title: Cisplatin enhances NK cells immunotherapy efficacy to suppress HCC progression via altering the androgen receptor (AR)-ULBP2 signals.
abstract: The aim of this study is to investigate the influence of cisplatin on the efficacy of natural killer (NK) cells immunotherapy to suppress HCC progression, and provide valuable information on better application of cisplatin in clinical settings. By using in vitro cell cytotoxicity test and in vivo liver orthotopic xenograft mice model, we identified the role of cisplatin in modulating NK cells cytotoxicity. Luciferase report assay and chromatin immunoprecipitation assay were applied for mechanism dissection. Immunohistochemistry is performed for sample staining. We found cisplatin could enhance the efficacy of NK cells immunotherapy to better suppress HCC progression via altering the androgen receptor (AR)-UL16-binding protein 2 (ULBP2) signals both in vitro and in vivo. Mechanism dissection revealed that cisplatin could suppress AR expression via two distinct ways: increasing miR-34a-5p to suppress AR expression and altering the ubiquitination to accelerate the AR protein degradation. The suppressed AR might then function through up-regulating ULBP2, a natural-killer group 2 member D ligand, to enhance the cytotoxicity of NK cells. Together, these results indicated an unrecognized favoring effect of cisplatin in HCC treatment. By suppressing AR in HCC, cisplatin could up-regulate cytotoxicity of NK cells to better target HCC. This finding may provide a potential new approach to control HCC by combining traditional chemotherapy with immunotherapy.
authors.affiliation: Chawnshang Chang Liver Cancer Center, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou 310016, China; George Whipple Lab for Cancer Research, Departments of Pathology and Urology, The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Shi
authors.affiliation: Chawnshang Chang Liver Cancer Center, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou 310016, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Lin
authors.affiliation: Chawnshang Chang Liver Cancer Center, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou 310016, China.
authors.forename: Gonghui
authors.initials: G
authors.lastname: Li
authors.affiliation: George Whipple Lab for Cancer Research, Departments of Pathology and Urology, The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Yin
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Chawnshang Chang Liver Cancer Center, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou 310016, China.
authors.forename: Jiliang
authors.initials: J
authors.lastname: Shen
authors.affiliation: Chawnshang Chang Liver Cancer Center, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou 310016, China; George Whipple Lab for Cancer Research, Departments of Pathology and Urology, The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Junjie
authors.initials: J
authors.lastname: Xu
authors.affiliation: Collaborative Innovation Center of Biotherapy, Chengdu 610041, China.
authors.forename: Changyi
authors.initials: C
authors.lastname: Lin
authors.affiliation: George Whipple Lab for Cancer Research, Departments of Pathology and Urology, The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Shuyuan
authors.initials: S
authors.lastname: Yeh
authors.affiliation: Chawnshang Chang Liver Cancer Center, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou 310016, China. Electronic address: cxjzu@hotmail.com.
authors.forename: Xiujun
authors.initials: X
authors.lastname: Cai
authors.affiliation: George Whipple Lab for Cancer Research, Departments of Pathology and Urology, The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USA; Sex Hormone Research Center, China Medical University/Hospital, Taichung 404, Taiwan. Electronic address: chang@urmc.rochester.edu.
authors.forename: Chawnshang
authors.initials: C
authors.lastname: Chang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D008024:Ligands; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008297:Male; D008819:Mice, Nude; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism; D011485:Protein Binding; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D014162:Transfection; D054875:Ubiquitination; D023041:Xenograft Model Antitumor Assays
chemical_list: C410798:AR protein, human; D000970:Antineoplastic Agents; D058851:GPI-Linked Proteins; D036341:Intercellular Signaling Peptides and Proteins; C527085:KLRK1 protein, human; D008024:Ligands; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011944:Receptors, Androgen; C423230:ULBP2 protein, human; D002945:Cisplatin
keywords: Androgen receptor; Liver cancer; Natural killer cells