Pan Jie, Shen Jiaying, Si Wengong, Du Chengyong, Chen Danni, Xu Liang, Yao Minya, Fu Peifen, Fan Weimin
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.
Breast Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Zhejiang Province, Hangzhou 310003, China.
Oncotarget. 2017 Jul 22;8(39):65743-65758. doi: 10.18632/oncotarget.19445. eCollection 2017 Sep 12.
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 and . Antibodies against NK group 2 member D blocked this effect. The 3'-untranslated regions of and 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. overexpression/knockdown increased/decreased transcription of the cluster host gene. Resveratrol suppressed c-Myc expression, which inhibited the transcription of cluster, thereby downregulating miR-17. MiR-17 expression correlated inversely with and 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.
主要组织相容性复合体I类链相关蛋白A和B（MICA和MICB）是免疫效应细胞识别肿瘤细胞的重要配体。在此，我们报告白藜芦醇上调乳腺癌细胞中MICA和MICB的蛋白和mRNA表达，进而促进自然杀伤（NK）细胞对乳腺癌细胞的裂解，抗NK组2成员D抗体可阻断此效应。发现MICA和MICB的3'非翻译区是miR - 17的直接结合靶点。分别用miR - 17抑制剂或模拟物转染的乳腺癌细胞中，MICA和MICB表达增加或减少。miR - 17过表达/敲低分别增加/减少了MICA和MICB基因簇宿主基因的转录。白藜芦醇抑制c - Myc表达，从而抑制MICA和MICB基因簇的转录，进而下调miR - 17。在两组乳腺癌标本中，miR - 17表达与MICA和MICB表达及总生存期呈负相关。因此，白藜芦醇通过抑制乳腺癌细胞中的c - Myc/miR - 17途径上调MICA和MICB，并增加NK细胞对乳腺癌细胞的细胞溶解作用。这表明白藜芦醇具有促进乳腺癌患者抗肿瘤免疫反应的潜力。
