雌激素/miR-338-3p/ADAM17 轴通过抑制 NK 细胞功能增强乳腺癌细胞活力

Natural killer (NK) cells are the critical elements of the innate immune response and implicated in rapidly recognizing and eliminating cancer cells.

However, the tumor-suppressive ability of NK cells is often impaired in several cancer types. The critical roles of microRNAs have been elucidated by increasing evidences, while the regulation of miR-338-3p in anti-tumor activation of NK cells and its relationship with estrogen in breast cancer (BC) are still confusing.

Here, miR-338-3p level was found to be significantly downregulated in BC tissues and estrogen receptor positive (ER + ) cells, this difference was more obvious in ER + patients or BC patients at advanced stage (TNM III and IV). MiR-338-3p level was shown to be downregulated by 17 -estradiol in BC cells (MDA-MB-231 cells and MCF-7) in vitro. MiR-338-3p overexpression decreased disintegrin and metalloprotease-17 (ADAM17) secretion in MDA-MB-231 (ER - ) and MCF-7 (ER + ) cells.

In addition, miR-338-3p overexpression or treatment with anti-ADAM17 antibody could down-regulate granzyme B, CD16, and NKG2D in NK cells, which was reversed by human recombinant ADAM17.

Furthermore, these educated NK cells could promote the viability of MDA-MB-231 or MCF-7 cells. Taken together, our results demonstrate that miR-338-3p was negatively regulated by estrogen in BC cells, impairing NK cell's activity by the up-regulation of ADAM17, and conversely promoted the viability of BC cells.

Therefore, the estrogen/miR-338-3p/ADAM17 axis is critically implicated in BC pathogenesis and may provide potential targets for BC diagnosis and treatment.