Downregulation of hypermethylated in cancer-1 by miR-4532 promotes adriamycin resistance in breast cancer cells

Abstract

BackgroundMicroRNAs are small RNAs (~ 22 nt) that modulate the expression of thousands of genes in tumors and play important roles in the formation of multidrug resistance. In this study, we firstly investigated that miR-4532 involved in the multidrug resistance formation of breast cancer by targeting hypermethylated in cancer 1 (HIC-1), a tumor-suppressor gene.MethodsTo identify and characterize the possible miRNAs in regulating multidrug resistance, we employed the transcriptome sequencing approach to profile the changes in the expression of miRNAs and their target mRNAs were obtained by bioinformatics prediction. Then the molecular biology experiments were conducted to confirm miR-4532 involved in multidrug resistance formation of breast cancer.ResultsThe luciferase reporter assay experiment was employed to confirm that HIC-1 was the target of miR-4532. Transfection with an miR-4532 mimic indicated miR-4532 mimic significantly increased breast cancer cell resistance to adriamycin. Cell proliferation and invasion assay experiments showed overexpression of HIC-1 inhibited the invasion and metastasis of breast cancer cells. Meanwhile, the interleukin (IL)-6/signal transducer and activator of transcription 3 (STAT3) signaling pathway was confirmed to be involving in multidrug resistance by western blotting experiments.ConclusionsThese results suggest that downregulation of hypermethylated in cancer-1 by miR-4532 could promote adriamycin resistance in breast cancer cells, in which the IL-6/STAT3 pathway was regulated by the HIC-1. This finding might contribute to new therapeutic target for reversal of tumor resistance.Electronic supplementary materialThe online version of this article (10.1186/s12935-018-0616-x) contains supplementary material, which is available to authorized users.

Acute myeloid leukemia cells secrete microRNA-4532-containing exosomes to mediate normal hematopoiesis in hematopoietic stem cells by activating the LDOC1-dependent STAT3 signaling pathway

“…Another study has also highlighted the restored expression of miR-29a in AML [30]. Furthermore, consistent with our results, miR-4532 is highly expressed in breast cancer [12]. Generally, miRs interact with their target genes at specific sites and regulate expression of respective target genes of miRs at a post-transcriptional level [31].…”

“…Furthermore, aberrant miRs have also been implicated in various hematologic malignancies like AML [11]. A study conducted by Feng et al demonstrated the promoting role of miR-4532 overexpression in drug resistance of breast cancer cells [12]. Moreover, miR-4532 was predicted to possess putative binding site of the leucine zipper downregulated in cancer-1 (LDOC1) gene by online prediction software.…”

Role of STAT3 signaling pathway in breast cancer

“…Additionally, TFEB can activate the phosphorylation of STAT3 and AKT to promote breast cancer metastasis receptor (LIFR) could promote STAT3 activation and contribute to breast cancer resistance to Trastuzumabemtansine (T-DM1) [73]. Furthermore, miR-4532 is found to suppress hypermethylated in cancer-1 (HIC-1) and IL-6/STAT3 to promote Adriamycin resistance in breast cancer [74].…”

Comprehensive serum and tissue microRNA profiling in dedifferentiated liposarcoma

“…Meanwhile, other papers have reported that miR-4532 promotes tumor progression and that miR-6126 suppresses tumor progression. Breast cancer cells overexpressing miR-4532 have enhanced cell viability upon administration of adriamycin ( 37 ). miR-4532 targeting hypermethylation in cancer 1 (HIC-1), and overexpression of HIC-1 in breast cancer cells suppresses cell invasion in Transwell assays ( 37 ).…”

“…Breast cancer cells overexpressing miR-4532 have enhanced cell viability upon administration of adriamycin ( 37 ). miR-4532 targeting hypermethylation in cancer 1 (HIC-1), and overexpression of HIC-1 in breast cancer cells suppresses cell invasion in Transwell assays ( 37 ). Conversely, enhanced expression of miR-6126 suppresses ovarian cancer progression.…”