miR-134 in extracellular vesicles reduces triple-negative breast cancer aggression and increases drug sensitivity

Abstract

Exosomes (EVs) have relevance in cell-to-cell communication carrying pro-tumorigenic factors that participate in oncogenesis and drug resistance and are proposed to have potential as self-delivery systems. Advancing on our studies of EVs in triple-negative breast cancer, here we more comprehensively analysed isogenic cell line variants and their EV populations, tissues cell line variants and their EV populations, as well as breast tumour and normal tissues. Profiling 384 miRNAs showed EV miRNA content to be highly representative of their cells of origin. miRNAs most substantially down-regulated in aggressive cells and their EVs originated from 14q32. Analysis of miR-134, the most substantially down-regulated miRNA, supported its clinical relevance in breast tumours compared to matched normal breast tissue. Functional studies indicated that miR-134 controls STAT5B which, in turn, controls Hsp90. miR-134 delivered by direct transfection into Hs578Ts(i)8 cells (in which it was greatly down-regulated) reduced STAT5B, Hsp90, and Bcl-2 levels, reduced cellular proliferation, and enhanced cisplatin-induced apoptosis. Delivery via miR-134-enriched EVs also reduced STAT5B and Hsp90, reduced cellular migration and invasion, and enhanced sensitivity to anti-Hsp90 drugs. While the differing effects achieved by transfection or EV delivery are likely to be, at least partly, due to specific amounts of miR-134 delivered by these routes, these EV-based studies identified miRNA-134 as a potential biomarker and therapeutic for breast cancer.

Astragaloside IV Induced miR-134 Expression Reduces EMT and Increases Chemotherapeutic Sensitivity by Suppressing CREB1 Signaling in Colorectal Cancer Cell Line SW-480

“…Previous reports revealed miRNA-134 functioned as intrinsic suppressor and increased drug sensitivity in various cancers [29, 30]. Overexpression or downregulation of miR-134 expression by miR-134 mimics or miR-134 inhibitors in Small Cell Lung Cancer (SCLC) cell lines were significantly correlated with inhibition of cell growth and induction of apoptotic cell death [31].…”

Hsa-miR-134 suppresses non-small cell lung cancer (NSCLC) development through down-regulation of CCND1

“…Although dysregulation of miRNAs was reported in numerous of human cancers [53], aberrant expression and potential role of miRNAs in lung cancers were under studied. Decreased expression of miR-134 has been reported by miRNA profile studies on melanoma [25], breast cancer [26, 27], ovarian cancer [28], renal cell carcinoma [29], endometrial cancer [30], embryonal carcinoma [31], hepatocellular carcinoma [32, 33], head and neck carcinoma [34] and glioblastoma [35]. Our results also indicated that miR-134 was decreased in NSCLC tissues and cells, indicating disorder of miR-134 was an early event of NSCLC tumorigenesis.…”

“…MiR-134, a recognized tumor-suppressing miRNA, has been shown to be down-regulated in a variety of diseases [24] including cancers, such as melanoma [25], breast cancer [26, 27], ovarian cancer [28], renal cell carcinoma [29], endometrial cancer [30], embryonal carcinoma [31], hepatocellular carcinoma [32, 33], head and neck carcinoma [34] and glioblastoma [35]. It is also reported that miR-134 regulates small cell lung cancer (SCLC) cell H69 growth and apoptosis by suppressing the ERK1/2 signaling pathway and directly targeting WWOX gene [36].…”

Exosome-Based Cancer Therapy: Implication for Targeting Cancer Stem Cells

“…Furthermore, miR-122-loaded exosomes dramatically reduced human hepatocellular carcinoma growth in xenograft mice (Lou et al, 2015). MiR-134-enriched exosomes can reduce breast cancer cell migration, invasion, and enhance their chemosensitivity through suppressing transcription 5B, heat shock protein 90, and Bcl-2 (O'Brien et al, 2015). MSC-derived exosomes loaded with anti-miR-9 are able to reverse the expression of multidrug transporters in drug resistant glioblastoma multiforme cells, leading to an enhanced sensitivity to temozolomide treatment (Munoz et al, 2013).…”