N-peptide of vMIP-Ⅱ reverses paclitaxel-resistance by regulating miRNA-335 in breast cancer.

Acquisition of resistance to paclitaxel is one of the most important problems in treatment of breast cancer patients, but the molecular mechanisms underlying sensitivity to paclitaxel remains elusive. Emerging evidence has demonstrated that microRNAs (miRNAs) play important roles in regulation of cell growth, migration and invasion through inhibiting the expression of its target genes. In our previous studies, we have shown that microRNA-335 (miR‑335) decreased obviously between paclitaxel-resistant (PR) and parental breast cancer cells through miRNA microarray. However, the roles of miR‑335 in breast cancer progression and metastasis are still largely unknown. NT21MP was designed and synthesized as an antagonist with CXCR4 to inhibit cellular proliferation and induce apoptosis. Therefore, the aim of this study was to explore the underlying mechanism of miR‑335 and NT21MP in reverse PR in breast cancer cells. In this study, we found that miR‑335 expression is significantly lower in PR MCF‑7 and SKBR-3 cells (MCF‑7/PR and SKBR-3/PR) compared with their parental MCF‑7 and SKBR-3 cells. Functional experiments showed that overexpression of miR‑335 and NT21MP increased the number of apoptosis cells, arrested cells in G0/G1 phase transition, and suppressed cell migration and invasion in vitro. Dual luciferase assays revealed that SETD8 is a direct target gene of miR‑335. Furthermore, miR‑335 markedly inhibited expression of SETD8 via Wnt/β‑catenin signaling and subsequently inhibited the expression of its downstream genes cyclin D1, and c‑Myc. Additionally, ectopic expression of miR‑335 or depletion of its target gene SETD8 could enhance the sensitivity of PR cells to paclitaxel. Taken together, these date elucidated that NT21MP and miR‑335 mediated PR of breast cancer cells partly through regulation of Wnt/β‑catenin signaling pathway. Activation of miR‑335 or inactivation of SETD8 could be a novel approach for the treatment of breast cancer.