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

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.

Anticancer potential of naturally occurring immunoepigenetic modulators: A promising avenue?

“…Conversely, resveratrol upregulates MICA/MICB mRNA and protein expression levels in breast cancer cells, which, in turn, enhances breast cancer cytolysis by NK cells in vitro and in vivo. In that study, the authors also demonstrated that resveratrol downregulates c‐Myc–dependent miR‐17 expression, which, if untreated, represses MICA/MICB expression . In agreement with these results, it has been reported that resveratrol prompts cytokine‐induced, killer cell‐mediated cytolysis of promyeloblastic leukemia KG‐1a cells through increased expression of NKG2D ligands and activation of the TNF‐related apoptosis‐inducing ligand (TRAIL) pathway .…”

“…In that study, the authors also demonstrated that resveratrol downregulates c-Myc-dependent miR-17 expression, which, if untreated, represses MICA/MICB expression. 91 In agreement with these results, it has been reported that resveratrol prompts cytokine-induced, killer cellmediated cytolysis of promyeloblastic leukemia KG-1a cells through increased expression of NKG2D ligands and activation of the TNF-related apoptosis-inducing ligand (TRAIL) pathway. 92 Accumulating evidence also suggests that resveratrol can be a good candidate for combination immunotherapy.…”

Traditional Chinese medicine as a cancer treatment: Modern perspectives of ancient but advanced science

“…Curcumin induces apoptosis in multiple myeloma via modulation of the EZH2‐miR‐101 regulatory feedback loop . Resveratrol enhances the expression of major histocompatibility complex class I chain‐related proteins A and B via inhibition of the c‐Myc/miR‐17 pathway in breast cancer cells . Berberine also regulates the expression of microRNAs in various cancers.…”

“…190 Resveratrol enhances the expression of major histocompatibility complex class I chain-related proteins A and B via inhibition of the c-Myc/miR-17 pathway in breast cancer cells. 199 Berberine also regulates the expression of microRNAs in various cancers. In SGC-7901 cells treated with berberine, 347 microRNAs were found to be upregulated and 93 downregulated following miRNA sequencing.…”

Diversity and characterisation of polymorphic 3' untranslated region haplotypes of MICA and MICB genes

“…Several cancers have been found to overexpress miRNAs that can bind the 3'UTR of MICA and MICB genes. Specifically, miR‐17, miR‐20a, and miR‐93 are components of the miR‐17‐92 cluster and all bind to the same regions in both MICA and MICB genes. While this site is conserved among MICB 3'UTR sequences, these miRNAs bind positions 11640‐11662 encompassing the A/G dimorphism at position 11653 of the MICA gene.…”