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MiR-338-5p enhances the radiosensitivity of esophageal squamous cell carcinoma by inducing apoptosis through targeting survivin.

ABSTRACT: Radioresistance is a challenge in the treatment of esophageal squamous cell carcinoma (ESCC). MicroRNAs (miRNAs) are known to play an important role in the functional modification of cancer cells and recent studies have reported miRNA-mediated radiotherapy resistance. However, further research is necessary to reveal the regulation mechanisms, and treatment strategies using miRNA are yet to be established for ESCC. We compared the miRNA expression profiles of ESCC parental (TE-4) and acquired radioresistance (TE-4R) cell lines using a miRNA microarray and qRT-PCR. Our data showed that miR-338-5p, one of the target miRNA biomarkers, was significantly downregulated in TE-4R. Ectopic overexpression of miR-338-5p induced apoptosis and sensitivity to radiation treatment by interfering with survivin, which is a known inhibitor of apoptosis. Overexpression of survivin reversed miR-338-5p-induced apoptosis. Tumor xenograft experiments indicated that therapeutic delivery of the miR-338-5p mimics via direct injection into tumor mass increased sensitivity to radiation therapy. In conclusion, our findings suggest that miR-338-5p is a potential radiosensitizer and may be a therapeutic biomarker for radioresistant in ESCC.

SUBMITTER: Park M

PROVIDER: S-EPMC5589838 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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MiR-338-5p enhances the radiosensitivity of esophageal squamous cell carcinoma by inducing apoptosis through targeting survivin.

Park Misun M Yoon Hyeon-Joon HJ Kang Moon Chul MC Kwon Junhye J Lee Hae Won HW

Scientific reports 20170907 1

Radioresistance is a challenge in the treatment of esophageal squamous cell carcinoma (ESCC). MicroRNAs (miRNAs) are known to play an important role in the functional modification of cancer cells and recent studies have reported miRNA-mediated radiotherapy resistance. However, further research is necessary to reveal the regulation mechanisms, and treatment strategies using miRNA are yet to be established for ESCC. We compared the miRNA expression profiles of ESCC parental (TE-4) and acquired rad ...[more]

PMID: 28883406

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Project description:PurposeStrategies to increase radiosensitivity are urgently needed. Combining radiosensitizing reagents with radiotherapy could improve the outcome of cancer treatment. Some preclinical studies showed that sepantronium bromide (YM155) could sensitize cancer cells to radiation by inhibiting the survivin protein. In this study, we try to investigate the function of YM155 on radiosensitivity of esophageal squamous cell carcinoma (ESCC) cells.Materials and methodsESCC cell lines were treated with radiation and YM155, and the radiation efficacy was evaluated by cell counting kit-8 assay and clonogenic survival assay. Cell senescence was measured by senescence-associated β-galactosidase staining. Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay, fluorescein isothiocyanate-labeled Annexin V/propidium iodide assay, and poly ADP-ribose polymerase cleavage were used to detect apoptosis. KYSE150 xenografts model was used to test the efficacy of radiation combined with YM155.ResultsYM155 could inhibit the upregulation of survivin induced by radiation in all ESCC cell lines, but the efficacy of radiosensitization varied in different cell lines. Radiation-induced senescence in KYSE150 and KYSE410 cells, and the combination with YM155 inhibited senescence and promoted apoptosis of ESCC cells, thereby enhancing radiosensitivity. Combination with YM155 and radiation delayed the growth of KYSE150 xenografts in nude mice by switching radiation-induced senescence to apoptosis. When p21 was inhibited in KYSE150 cells, radiation did not induce senescence, and the radiosensitization of YM155 was also attenuated. In KYSE510 and KYSE180 cells, radiation did not induce senescence, and YM155 could not enhance the radiosensitivity.ConclusionOur results suggest a new mechanism that YM155 might sensitize ESCC cells to radiation by switching radiation-induced senescence to apoptosis. The major determinant of radiosensitization by YM155 might be the induction of senescence by radiation.

