microRNA-211-mediated targeting of the INHBA-TGF-β axis suppresses prostate tumor formation and growth

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Abstract

Prostate cancer (PCa) stem cells increase the sustainability of tumor growth, resulting in high relapse rates in patients with PCa. This goal of the present study was to elucidate the function of microRNA (miR)-211 in PCa stem cell activities. Based on the initial findings from the GSE26910 dataset, inhibin-β A (INHBA) was used for subsequent experiments, and miR-211 was then predicted as a candidate regulatory miR. Subsequently, INHBA and miR-211 were observed to be highly and poorly expressed in PCa tissues, respectively, and miR-211 negatively target INHBA. CD44+CD133+ cells were isolated, and both miR-211 and INHBA expression was altered in these cells to assess functional role of miR-211 and INHBA in PCa stem cells. Overexpression of miR-211 decreased expression of TGF-β1, TGF-β2, smad2, smad3, phosphorylated smad2 and smad3, and stem cell markers. miR-211 upregulation or INHBA knockdown resulted in reductions in the proliferation, invasion, colony-forming ability, sphere-forming ability, and stemness of PCa stem cells but enhanced their apoptosis in vitro. Furthermore, miR-211 upregulation or INHBA silencing decreased tumor growth and cell apoptosis in vivo. Taken together, these results indicate that upregulation of miR-211 has tumor-suppressive properties by inhibiting TGF-β pathway activation via INHBA in PCa stem cells.

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Fig. 1: Hsa-miR-211 might affect PCa progression by binding to 3′UTR of INHBA.
Fig. 2: Isolated CD44+CD133+ cells were selected for the subsequent analysis.
Fig. 3: MiR-211 inhibits activation of the TGF-β pathway by decreasing INHBA expression in PCa stem cells.
Fig. 4: Upregulation of miR-211 inhibits PCa stem cell proliferation and invasion while promoting apoptosis through inhibition of INHBA expression.
Fig. 5: Increased miR-211 expression inhibits the colony-forming ability, sphere-forming capacity, and stemness of PCa stem cells by suppressing INHBA.
Fig. 6: Upregulation of miR-211 impedes the growth rate of PCa tumors in nude mice.
Fig. 7: A mechanistic scheme demonstrating the regulatory role of miR-211 in the biological activities of PCa stem cells.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We would like to acknowledge the reviewers for their helpful comments on this paper.

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ZZ and KW conceived and designed the research, ST and KW participated in the data collection and the data interpretation, ZZ and KW drafted and completed manuscript. All authors read and approved the final manuscript.

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Correspondence to Kai Wang or Shanfeng Tan.

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Zhao, Z., Wang, K. & Tan, S. microRNA-211-mediated targeting of the INHBA-TGF-β axis suppresses prostate tumor formation and growth. Cancer Gene Ther (2020). https://doi.org/10.1038/s41417-020-00237-w

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