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...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-03-01
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| Series: | Frontiers in Pharmacology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fphar.2019.00216/full |
| _version_ | 1831791451461124096 |
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| author | Nicole E. James Nicole E. James Matthew T. Oliver Jennifer R. Ribeiro Evelyn Cantillo Rachael B. Rowswell-Turner Kyu-Kwang Kim Clinton O. Chichester Paul A. DiSilvestro Richard G. Moore Rakesh K. Singh Rakesh K. Singh Naohiro Yano Naohiro Yano Ting C. Zhao |
| author_facet | Nicole E. James Nicole E. James Matthew T. Oliver Jennifer R. Ribeiro Evelyn Cantillo Rachael B. Rowswell-Turner Kyu-Kwang Kim Clinton O. Chichester Paul A. DiSilvestro Richard G. Moore Rakesh K. Singh Rakesh K. Singh Naohiro Yano Naohiro Yano Ting C. Zhao |
| author_sort | Nicole E. James |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-22T14:53:01Z |
| format | Article |
| id | doaj.art-1d40d022ef174c3eb530873e0bececed |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-22T14:53:01Z |
| publishDate | 2019-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-1d40d022ef174c3eb530873e0bececed2022-12-21T18:22:16ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122019-03-011010.3389/fphar.2019.00216439465Human Epididymis Secretory Protein 4 (HE4) Compromises Cytotoxic Mononuclear Cells via Inducing Dual Specificity Phosphatase 6Nicole E. James0Nicole E. James1Matthew T. Oliver2Jennifer R. Ribeiro3Evelyn Cantillo4Rachael B. Rowswell-Turner5Kyu-Kwang Kim6Clinton O. Chichester7Paul A. DiSilvestro8Richard G. Moore9Rakesh K. Singh10Rakesh K. Singh11Naohiro Yano12Naohiro Yano13Ting C. Zhao14Program in Women's Oncology, Department of Obstetrics and Gynecology, Women & Infants Hospital, Warren Alpert Medical School of Brown University, Providence, RI, United StatesDepartment of Pharmacy, University of Rhode Island, Kingston, RI, United StatesProgram in Women's Oncology, Department of Obstetrics and Gynecology, Women & Infants Hospital, Warren Alpert Medical School of Brown University, Providence, RI, United StatesProgram in Women's Oncology, Department of Obstetrics and Gynecology, Women & Infants Hospital, Warren Alpert Medical School of Brown University, Providence, RI, United StatesProgram in Women's Oncology, Department of Obstetrics and Gynecology, Women & Infants Hospital, Warren Alpert Medical School of Brown University, Providence, RI, United StatesDivision of Gynecologic Oncology, Department of Obstetrics and Gynecology, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, United StatesDivision of Gynecologic Oncology, Department of Obstetrics and Gynecology, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, United StatesDepartment of Pharmacy, University of Rhode Island, Kingston, RI, United StatesProgram in Women's Oncology, Department of Obstetrics and Gynecology, Women & Infants Hospital, Warren Alpert Medical School of Brown University, Providence, RI, United StatesDivision of Gynecologic Oncology, Department of Obstetrics and Gynecology, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, United StatesProgram in Women's Oncology, Department of Obstetrics and Gynecology, Women & Infants Hospital, Warren Alpert Medical School of Brown University, Providence, RI, United StatesDivision of Gynecologic Oncology, Department of Obstetrics and Gynecology, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, United StatesProgram in Women's Oncology, Department of Obstetrics and Gynecology, Women & Infants Hospital, Warren Alpert Medical School of Brown University, Providence, RI, United StatesDepartment of Surgery, Roger Williams Medical Center, Boston University Medical School, Providence, RI, United StatesDepartment of Surgery, Roger Williams Medical Center, Boston University Medical School, Providence, RI, United StatesWhile 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.https://www.frontiersin.org/article/10.3389/fphar.2019.00216/fullHE4ovarian cancerDUSP6CD8 T cellstumor immunology |
| spellingShingle | Nicole E. James Nicole E. James Matthew T. Oliver Jennifer R. Ribeiro Evelyn Cantillo Rachael B. Rowswell-Turner Kyu-Kwang Kim Clinton O. Chichester Paul A. DiSilvestro Richard G. Moore Rakesh K. Singh Rakesh K. Singh Naohiro Yano Naohiro Yano Ting C. Zhao Human Epididymis Secretory Protein 4 (HE4) Compromises Cytotoxic Mononuclear Cells via Inducing Dual Specificity Phosphatase 6 Frontiers in Pharmacology HE4 ovarian cancer DUSP6 CD8 T cells tumor immunology |
| title | Human Epididymis Secretory Protein 4 (HE4) Compromises Cytotoxic Mononuclear Cells via Inducing Dual Specificity Phosphatase 6 |
| title_full | Human Epididymis Secretory Protein 4 (HE4) Compromises Cytotoxic Mononuclear Cells via Inducing Dual Specificity Phosphatase 6 |
| title_fullStr | Human Epididymis Secretory Protein 4 (HE4) Compromises Cytotoxic Mononuclear Cells via Inducing Dual Specificity Phosphatase 6 |
| title_full_unstemmed | Human Epididymis Secretory Protein 4 (HE4) Compromises Cytotoxic Mononuclear Cells via Inducing Dual Specificity Phosphatase 6 |
| title_short | Human Epididymis Secretory Protein 4 (HE4) Compromises Cytotoxic Mononuclear Cells via Inducing Dual Specificity Phosphatase 6 |
| title_sort | human epididymis secretory protein 4 he4 compromises cytotoxic mononuclear cells via inducing dual specificity phosphatase 6 |
| topic | HE4 ovarian cancer DUSP6 CD8 T cells tumor immunology |
| url | https://www.frontiersin.org/article/10.3389/fphar.2019.00216/full |
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