Studies On Anti-tumor Activity And Immune Regulatory Role Of Modified MiR-34a-5p

MiR-34a-5p-based cancer therapy has entered clinics in 2013 and showed acceptable safety and antitumor activity in patients with refractory advanced solid tumors.However,the clinical trial was terminated in 2016 because of multiple immune-related severe adverse events.In the current study,we revealed a novel mechanism of miR-34a-5p-based augmentation of immune response through triggering NF-?B/B7-H3/TNF-a feedback loop via SIRT1 in colorectal carcinoma.We identified upregulated miR-34a-5p and B7-H3 in colorectal carcinoma.Overexpression of miR-34a-3p and B7-H3 were correlated with poor outcome of patients with colorectal carcinoma.MiR-34a-5p elevated B7-H3 expression through inhibiting SIRT1 and acetylating NF-?B p65 subunit.As a result,B7-H3 induced secretion of autocrine and paracrine pro-inflammatory cytokines including TNF-?,which further promoted p65 acetylation and B7-H3 expression.Then we proposed a new microRNA,with a G-to-C alteration at the 3'-terminal of miR-34a-5p,which reversed miR-34a-5p-mediated immune response through relinquishing SIRT1 inhibition and directly repressing B7-H3.Furthermore,miR-34a-5p₃ significantly inhibits the growth of colorectal cancer cells in vitro and in vivo by targeting B7-H3 and PD-L1.These results suggest that miR-34a-5p₃ abolishes miR-34a-5p-induced immune responses by targeting B7-H3 and could be a promising antitumor therapy for patients.