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STAT3 regulates miR93-mediated apoptosis through inhibiting DAPK1 in renal cell carcinoma

Cancer Gene Therapy volume 28, pages 502–513 (2021)Cite this article

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Abstract

Signal transducer and activator of transcription 3 (STAT3) is an essential member of the STAT family. STAT3 regulates diverse genes that mediate inflammatory reactions, cell survival, proliferation, and angiogenesis, and it is aberrantly upregulated and activated in various types of malignancies. Furthermore, STAT3 signalling is involved in multiple feedback loops and pathways. In this study, we demonstrate that miR-93-3p plays an oncogenic role in renal cell carcinoma (RCC) by enhancing RCC cell proliferation and suppressing apoptosis. In addition, STAT3 can regulate the transcription of miR-93 by directly binding its promoter region. miR-93 can inhibit death-associated protein kinase 1 (DAPK1) at the protein level. Moreover, STAT3 can block DAPK1 expression at the RNA level. Importantly, we verified that DAPK1 overexpression in turn suppresses the entry of activated STAT3 into the cell nucleus. Thus, this study reveals a potential continuously activated signalling transduction pathway, STAT3-miR93-DAPK1, and may provide a novel clinical therapeutic approach for RCC.

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Fig. 1: miR-93 promoted RCC cells proliferation in vivo and vitro.
Fig. 2: miR-93 suppressed the protein level of DAPK1 to down-regulated RCC cells apoptosis.
Fig. 3: STAT3 up-regulated the expression miR-93.
Fig. 4: STAT3, as a transcription factor, bound with the promoter region of miR-93.
Fig. 5: STAT3 inhibited the mRNA and protein level of DAPK1, and DAPK1 deactivated STAT3.
Fig. 6: STAT3 regulates miR93-mediated apoptosis through inhibiting DAPK1 in Renal cell carcinoma.

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Acknowledgements

We are particularly grateful to Professor Xueshan Qiu for his timely help.

Fundings

This work was supported by Shenyang Plan Project of Science and Technology (Grant No. F19-112-4-098), National key R & D plan key research projects of precision medicine (2017YFC0908000), China Medical University’s 2018 discipline promotion program. Funding agency did not participate in the design of the study and collection, analysis and interpretation of data and in writing the manuscript.

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  1. Department of Urology, First Hospital of China Medical University, 110001, Shenyang, China

    Yang Du & Chuize Kong

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  1. Yang Du
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  2. Chuize Kong
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YD designed, performed the experiments, organized data and wrote the paper. CK acquired funding, established the urology laboratory, provided the required equipment and instruments, supervised assays, contributed to the critical reading of the paper, generated the figures, and gave final approval of the paper.

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Correspondence to Chuize Kong.

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Du, Y., Kong, C. STAT3 regulates miR93-mediated apoptosis through inhibiting DAPK1 in renal cell carcinoma. Cancer Gene Ther 28, 502–513 (2021). https://doi.org/10.1038/s41417-020-00235-y

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