Resveratrol promotes MICA/B expression and natural killer cell lysis of breast cancer cells by suppressing c-Myc/miR-17 pathway

// Jie Pan 1, * , Jiaying Shen 1, * , Wengong Si 1 , Chengyong Du 2 , Danni Chen 1 , Liang Xu 1, 3 , Minya Yao 2 , Peifen Fu 2 and Weimin Fan 1, 4 1 Program of Innovative Cancer Therapeutics, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Zhejiang Province, Hangzhou 310003, China 2 Breast Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Zhejiang Province, Hangzhou 310003, China 3 Clinical Research Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Zhejiang Province, Hangzhou 310003, China 4 Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA * These authors have contributed equally to this work Correspondence to: Weimin Fan, email: fanw@zju.edu.cn Keywords: resveratrol, NKG2D, miR-17, MICA, c-Myc Received: January 25, 2017 Accepted: April 26, 2017 Published: July 22, 2017 ABSTRACT Major histocompatibility complex class I chain-related proteins A and B (MICA and MICB) are important ligands for recognition of tumor cells by immune effector cells. Here, we report that resveratrol upregulated the protein and mRNA expression of MICA and MICB in breast cancer cells, which in turn promoted breast cancer cell lysis by natural killer (NK) cells in vitro and in vivo . Antibodies against NK group 2 member D blocked this effect. The 3′-untranslated regions of MICA and MICB were found to be direct binding targets of miR-17. MICA and MICB expression increased or decreased in breast cancer cells transfected with a miR-17 inhibitor or mimic, respectively. C-Myc overexpression/knockdown increased/decreased transcription of the miR-17-92 cluster host gene. Resveratrol suppressed c-Myc expression, which inhibited the transcription of miR-17-92 cluster, thereby downregulating miR-17. MiR-17 expression correlated inversely with MICA and MICB expression and overall survival in two sets of breast cancer specimens. Resveratrol thus upregulates MICA and MICB by suppressing the c-Myc/miR-17 pathway in breast cancer cells, and increases the cytolysis of breast cancer cells by NK cells. This suggests resveratrol has the potential to promote antitumor immune responses in breast cancer patients.