Project description:BackgroundChemoresistance is one of the major obstacles for cancer therapy in the clinic. Circular RNAs (circRNAs) are involved in the pathogenesis of esophageal squamous cell carcinoma (ESCC) and chemoresistance. This study aimed to explore the role and molecular mechanism of circ_0006168 in Taxol resistance of ESCC.MethodsThe expression levels of circ_0006168, microRNA-194-5p (miR-194-5p) and jumonji domain containing 1C (JMJD1C) were measured by quantitative real-time polymerase chain reaction (qRT-PCR) or western blot. The half-inhibition concentration (IC50) value of Taxol was evaluated by Cell Counting Kit-8 (CCK-8) assay. Cell proliferation was evaluated by CCK-8 and colony formation assays. Cell migration and invasion were detected by transwell assay. Cell apoptosis was determined by flow cytometry. The interaction between miR-194-5p and circ_0006168 or JMJD1C was predicted by bioinformatics analysis (Circinteractome and TargetScan) and verified by dual-luciferase reporter and RNA Immunoprecipitation (RIP) and RNA pull-down assays. The mice xenograft model was established to investigate the roles of circ_0006168 in vivo.ResultsCirc_0006168 and JMJD1C were upregulated and miR-194-5p was downregulated in ESCC tissues, ESCC cells, and Taxol-resistant cells. Functionally, knockdown of circ_0006168 or JMJD1C increased Taxol sensitivity of ESCC in vitro via inhibiting cell proliferation, migration and invasion, and promoting apoptosis. Moreover, circ_0006168 could directly bind to miR-194-5p and JMJD1C was verified as a direct target of miR-194-5p. Mechanically, circ_0006168 was a sponge of miR-194-5p to regulate JMJD1C expression in ESCC cells. Furthermore, JMJD1C overexpression reversed the promotive effect of circ_0006168 knockdown on Taxol sensitivity. Besides, circ_0006168 silence suppressed tumor growth in vivo.ConclusionCirc_0006168 facilitated Taxol resistance in ESCC by regulating miR-194-5p/JMJD1C axis, providing a promising therapeutic target for ESCC chemotherapy.

Project description:Based on its marked overexpression in multiple malignancies and its roles in promoting cell survival and proliferation, survivin is an attractive candidate for targeted therapy. Toward this end, a detailed understanding of the mechanisms regulating survivin expression in different cancer cells will be critical. We have previously shown that the RNA-binding protein (RBP) CUG-BP1 is overexpressed in esophageal cancer cells and post-transcriptionally regulates survivin in these cells. The objective of this study was to investigate the role of microRNAs (miRs) in regulating survivin expression in esophageal cancer cells. Using miR expression profiling analysis, we found that miR-214-3p is one of the most markedly downregulated miRs in two esophageal squamous cancer cell lines compared with esophageal epithelial cells. Interestingly, using miR target prediction programs, both survivin and CUG-BP1 mRNA were found to contain potential binding sites for miR-214-3p. Forced expression of miR-214-3p in esophageal cancer cells leads to a decrease in the mRNA and protein levels of both survivin and CUG-BP1. This effect is due to decreased mRNA stability of both targets. By contrast, silencing miR-214-3p in esophageal epithelial cells leads to an increase in both survivin and CUG-BP1 mRNA and protein. To determine whether the observed effect of miR-214-3p on survivin expression was direct, mediated through CUG-BP1, or both, binding studies utilizing biotin pull-down assays and heterologous luciferase reporter constructs were performed. These demonstrated that the mRNA of survivin and CUG-BP1 each contain two functional miR-214-3p-binding sites as confirmed by mutational analysis. Finally, forced expression of miR-214-3p enhances the sensitivity of esophageal cancer cells to cisplatin-induced apoptosis. This effect is abrogated with rescue expression of survivin or CUG-BP1. These findings suggest that miR-214-3p acts as a tumor suppressor and that its downregulation contributes to chemoresistance in esophageal cancer cells by targeting both survivin and CUG-BP1.

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MiR-338-5p enhances the radiosensitivity of esophageal squamous cell carcinoma by inducing apoptosis through targeting survivin.

Publications

MiR-338-5p enhances the radiosensitivity of esophageal squamous cell carcinoma by inducing apoptosis through targeting survivin.

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