title: Upregulation of CD54 and downregulation of HLA‑ABC contribute to the novel enhancement of the susceptibility of HL-60 cells to NK cell-mediated cytolysis induced by ATRA plus VPA.
abstract: Enhancement of the susceptibility of HL-60 cells to NK cell-mediated cytolysis induced by all-trans-retinoic acid (ATRA) plus valproate (VPA) was evaluated. In addition to the synergistic effect of ATRA plus VPA on HL-60 cells, the optimal concentration of 1 mM VPA plus 0.5 µM ATRA increased the cytotoxic sensitivity of HL-60 cells to NK cells. The expression of the activated receptors NKp30 and NKG2D on NK-92 cells was higher compared with the levels noted for the other receptors, and the expression of NKG2D ligands MICA/B on HL-60 cells was not significantly upregulated in the ATRA plus VPA goup compared with the control. Moreover, it was observed that the ligands of NKp30 on HL-60 cells presented the same variation trend. As to the co-stimulatory and adhesion molecules on NK-92 and their ligands on HL-60 cells post exposure to ATRA and VPA alone or their combination, there was no obvious change in the expression of CD112, CD48 and CD70 on the HL-60 cells. However, the expression of CD54 on HL-60 cells was significantly upregulated. In contrast, the expression of NKG2A ligands HLA-ABC on HL-60 cells was obviously downregulated. In addition, the expression of HLA-E on the HL-60 cells in the group treated with ATRA plus VPA was not significantly increased. In conclusion, the combination of VPA and ATRA not only induced the differentiation of HL-60 cells, but also induced enhancement of the sensitivity of HL-60 cells to NK cells by downregulating the expression of HLA-ABC and upregulating the expression of CD54, but not MICA/MICB. The results provide experimental and theoretical basis for the clinical combination of a low-dose of ATRA plus VPA for the treatment of leukemia.
authors.affiliation: Department of Hemato-Oncology, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Key Medical Laboratory for Tumor Immunology and Traditional Chinese Medicine Immunology of Shandong, Jinan, Shandong 250062, P.R. China.
authors.forename: Huijuan
authors.initials: H
authors.lastname: Zou
authors.affiliation: Department of Hemato-Oncology, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Key Medical Laboratory for Tumor Immunology and Traditional Chinese Medicine Immunology of Shandong, Jinan, Shandong 250062, P.R. China.
authors.forename: Lianlian
authors.initials: L
authors.lastname: Li
authors.affiliation: School of Medicine and Life Sciences, University of Jinan‑Shandong Academy of Medical Sciences, Jinan, Shandong 250062, P.R. China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of Oncology, Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, P.R. China.
authors.forename: Ruiping
authors.initials: R
authors.lastname: Ma
authors.affiliation: Department of Hemato-Oncology, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Key Medical Laboratory for Tumor Immunology and Traditional Chinese Medicine Immunology of Shandong, Jinan, Shandong 250062, P.R. China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Liao
authors.affiliation: Department of Hemato-Oncology, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Key Medical Laboratory for Tumor Immunology and Traditional Chinese Medicine Immunology of Shandong, Jinan, Shandong 250062, P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Tian
authors.affiliation: Department of Hemato-Oncology, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Key Medical Laboratory for Tumor Immunology and Traditional Chinese Medicine Immunology of Shandong, Jinan, Shandong 250062, P.R. China.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Hemato-Oncology, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Key Medical Laboratory for Tumor Immunology and Traditional Chinese Medicine Immunology of Shandong, Jinan, Shandong 250062, P.R. China.
authors.forename: Xia
authors.initials: X
authors.lastname: Ren
authors.affiliation: Department of Hemato-Oncology, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Key Medical Laboratory for Tumor Immunology and Traditional Chinese Medicine Immunology of Shandong, Jinan, Shandong 250062, P.R. China.
authors.forename: Guanhua
authors.initials: G
authors.lastname: Song
authors.affiliation: Department of Hemato-Oncology, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Key Medical Laboratory for Tumor Immunology and Traditional Chinese Medicine Immunology of Shandong, Jinan, Shandong 250062, P.R. China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Guo
authors.affiliation: Department of Hemato-Oncology, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Key Medical Laboratory for Tumor Immunology and Traditional Chinese Medicine Immunology of Shandong, Jinan, Shandong 250062, P.R. China.
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Hematology, Shengli Oilfield Central Hospital, Dongying, Shandong 257034, P.R. China.
authors.forename: Huifang
authors.initials: H
authors.lastname: Ding
authors.affiliation: Department of Hemato-Oncology, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Key Medical Laboratory for Tumor Immunology and Traditional Chinese Medicine Immunology of Shandong, Jinan, Shandong 250062, P.R. China.
authors.forename: Guosheng
authors.initials: G
authors.lastname: Jiang
mesh_terms: D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D018922:HL-60 Cells; D015234:HLA-A Antigens / Q000235:genetics; D015235:HLA-B Antigens / Q000235:genetics; D015236:HLA-C Antigens / Q000235:genetics; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics* / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D014212:Tretinoin / Q000494:pharmacology*; D015854:Up-Regulation; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D015234:HLA-A Antigens; D015235:HLA-B Antigens; D015236:HLA-C Antigens; D018799:Intercellular Adhesion Molecule-1; D014212:Tretinoin; D014635:Valproic Acid