Chia Yi ; Lee, Jih Jong ; Liao, Albert Taiching ; Lin, Yuan Feng ; Hsieh, Shu Chen ; Wu, Alexander T.H. ; Hsiao, Michael. / Granulysin expressed in a humanized mouse model induces apoptotic cell death and suppresses tumorigenicity. In: Oncotarget. 2017 ; Vol. 8, No. 48. pp. 83495-83508.
@article{ad1d1459017e45c2906d276f26e1d6b9,
title = "Granulysin expressed in a humanized mouse model induces apoptotic cell death and suppresses tumorigenicity",
abstract = "Granulysin (GNLY) is a cytolytic and proinflammatory protein expressed in activated human cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. Conventional mouse models cannot adequately address the triggering mechanism and immunopathological pathways in GNLY-associated diseases due to lack of the GNLY gene in the mouse genome. Therefore, we generated a humanized immune system (HIS) mouse model by transplanting human umbilical cord blood mononuclear cells into NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice after sublethally irradiation. We examined the GNLY expression and its effects on tumor growth using this system. Our HIS mice expressed human CD45+, CD4+, CD8+ and CD56+ cells in the peripheral blood and spleen. A high expression level of human Th1/Th2 and NK cytokines was detected, indicating the activation of both T and NK cells. Importantly, we found an elevated level of GNLY in the serum and it was produced by human CTLs and NK cells obtained from the peripheral blood mononuclear cells and spleen cells in the HIS mice. The serum level of GNLY was negatively correlated with the proliferation of transplanted tumor cells in HIS mice. Collectively, our findings strongly supported that HIS mouse as a valuable model for studying human cancer under an intact immune system and the role of GNLY in tumorigenesis.",
keywords = "Apoptosis, Granulysin, Humanized mouse model, Tumorigenicity",
author = "Hsiao, {Ya Wen} and Lai, {Tsung Ching} and Lin, {Yu Hsiang} and Su, {Chia Yi} and Lee, {Jih Jong} and Liao, {Albert Taiching} and Lin, {Yuan Feng} and Hsieh, {Shu Chen} and Wu, {Alexander T.H.} and Michael Hsiao",
year = "2017",
doi = "10.18632/oncotarget.11473",
language = "English",
volume = "8",
pages = "83495--83508",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals LLC",
number = "48",

}

TY - JOUR

T1 - Granulysin expressed in a humanized mouse model induces apoptotic cell death and suppresses tumorigenicity

AU - Hsiao, Ya Wen

AU - Lai, Tsung Ching

AU - Lin, Yu Hsiang

AU - Su, Chia Yi

AU - Lee, Jih Jong

AU - Liao, Albert Taiching

AU - Lin, Yuan Feng

AU - Hsieh, Shu Chen

AU - Wu, Alexander T.H.

AU - Hsiao, Michael

PY - 2017

Y1 - 2017

N2 - Granulysin (GNLY) is a cytolytic and proinflammatory protein expressed in activated human cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. Conventional mouse models cannot adequately address the triggering mechanism and immunopathological pathways in GNLY-associated diseases due to lack of the GNLY gene in the mouse genome. Therefore, we generated a humanized immune system (HIS) mouse model by transplanting human umbilical cord blood mononuclear cells into NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice after sublethally irradiation. We examined the GNLY expression and its effects on tumor growth using this system. Our HIS mice expressed human CD45+, CD4+, CD8+ and CD56+ cells in the peripheral blood and spleen. A high expression level of human Th1/Th2 and NK cytokines was detected, indicating the activation of both T and NK cells. Importantly, we found an elevated level of GNLY in the serum and it was produced by human CTLs and NK cells obtained from the peripheral blood mononuclear cells and spleen cells in the HIS mice. The serum level of GNLY was negatively correlated with the proliferation of transplanted tumor cells in HIS mice. Collectively, our findings strongly supported that HIS mouse as a valuable model for studying human cancer under an intact immune system and the role of GNLY in tumorigenesis.

AB - Granulysin (GNLY) is a cytolytic and proinflammatory protein expressed in activated human cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. Conventional mouse models cannot adequately address the triggering mechanism and immunopathological pathways in GNLY-associated diseases due to lack of the GNLY gene in the mouse genome. Therefore, we generated a humanized immune system (HIS) mouse model by transplanting human umbilical cord blood mononuclear cells into NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice after sublethally irradiation. We examined the GNLY expression and its effects on tumor growth using this system. Our HIS mice expressed human CD45+, CD4+, CD8+ and CD56+ cells in the peripheral blood and spleen. A high expression level of human Th1/Th2 and NK cytokines was detected, indicating the activation of both T and NK cells. Importantly, we found an elevated level of GNLY in the serum and it was produced by human CTLs and NK cells obtained from the peripheral blood mononuclear cells and spleen cells in the HIS mice. The serum level of GNLY was negatively correlated with the proliferation of transplanted tumor cells in HIS mice. Collectively, our findings strongly supported that HIS mouse as a valuable model for studying human cancer under an intact immune system and the role of GNLY in tumorigenesis.

KW - Apoptosis

KW - Granulysin

KW - Humanized mouse model

KW - Tumorigenicity

UR - http://www.scopus.com/inward/record.url?scp=85031023048&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85031023048&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.11473

DO - 10.18632/oncotarget.11473

M3 - Article

AN - SCOPUS:85031023048

VL - 8

SP - 83495

EP - 83508

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 48

ER -