Human Epididymis Secretory Protein 4 (HE4) Compromises Cytotoxic Mononuclear Cells via Inducing Dual Specificity Phosphatase 6

While selective overexpression of serum clinical biomarker Human epididymis secretory protein 4 (HE4) is indicative of ovarian cancer tumorigenesis, much is still known about the mechanistic role of the HE4 gene or gene product. Here, we examine the role of the secretory glycoprotein HE4 in ovarian...

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Published inFrontiers in pharmacology Vol. 10; p. 216
Main Authors James, Nicole E, Oliver, Matthew T, Ribeiro, Jennifer R, Cantillo, Evelyn, Rowswell-Turner, Rachael B, Kim, Kyu-Kwang, Chichester, 3rd, Clinton O, DiSilvestro, Paul A, Moore, Richard G, Singh, Rakesh K, Yano, Naohiro, Zhao, Ting C
Format Journal Article
LanguageEnglish
Published Switzerland Frontiers Media S.A 19.03.2019
Subjects
CD8 T cells
DUSP6
HE4
ovarian cancer
Pharmacology
tumor immunology
tumor immunology
ovarian cancer
HE4
DUSP6
CD8 T cells
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Abstract While selective overexpression of serum clinical biomarker Human epididymis secretory protein 4 (HE4) is indicative of ovarian cancer tumorigenesis, much is still known about the mechanistic role of the HE4 gene or gene product. Here, we examine the role of the secretory glycoprotein HE4 in ovarian cancer immune evasion. Through modified subtractive hybridization analyses of human peripheral blood mononuclear cells (PBMCs), we have characterized gene targets of HE4 and established a preliminary mechanism of HE4-mediated immune failure in ovarian tumors. Dual specificity phosphatase 6 (DUSP6) emerged as the most upregulated gene in PBMCs upon exposure to HE4. DUSP6 was found to be upregulated in CD8 cells and CD56 cells. HE4 exposure reduced Erk1/2 phosphorylation specifically in these cell populations and the effect was erased by co-incubation with a DUSP6 inhibitor, (E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one (BCI). In co-culture with PBMCs, HE4-silenced SKOV3 human ovarian cancer cells exhibited enhanced proliferation upon exposure to external HE4, while this effect was partially attenuated by adding BCI to the culture. Additionally, the reversal effects of BCI were erased in the co-culture with CD8 / CD56 cell deprived PBMCs. Taken together, these findings show that HE4 enhances tumorigenesis of ovarian cancer by compromising cytotoxic CD8 and CD56 cells through upregulation of self-produced DUSP6.
AbstractList While selective overexpression of serum clinical biomarker Human epididymis secretory protein 4 (HE4) is indicative of ovarian cancer tumorigenesis, much is still known about the mechanistic role of the HE4 gene or gene product. Here, we examine the role of the secretory glycoprotein HE4 in ovarian cancer immune evasion. Through modified subtractive hybridization analyses of human peripheral blood mononuclear cells (PBMCs), we have characterized gene targets of HE4 and established a preliminary mechanism of HE4-mediated immune failure in ovarian tumors. Dual specificity phosphatase 6 (DUSP6) emerged as the most upregulated gene in PBMCs upon exposure to HE4. DUSP6 was found to be upregulated in CD8 cells and CD56 cells. HE4 exposure reduced Erk1/2 phosphorylation specifically in these cell populations and the effect was erased by co-incubation with a DUSP6 inhibitor, (E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one (BCI). In co-culture with PBMCs, HE4-silenced SKOV3 human ovarian cancer cells exhibited enhanced proliferation upon exposure to external HE4, while this effect was partially attenuated by adding BCI to the culture. Additionally, the reversal effects of BCI were erased in the co-culture with CD8 / CD56 cell deprived PBMCs. Taken together, these findings show that HE4 enhances tumorigenesis of ovarian cancer by compromising cytotoxic CD8 and CD56 cells through upregulation of self-produced DUSP6.
While selective overexpression of serum clinical biomarker Human epididymis secretory protein 4 (HE4) is indicative of ovarian cancer tumorigenesis, much is still known about the mechanistic role of the HE4 gene or gene product. Here, we examine the role of the secretory glycoprotein HE4 in ovarian cancer immune evasion. Through modified subtractive hybridization analyses of human peripheral blood mononuclear cells (PBMCs), we have characterized gene targets of HE4 and established a preliminary mechanism of HE4-mediated immune failure in ovarian tumors. Dual specificity phosphatase 6 (DUSP6) emerged as the most upregulated gene in PBMCs upon in vitro exposure to HE4. DUSP6 was found to be upregulated in CD8+ cells and CD56+ cells. HE4 exposure reduced Erk1/2 phosphorylation specifically in these cell populations and the effect was erased by co-incubation with a DUSP6 inhibitor, (E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one (BCI). In co-culture with PBMCs, HE4-silenced SKOV3 human ovarian cancer cells exhibited enhanced proliferation upon exposure to external HE4, while this effect was partially attenuated by adding BCI to the culture. Additionally, the reversal effects of BCI were erased in the co-culture with CD8+ / CD56+ cell deprived PBMCs. Taken together, these findings show that HE4 enhances tumorigenesis of ovarian cancer by compromising cytotoxic CD8+ and CD56+ cells through upregulation of self-produced DUSP6.
