miR-181b promotes chemoresistance in breast cancer by regulating Bim expression

Abstract

MicroRNAs are emerging as critical regulators of the initiation and progression of multiple types of human cancers, including breast cancer. In the present study, the expression of miR-181b in breast cancer patient serum and breast cancer cell lines was evaluated. It was demonstrated that the miR-181b level was significantly upregulated in patient serum and breast cancer cell lines compared with that in normal controls. The results of in vitro 3H thymidine incorporation and Transwell migration assay indicated that miR-181b overexpression markedly promoted the proliferation and metastasis of breast cancer cells. These data suggest that miR-181b is a tumor promoter in breast cancer. Furthermore, miR-181b expression was found to be upregulated in doxorubicin (DOX)-resistant T-47D cells (T-47D-R) compared with that in the parental T-47D cells, and upregulation of miR-181b expression decreased the anticancer effect of DOX in the T-47D cells. Mechanistic studies demonstrated that the Bim gene, an essential initiator of apoptosis, was inhibited by miR-181b overexpression. We observed that knockdown of miR-181b by its specific inhibitors significantly re-sensitized the T-47D-R cells to the cytotoxicity of DOX. Importantly, we demonstrated that miR-181b inhibitors increased the level of Bim in the T-47D-R cells, resulting in the loss of mitochondrial membrane potential (MMP) and the activation of caspases caused by DOX. In summary, the results of the present study suggest that miR-181b functions as an oncogene during breast cancer development, and the miR-181b/Bim pathway may be a novel target used to overcome the chemoresistance in breast cancer.

MiR-128 reverses the gefitinib resistance of the lung cancer stem cells by inhibiting the c-met/PI3K/AKT pathway

“…Increasing evidence has indicated that miRNAs are related with the drug-resistance of the tumor cells to cancer therapy [26–28]. Although these researches have demonstrated the responsibility of miRNAs dysregulation for the drug-resistance, the role of miRNAs in regulating the drug-resistance of CSCs is not clear.…”

Onco-miR-130 promotes cell proliferation and migration by targeting TGFβR2 in gastric cancer

“…For example, miR-24 can target Bim [25] and FSCN1 [26], and Bim can both be mediated by miR-24 and miR-181b [27]. Therefore, identification and perfect the pathway connecting miRNA to their target genes will be helpful to highlight the functions of miRNA in various biological processes containing carcinogenesis.…”

The Pervasive Role of the miR-181 Family in Development, Neurodegeneration, and Cancer

“…Furthermore, Yoo et al reported that miR-181b can increase invasiveness and induce epithelial-mesenchymal transition in breast cancer cells by targeting YWHAG (tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein γ) expression [54]. The tumor-promoting function of miR-181b was further demonstrated by Zheng et al who confirmed the up-regulation of miR-181b in breast cancer cell lines and patients and its oncogenetic role in promoting cell proliferation and migration in addition to inducing chemoresistance by targeting the mitochondrial-derived apoptogenic proteins Bim [55]. Similarly, Neel et al reported that miR-181s exhibits pro-migratory and pro-invasive effects in breast cancer cells [84].…”