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CircMAN1A2 contributes to nasopharyngeal carcinoma progression via enhancing the ubiquitination of ATMIN through miR-135a-3p/UBR5 axis

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Abstract

Recently, the dysregulation of circRNAs has been increasingly implicated in the pathogenesis of nasopharyngeal carcinoma (NPC). Among these circRNAs, circMAN1A2 has been highlighted for the up-regulated expression in NPC, whereas the underlying mechanisms have not been clearly established. Thus, the aim of this study was to delineate the tumor-supporting role of circMAN1A2 in the oncogenesis and metastases of NPC. We validated through qRT-PCR that circMAN1A2 was highly expressed in NPC tissues and NPC cells. Survival analysis through Kaplan–Meier method showed that the overall survival, disease-free survival, and distant metastasis-free survival of patients was negatively correlated with the expression of circMAN1A2. Then, gain- and loss-of function assays demonstrated that circMAN1A2 knockdown could impede the proliferation, migration, invasion, and EMT in NPC cells. Further, we conducted dual luciferase reporter gene, RIP, and RNA pull down assays, unveiling that circMAN1A2 functioned as a sponge of miR-135a-3p, and miR-135a-3p targeted UBR5. Additionally, UBR5 interacted with ATMIN to foster the ubiquitination of ATMIN, thereby expediting the malignant behaviors of NPC cells as well as the lung and inguinal lymph node metastases of NPC tumors in vivo. Together, our study uncovered the tumor-initiating and pro-metastatic role of circMAN1A2-miR-135a-3p-UBR5-ATMIN axis in NPC regulation that may be a potential therapeutic target for human NPC.

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The data underlying this article will be shared on reasonable request to the corresponding author.

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Funding

This study was supported by 2019 Henan Medical Science and Technology Research Plan Joint Construction Project (No. LHGJ20190058).

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  1. Qian-Qian Dang, Pei-Hong Li are regarded as co-first authors.

Authors and Affiliations

  1. Department of Radiotherapy, the First Affiliated Hospital of Zhengzhou University, No. 1, East Jianshe Road, Zhengzhou, 450018, Henan Province, People’s Republic of China

    Qian-Qian Dang, Pei-Hong Li, Juan Wang, Jing-Yi Zhao, Su-Nan Zhai, Ying-Juan Zheng & Dao-Ke Yang

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Contributions

DKY conceived and designed research. QQD performed experiments. JW interpreted results of experiments. JYZ analyzed data. SNZ prepared figures. YJZ drafted paper. DKY and PHL edited and revised manuscript. All authors read and approved final version of manuscript.

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Correspondence to Ying-Juan Zheng or Dao-Ke Yang.

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The authors declare that they have no competing interests.

Ethical approval and consent to participate

The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the First Affiliated Hospital of Zhengzhou University (Approval number: 2016-KY-142). All patients or legal guardians provided written informed consents. Animal experiments were approved by the Animal Care and Use Committee of the First Affiliated Hospital of Zhengzhou University (Approval number: KY-2021-0728) and performed in accordance with Guide for the Care and Use of Laboratory Animals.

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Dang, QQ., Li, PH., Wang, J. et al. CircMAN1A2 contributes to nasopharyngeal carcinoma progression via enhancing the ubiquitination of ATMIN through miR-135a-3p/UBR5 axis. Human Cell 36, 657–675 (2023). https://doi.org/10.1007/s13577-022-00831-0

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