Blocking of SIRT7/FOXO3a Axis by miR-152-3p Enhances Cisplatin Sensitivity in Breast Cancer.

Abstract

Background: Cisplatin-based chemoresistance is major obstacle for breast cancer (BC) including Triple-negative breast cancer (TNBC). SIRT7 is reportedly involved in the progression of BC, the underlining mechanism in Cisplatin-based chemoresistance in BC remains unclear. This work is to elucidate effects of SIRT7 on cisplatin resistance in breast cancer regulated by miR-152-3p.

Methods: The RNA expression of SIRT7 and miRNAs in breast cancer were available from TCGA database. SIRT7-targeted miRNAs were predicted by TargetScan, miRanda, miRDB databases. The association of SIRT7 expression with predicted miRNA was validated by Luciferase assay. Cell apoptosis was determined by Flow cytometry. Cell viability was detected by CCK8 assay. The mRNA expression was measured by quantitative real-time polymerase chain reaction (qRT-PCR) assay. Protein expression was determined by Western blotting assay.

Results: SIRT7 mRNA levels were dramatically enhanced in BC tissues compared to para-carcinoma tissues, also increased in BC patients with Cisplatin-based chemotherapy containing TNBC compared with those without. The increase of SIRT7 expression was obviously relevant to shorter survive time of them. Importantly, SIRT7 inhibition facilitated Cisplatin-induced cell apoptosis of TNBC (MDA-MB-231 and MDA-MB-468) and non- TNBC (MCF-7). Notably, miR-152-3p was predicted as a negative regulator of SIRT7 by overlapping downregulated miRNAs in BC patients treated with Cisplatin-based chemotherapy and miRNAs to target SIRT7. Mechanically, miR-152-3p blocked SIRT7 to stimulate an activation of FOXO3a, cleaved PARP1 and Caspase-3, sensitizing Cisplatin-induced apoptosis of BC cells.

Conclusions: Inhibition of SIRT7 by miR-152-3p may be a promising strategy against the resistance to cisplatin-based chemotherapy in BC containing TNBC.