Extracellular miR-1246 promotes lung cancer cell proliferation and enhances radioresistance by directly targeting DR5

Abstract

MiRNAs in the circulation have been demonstrated to be a type of signaling molecule involved in intercellular communication but little is known about their role in regulating radiosensitivity. This study aims to investigate the effects of extracellular miRNAs induced by ionizing radiation (IR) on cell proliferation and radiosensitivity. The miRNAs in the conditioned medium (CM) from irradiated and non-irradiated A549 lung cancer cells were compared using a microarray assay and the profiles of 21 miRNAs up and down-regulated by radiation were confirmed by qRT-PCR. One of these miRNAs, miR-1246, was especially abundant outside the cells and had a much higher level compared with that inside of cells. The expressions of miR-1246 in both A549 and H446 cells increased along with irradiation dose and the time post-irradiation. By labeling exosomes and miR-1246 with different fluorescence dyes, it was found that the extracellular miR-1246 could shuttle from its donor cells to other recipient cells by a non-exosome associated pathway. Moreover, the treatments of cells with miR-1246 mimic or its antisense inhibitor showed that the extracellular miR-1246 could enhance the proliferation and radioresistance of lung cancer cells. A luciferase reporter-gene transfer experiment demonstrated that the death receptor 5 (DR5) was the direct target of miR-1246, and the kinetics of DR5 expression was opposite to that of miR-1246 in the irradiated cells. Our results show that the oncogene-like extracellular miR-1246 could act as a signaling messenger between irradiated and non-irradiated cells, more importantly, it contributes to cell radioresistance by directly suppressing the DR5 gene.

Exosomal microRNA miR-1246 induces cell motility and invasion through the regulation of DENND2D in oral squamous cell carcinoma

“…Therefore, we excluded miR-342–3p from further investigation and continued exploring the functional mechanism of miR-1246 . Recently, extracellular miR-1246 has been reported to promote lung cancer proliferation and enhance radioresistance2728. Importantly, in our study, we found that DENND2D is a direct target of miR-1246 and demonstrated a gene expression pattern that resembled that of HOC313-LM cells (Fig.…”

“…The most salient finding was a set of 11 miRNAs that are commonly upregulated in HOC313-LM cells at the cellular and exosomal level (Table 1). Based on these results, we focused on seven miRNAs, miR-17, miR-30a-3p, miR-30a-5p, miR-92a, miR-181a, miR-342–3p and miR-1246 , all of which have been reported as oncogenic miRNAs (oncomiRs)22232425262728. Using quantitative RT-PCR (qRT-PCR), we could validate the differential expression of six of these miRNAs (all except miR-92a ) in cells and exosomes (Supplementary Fig.…”

Cisplatin-resistant lung cancer cell–derived exosomes increase cisplatin resistance of recipient cells in exosomal miR-100–5p-dependent manner

“…9 Therefore, the roles that miRNAs play in exosomes are gaining increased attention. [10][11][12] Recently, accumulating evidence proved that exosomes could participate in communication of tumor cells. 13,14 Corcoran et al found that exosomes may play an important role in docetaxel resistance of prostate cancer in vitro observations.…”

Potential role of exosomes in cancer therapy

“…Yuan et al. showed that exosomal miR‐1246 could promote proliferation of lung cancer cells and enhance their radioresistance by directly suppressing the DR5 gene . Expression of miR‐29a‐3p and miR‐150‐5p in secreted exosomes was decreased with radiation exposure.…”