Corticotropin-releasing factor induces immune escape of cervical cancer cells by downregulation of NKG2D

Song,Hyunkeun; Park,Hyunjin; Park,Gabin; Kim,Yeong Seok; Lee,Hyun-Kyung; Jin,Dong-Hoon; Kang,Hyung-Sik; Cho,Dae-Ho; Hur,Daeyoung

doi:10.3892/or.2014.3191

Corticotropin-releasing factor induces immune escape of cervical cancer cells by downregulation of NKG2D

Authors:
- Hyunkeun Song
- Hyunjin Park
- Gabin Park
- Yeong Seok Kim
- Hyun-Kyung Lee
- Dong-Hoon Jin
- Hyung-Sik Kang
- Dae-Ho Cho
- Daeyoung Hur
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Affiliations: Department of Anatomy and Research Center for Tumor Immunology, Inje University College of Medicine, Busan 614-735, Republic of Korea, Department of Internal Medicine, Inje University Busan Paik Hospital, Busan 614-735, Republic of Korea, Institute for Innovative Cancer Research, College of Medicine, University of Ulsan, Asan Medical Center, Seoul 138-736, Republic of Korea, School of Biological Sciences and Technology, Chonnam National University, Buk-gu, Gwangju 500-757, Republic of Korea, Department of Life Science, Sookmyung Women's University, Yongsan-ku, Seoul 140-742, Republic of Korea
Published online on: May 16, 2014 https://doi.org/10.3892/or.2014.3191
Pages: 425-430

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Abstract

Corticotropin-releasing factor (CRF), a coordinator of the body's responses to stress, is found in various cancer tissues and cell lines. However, the exact abilities of CRF to manipulate natural killer (NK) cells during immune response have not been studied. NKG2D is an activating receptor that is expressed on most NK and CD8+ T cells. MHC class I-related chain A (MICA) and UL16-binding protein (ULBP) 1, 2 and 3 are well-known ligands for NKG2D. In the present study, we reported our findings regarding the role of CRF in cervical cancer cell survival. Human cervical cancer cell line, HeLa cells, had significantly higher intracellular expression of UL16-binding protein 2 (ULBP2) following CRF treatment but had only slightly increased surface expression of ULBP2. Notably, MMPi (pan-metalloproteases inhibitor) blocked the release of ULBP2 molecules from the surface of HeLa cells. Furthermore, incubating NK cells with culture supernatants from CRF-treated HeLa cells, which contained soluble NKG2D ligand, reduced NK cell activity by decreasing surface expression of NKG2D. Collectively, downregulation of NKG2D by CRF-induced soluble NKG2D ligand provides a potential mechanism by which cervical cancer cells escape NKG2D-mediated attack under stress conditions.

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