While selective overexpression of serum clinical biomarker Human epididymis secretory protein 4 (HE4) is indicative of ovarian cancer tumorigenesis, much is still known about the mechanistic role of the HE4 gene or gene product. Here, we examine the role of the secretory glycoprotein HE4 in ovarian cancer immune evasion. Through modified subtractive hybridization analyses of human peripheral blood mononuclear cells (PBMCs), we have characterized gene targets of HE4 and established a preliminary mechanism of HE4-mediated immune failure in ovarian tumors. Dual specificity phosphatase 6 (DUSP6) emerged as the most upregulated gene in PBMCs upon in vitro exposure to HE4. DUSP6 was found to be upregulated in CD8 + cells and CD56 + cells. HE4 exposure reduced Erk1/2 phosphorylation specifically in these cell populations and the effect was erased by co-incubation with a DUSP6 inhibitor, (E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one (BCI). In co-culture with PBMCs, HE4-silenced SKOV3 human ovarian cancer cells exhibited enhanced proliferation upon exposure to external HE4, while this effect was partially attenuated by adding BCI to the culture. Additionally, the reversal effects of BCI were erased in the co-culture with CD8 + / CD56 + cell deprived PBMCs. Taken together, these findings show that HE4 enhances tumorigenesis of ovarian cancer by compromising cytotoxic CD8 + and CD56 + cells through upregulation of self-produced DUSP6.
Author Oliver, Matthew T
Rowswell-Turner, Rachael B
James, Nicole E
Yano, Naohiro
Ribeiro, Jennifer R
Moore, Richard G
Cantillo, Evelyn
Singh, Rakesh K
Kim, Kyu-Kwang
Zhao, Ting C
DiSilvestro, Paul A
Chichester, 3rd, Clinton O
AuthorAffiliation 4 Department of Surgery, Roger Williams Medical Center, Boston University Medical School , Providence, RI , United States
3 Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Wilmot Cancer Institute, University of Rochester Medical Center , Rochester, NY , United States
2 Department of Pharmacy, University of Rhode Island , Kingston, RI , United States
1 Program in Women's Oncology, Department of Obstetrics and Gynecology, Women & Infants Hospital, Warren Alpert Medical School of Brown University , Providence, RI , United States
AuthorAffiliation_xml – name: 3 Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Wilmot Cancer Institute, University of Rochester Medical Center , Rochester, NY , United States
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– name: 4 Department of Surgery, Roger Williams Medical Center, Boston University Medical School , Providence, RI , United States
– name: 1 Program in Women's Oncology, Department of Obstetrics and Gynecology, Women & Infants Hospital, Warren Alpert Medical School of Brown University , Providence, RI , United States
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Copyright Copyright © 2019 James, Oliver, Ribeiro, Cantillo, Rowswell-Turner, Kim, Chichester, DiSilvestro, Moore, Singh, Yano and Zhao. 2019 James, Oliver, Ribeiro, Cantillo, Rowswell-Turner, Kim, Chichester III, DiSilvestro, Moore, Singh, Yano and Zhao
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Keywords tumor immunology
ovarian cancer
HE4
DUSP6
CD8 T cells
Language English
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This article was submitted to Translational Pharmacology, a section of the journal Frontiers in Pharmacology
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Edited by: Lei Xi, Virginia Commonwealth University, United States
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Snippet While selective overexpression of serum clinical biomarker Human epididymis secretory protein 4 (HE4) is indicative of ovarian cancer tumorigenesis, much is...
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SubjectTerms CD8 T cells
DUSP6
HE4
ovarian cancer
Pharmacology
tumor immunology
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Title Human Epididymis Secretory Protein 4 (HE4) Compromises Cytotoxic Mononuclear Cells via Inducing Dual Specificity Phosphatase 6
URI https://www.ncbi.nlm.nih.gov/pubmed/30941033
https://search.proquest.com/docview/2202673975
https://pubmed.ncbi.nlm.nih.gov/PMC6433991
https://doaj.org/article/1d40d022ef174c3eb530873e0bececed
Volume 10
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