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EIF4A3-induced circFIP1L1 represses miR-1253 and promotes radiosensitivity of nasopharyngeal carcinoma

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Abstract

Background

Radiation is currently used to be a mainstay of salvage therapy for nasopharyngeal carcinoma (NPC), however, development of radioresistance largely limits the radiation efficacy. Circular RNAs (circRNAs) have been shown to affect NPC progression, but its role in radioresistance remain unclear.

Methods

The circular structure of circFIP1L1(circ_0069740) was verified by RNA-sequencing, RT-PCR based on gDNA or cDNA, RNase R treatment, and actinomycin D treatment. Cellular localization of circFIP1L1 and miR-1253 was detected by nucleoplasmic separation and/or fluorescence in situ hybridization. Expression of non-coding RNAs and mRNAs was detected by qRT-PCR, protein expression was detected by Western blot. Functionally, EdU, CCK-8, and colony formation experiments were employed to assess cell proliferation, flow cytometry was adopted to estimate cell cycle and apoptosis. Xenograft tumor growth was performed to detect the role of circFIP1L1 in vivo. Mechanistically, we examined the interplay between miR-1253 and circFIP1L1 or EIF4A3 through dual-luciferase reporter assay. The potential regulatory impacts of EIF4A3 on circFIP1L1 or PTEN was examined by RNA immunoprecipitation and RNA pull-down assays.

Results

CircFIP1L1 overexpression and miR-1253 knockdown repressed NPC cell proliferation, facilitated NPC cell apoptosis, and enhanced NPC radiosensitivity. Mechanistically, circFIP1L1 was revealed to repress miR-1253 by binding to it, and EIF4A3 is a target gene of miR-1253. CircFIP1L1 regulated NPC proliferation, apoptosis, and radiosensitivity through miR-1253/EIF4A3. Moreover, we found that EIF4A3 bound to FIP1L1 mRNA transcript and induced circFIP1L1 formation, and thus stabilizing PTEN mRNA.

Conclusion

Our findings suggested that EIF4A3-induced circFIP1L1 repressed NPC cell proliferation, facilitated NPC cell apoptosis, and enhanced NPC radiosensitivity by miR-1253.

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Data availability

The datasets used or analyzed during the current study are available from the corresponding author on reasonable request.

Code availability

Not applicable.

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Funding

This work was supported by grants from Health Commission of Hunan Province (202203033073); Education Department of Hunan Province (235355).

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Authors and Affiliations

  1. Oncology Department, Affiliated Nanhua Hospital of University of South China, No 336, Dongfeng Road, Hengyang, 421002, Hunan Province, People’s Republic of China

    Xiangqi Zhou, Guangjin Yuan, Sijia Yan & Sanyuan Tang

  2. Oncology Department, The First Affiliated Hospital, University of South China, Hengyang, 421001, Hunan Province, People’s Republic of China

    Yangjie Wu

  3. Otolaryngological Department, The First Affiliated Hospital, University of South China, No 69, Chuanshan Road, Hengyang, 421001, Hunan Province, People’s Republic of China

    Qingshan Jiang

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  1. Xiangqi Zhou
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Contributions

XZ: experimental studies, writing- original draft preparation. GY: data acquisition, writing- reviewing and editing. YW: design, experimental studies. SY: data analysis. QJ: concepts. ST: supervision, writing- reviewing and editing. All the authors approved for the final version.

Corresponding authors

Correspondence to Qingshan Jiang or Sanyuan Tang.

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The authors have no commercial or other associations that might pose a conflict of interest.

Ethical approval

This study was approved by the Ethics Committee of Affiliated Nanhua Hospital of University of South China, and informed consents were provided to each patient.

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Animal manipulates were conducted in accordance with the guidelines approved by the Committee on the Ethics of Animal Experiments of Affiliated Nanhua Hospital of University of South China.

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Supplementary Information

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18_2022_4350_MOESM1_ESM.tif

Supplementary file1 CircFIP1L1 knockdown promoted NPC cell proliferation, inhibited NPC cell apoptosis, and attenuated NPC cell radiosensitivity. (A-C) EdU, CCK-8, and colony formation assays were performed to analyze the effects of circFIP1L1 knockdown on NPC cell proliferation viability. (D and E) Effects of circFIP1L1 knockdown on NPC cell cycle and apoptosis were assessed through flow cytometry analysis. (F) Effects of circFIP1L1 knockdown on NPC cell radiosensitivity were evaluated by flow cytometry analysis under 2 Gy radiation. *, P<0.05, and **, P<0.01. Error bars represented mean ± standard deviation (SD). N=3 (TIF 16763 KB)

18_2022_4350_MOESM2_ESM.tif

Supplementary file2 Bioinformatics analysis of circFIP1L1 target miRNAs and proteins. (A) Venn diagram of target miRNAs identified by circinteractome and circBank. (B) Expression of the RBP proteins upstream of circFIP1L1 (AUF1, DGCR8, EIF4A3, HNRNPC, HuR and IGF2BP1/3) were detected in CNE1 and HONE1 cells treated with 2 Gy radiation (TIF 3244 KB)

18_2022_4350_MOESM3_ESM.tif

Supplementary file3 Effects of EIF4A3 overexpression on NPC cell proliferation and radiosensitivity were reversed by PTEN knockdown. (A) PTEN protein level in CNE1 and HONE1 cells treated with EIF4A3 or/and si-PTEN. (B and C) After treatment with EIF4A3 or/and si-PTEN, CNE1 and HONE1 cells were subjected to proliferation analysis using CCK-8 and colony formation assays. (D and E) CNE1 and HONE1 cells transfected with EIF4A3 or/and si-PTEN were subjected for cell apoptosis analysis using flow cytometry analysis under radiation (2 Gy). *, P<0.05, and **, P<0.01. Error bars represented mean ± standard deviation (SD). N=3 (TIF 3194 KB)

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Zhou, X., Yuan, G., Wu, Y. et al. EIF4A3-induced circFIP1L1 represses miR-1253 and promotes radiosensitivity of nasopharyngeal carcinoma. Cell. Mol. Life Sci. 79, 357 (2022). https://doi.org/10.1007/s00018-022-04350-x

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  • DOI: https://doi.org/10.1007/s00018-022-04350-x

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