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MicroRNA-135 inhibits initiation of epithelial-mesenchymal transition in breast cancer by targeting ZNF217 and promoting m6A modification of NANOG

Oncogene volume 41, pages 1742–1751 (2022)Cite this article

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Abstract

MicroRNAs play significant roles in various malignancies, with breast cancer (BC) being no exception. Consequently, we explored the functional mechanism of miR-135 in the progression of BC. In total, 55 pairs of BC and matched adjacent normal tissues were clinically collected from patients, followed by quantification of miR-135 and zinc finger protein 217 (ZNF217) expression patterns in BC tissues and cells. Accordingly, high ZNF217 expression and low miR-135 expression levels were identified in BC tissues and cells. Subsequently, the expressions of miR-135 and ZNF217 were altered to evaluate their effects on BC cell migration, invasion and EMT initiation. It was found that when ZNF217 was silenced or miR-135 was elevated, BC cell malignant behaviors were significantly inhibited, which was reproduced in nude mice for in vivo evidence. Furthermore, dual-luciferase reporter gene assay revealed the presence of direct binding between miR-135 and ZNF217. Subsequent co-immunoprecipitation, methylated-RNA binding protein immunoprecipitation and photoactivatable ribonucleoside enhanced-crosslinking and immunoprecipitation assays further revealed that ZNF217 could upregulate NANOG by reducing N6-methyladenosine levels via methyltransferase-like 13 (METTL3). Collectively, our findings highlighted the role of the miR-135/ZNF217/METTL3/NANOG axis in the progression of BC, emphasizing potential therapeutic targets ZNF217 silencing and miR-135 upregulation in preventing or treating BC.

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Fig. 1: miR-135 is downregulated in BC and targets ZNF217.
Fig. 2: Upregulated miR-135 suppresses EMT initiation, migration and invasion of MCF-7 cells by inhibiting ZNF217 expression.
Fig. 3: ZNF217 interacts with m6A methyltransferase METTL3 to upregulate NANOG by inhibiting the m6A methylation of NANOG in BC cells.
Fig. 4: Silencing of ZNF217 leads to suppressed EMT initiation, migration and invasion of MCF-7 cells by downregulating NANOG.
Fig. 5: miR-135 promotes the m6A methylation of NANOG by targeting ZNF217.
Fig. 6: miR-135 arrests the tumor growth and metastasis in vivo through repression of ZNF217/NANOG.
Fig. 7: A schematic map showing the involvement of miR-135/ZNF217/METTL3/NANOG in the progression of BC.

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All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Material.

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Funding

This study was supported by the National Natural Science Foundation of China (No. 81502656 and No. 81501140).

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Author notes

  1. These authors contributed equally: Li-Ming Xu, Jiao Zhang, Yue Ma.

Authors and Affiliations

  1. Department of Radiotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, 300060, P.R. China

    Li-Ming Xu, Hao Yu, Jun Wang, Li Zhu & Ping Wang

  2. Department of Radiotherapy, Tianjin Medical University Cancer Hospital Airport Hospital, Tianjin, 300308, P.R. China

    Li-Ming Xu & Jun Wang

  3. The First Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, 300060, P.R. China

    Jiao Zhang, Yue Ma & Xu-Chen Cao

  4. Department of Breast Disease, Henan Breast Cancer Center, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, P.R. China

    Jiao Zhang

  5. Department of Anesthesia, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, 300060, P.R. China

    Ya-Jing Yuan

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Contributions

Conception and design of research: L-MX, JZ, YM, PW; performed experiments: YM, Y-JY, HY, L-MX; analyzed data: LZ, JZ, Y-JY, HY; interpreted results of experiments: YM, Y-JY, PW; prepared figures: HY, JW, X-CC; drafted manuscript: HY, JW, X-CC; edited and revised manuscript: L-MX, JZ, LZ; approved final version of manuscript: L-MX, JZ, YM, Y-JY, HY, JW, X-CC, LZ, PW.

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Correspondence to Xu-Chen Cao, Li Zhu or Ping Wang.

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Xu, LM., Zhang, J., Ma, Y. et al. MicroRNA-135 inhibits initiation of epithelial-mesenchymal transition in breast cancer by targeting ZNF217 and promoting m6A modification of NANOG. Oncogene 41, 1742–1751 (2022). https://doi.org/10.1038/s41388-022-02211-2

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