MicroRNA-577/EIF5A2 axis suppressed the proliferation of DDP-resistant nasopharyngeal carcinoma cells by blocking TGF-β signaling pathway.

Diaminodichoroplatinum (DDP) resistance of tumor cells is the culprit of nasopharyngeal carcinoma (NPC) treatment failure. MicroRNA-577 is lowly expressed in NPC tissues, but relevant mechanism is poorly studied. Therefore, this study investigated the role of microRNA-577 in NPC cells with DDP resistance and its mechanism. DDP-resistant NPC cells were established by treatment with DDP at increased concentrations (2, 4, 6, 8, or 10 μg/mL). MicroRNA-577 and EIF5A2 mRNA expressions were detected by qRT-PCR. Cell biological behaviors were assessed via cell function experiments. Expressions of epithelial mesenchymal transformation (EMT)-related proteins were quantified by western blot. The targeting relationship between eukaryotic translation initiation factor 5A2 (EIF5A2) and microRNA-577 was verified through dual-luciferase reporter assay. The tumor volume and weight were measured after subcutaneous tumorigenesis in mice. As observed from the results, microRNA-577 expression was reduced in NPC cells and DDP-resistant NPC cells. Up-regulated microRNA-577 suppressed the malignant behaviors and EMT of DDP-resistant NPC cells, and facilitated cell apoptosis. MicroRNA-577 targeted EIF5A2, and overexpressed EIF5A2 reversed the above effects of up-regulated microRNA-577 on DDP-resistant NPC cells. Besides, EIF5A2 positively regulated TGF-β signaling pathway, and TGF-β treatment offset the promoting effects of EIF5A2 silencing on apoptosis of DDP-resistant NPC cells. Up-regulated microRNA-577 suppressed the proliferation of DDP-resistant NPC cells, and down-regulated the levels of EIF5A2 and TGF-β as well as EMT in vivo. Collectively, microRNA-577/EIF5A2 axis hinders the EMT progression through the blockage of TGF-β signaling pathway, so as to inhibit the proliferation of DDP-resistant NPC.

Wu R ，Zhong Q ，Liu H ，Liu S ... -  《-》

MicroRNA-588 regulates migration capacity and invasiveness of renal cancer cells by targeting EIF5A2.

Dong JS ，Wu B ，Zha ZL 《-》

MicroRNA-296-5p inhibits cell metastasis and invasion in nasopharyngeal carcinoma by reversing transforming growth factor-β-induced epithelial-mesenchymal transition.

Chen M ，Chen C ，Luo H ，Ren J ，Dai Q ，Hu W ，Zhou K ，Tang X ，Li X ... -  《-》

miR-205-5p regulates epithelial-mesenchymal transition by targeting PTEN via PI3K/AKT signaling pathway in cisplatin-resistant nasopharyngeal carcinoma cells.

Epithelial-mesenchymal transition (EMT) symbolizes the predominant program of advanced-stage cancer, it is critical in cancer progression, metastasis, and chemotherapy resistance. In this study, the metastatic properties of nasopharyngeal carcinoma (NPC) cells were evaluated by morphological examination, wound healing assay, migration and invasion assay. Western blotting and qRT-PCR were used to ascertain the expression of markers which were associated with EMT. The effects of miR-205-5p on invasion, migration, EMT and proliferation of NPC cells were evaluated and the molecular mechanisms of their interaction were explored. In this study, we manifested firstly that the expression of miR-205-5p in cisplatin-resistant NPC cell line HNE1/DDP was obviously up-regulated than that in its parental cell line HNE1. Then we analyzed the specific role of miR-205-5p through functional assays by transfecting specific mimics and inhibitors. The results indicated that low expression of miR-205-5p restrained EMT progression of HNE1/DDP cells. Further studies on the mechanism of miR-205-5p manifested that PTEN was a downstream candidate gene of miR-205-5p, down-regulated PTEN expression could counteract the effect of miR-205-5p inhibitors, and the regulation of EMT by miR-205-5p on HNE1/DDP cells depended on the PI3K/AKT signaling pathway. Overall, our results indicated that miR-205-5p was targeting PTEN to regulate EMT through the PI3K/AKT pathway. This study will supply a new treatment target for advanced NPC.

Zhang P ，Lu X ，Shi Z ，Li X ，Zhang Y ，Zhao S ，Liu H ... -  《-》

SATB1 Knockdown Inhibits Proliferation and Invasion and Decreases Chemoradiation Resistance in Nasopharyngeal Carcinoma Cells by Reversing EMT and Suppressing MMP-9.

Background: Special AT-rich sequence binding protein 1 (SATB1) is a chromatin organizer and transcriptional regulator which regulate numerous cellular processes through effects on multiple gene expression. SATB1 is associated with drug resistance in several cancers. Whether SATB1 involves radiation resistance in nasopharyngeal carcinoma (NPC) and underlying mechanism of SATB1 to participate in chemoradiotherapy resistance in NPC have not been elaborated. Methods: Chemoradioresistant NPC cell lines 5-8F/DDP (cisplatin) and 5-8F/R (radiation) were developed from 5-8F cell line. The expressions of SATB1, MMP-9 and EMT markers (Vimentin and E-cadherin) in these cell lines were examined by reverse transcription-quantitative (RT-q) PCR and western blot (WB) analysis. Cell viabilities of 5-8F/DDP treated with various concentrations of DDP and 5-8F/R irradiated with various doses of X-ray at the indicated time were investigated by MTT test. SATB1 was silenced in 5-8F/DDP and 5-8F/R cells by short hairpin RNA, and then the expressions of SATB1, MMP-9, Vimentin and E-cadherin were evaluated by RT-qPCR and WB analysis; the abilities of cell proliferation and invasion were assessed using MTT and transwell assays, respectively. Drug and radiation resistance assays were performed after SATB1 knockdown and cell viability was detected by MTT method. Results: SATB1, MMP-9 and Vimentin were markedly upregulated in 5-8F/DDP and 5-8F/R cells compared with 5-8F cell, whereas E-cadherin was obviously downregulated. 5-8F/DDP and 5-8F/R cells displayed drug and radiation resistance to DDP or X-irradiation, respectively, while DDP or X-irradiation inhibited 5-8F cell viability in a time- and dose-dependent manner. Subsequently, knockdown of SATB1 resulted in decreased MMP-9 and Vimentin expression and increased E-cadherin expression in 5-8F/DDP and 5-8F/R. Furthermore, silencing of SATB1 suppressed proliferative and invasive abilities of 5-8F/DDP and 5-8F/R cells. Additionally, SATB1 knockdown reduced drug resistance of 5-8F/DDP cell to DDP and decreased radiation resistance of 5-8F/R cell to X-ray. Conclusion: These results suggest that high expression of SATB1 plays an important role in the malignant behavior of NPC and leads to X-radiation and drug resistance in NPC through promoting EMT process and enhancing MMP-9 expression. SATB1 may be a promising therapeutic target for aggressive and chemoradiation resistant NPC.

Zhou D ，Ye C ，Pan Z ，Deng Y ... -  《International Journal of Medical Sciences》