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MiR-130b/TNF-α/NF-κB/VEGFA loop inhibits prostate cancer angiogenesis

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Abstract

Background

Angiogenesis is a critical biological process essential for solid cancer growth and metastasis. It has been shown that microRNAs (miRNAs) play a vital role in a variety of biological processes in cancers. However, whether miR-130b is involved in prostate cancer angiogenesis remains ill-defined.

Methods

We performed the miRNA microarray to analyze miRNA expression in human prostate cancer specimens. In vitro gain-of-function assays and loss-of-function assays were conducted to explore the potential functions of miR-130b in human prostate cancer cells. Correlation analysis and dual-luciferase reporter assay were performed to validate whether tumor necrosis factor-α (TNF-α) was a direct target of miR-130b. The Matrigel plug and tumor vascular imaging assays were performed to confirm the anti-angiogenic activity of miR-130b in nude mice.

Results

We found that miR-130b was one of the miRNAs being most significantly downregulated. Subsequently, we found that miR-130b expression was markedly downregulated in human prostate cancer cell lines. Down-regulation of miR-130b in prostate cancer cells significantly promoted the proliferation, invasion and tubule formation of human umbilical vein endothelial cells (HUVECs), while ectopic expression of miR-130b blocked prostate cancer angiogenesis in vitro and in vivo. Mechanistic analyses indicated that tumor necrosis factor-α (TNF-α) was regulated by miR-130b directly. MiR-130b attenuated nuclear factor-κB (NF-κB) signaling and its downstream gene vascular endothelial growth factor-A (VEGFA) by directly inhibiting TNF-α expression. Additionally, subsequent investigations identified that the ectopic level of VEGFA markedly abrogated the anti-angiogenic effect induced by miR-130b. Interestingly, VEGFA could in turn decrease the expression of miR-130b, thus forming a negative feedback loop that drives the angiogenesis of prostate cancer.

Conclusion

These findings show that miR-130b/TNF-α/NF-κB/VEGFA feedback loop is significantly correlated with angiogenesis in prostate cancer and miR-130b could be regarded as potential therapeutic target for prostate cancer anti-angiogenesis treatment.

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Abbreviations

miRNAs:

MicroRNAs

TNF-α:

Tumor necrosis factor-α

NF-κB:

Nuclear factor-κB

HUVECs:

Human umbilical vein endothelial cells

UTRs:

Untranslated regions

CM:

Conditioned medium

CCK-8:

Cell counting kit-8

RT-PCR:

Reverse transcription polymerase chain reaction

wt:

Wild type

mut:

Mutant

EMSA:

Electrophoretic mobility shift assay

VCAM-1:

Vascular cell adhesion molecule-1

ICAM-1:

Intracellular adhesion molecule-1

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Acknowledgements

We are grateful to Dr An Liu (Yueyang, China) for his generous support.

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Authors and Affiliations

  1. Department of Urology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China

    H. Q. Mu, Y. H. He, S. B. Wang, S. Yang, Y. J. Wang, C. J. Nan, Y. F. Bao & Y. H. Chen

  2. Clinical Laboratory, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China

    Q. P. Xie

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  1. H. Q. Mu
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  2. Y. H. He
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Correspondence to Y. H. Chen.

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The authors declare that they have no competing interests.

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This study was approved by the medical ethics committee of The Second Affiliated Hospital & Yuying Children’s Hospital of Wenzhou Medical University, and all the participants signed written informed consent forms.

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Mu, H.Q., He, Y.H., Wang, S.B. et al. MiR-130b/TNF-α/NF-κB/VEGFA loop inhibits prostate cancer angiogenesis. Clin Transl Oncol 22, 111–121 (2020). https://doi.org/10.1007/s12094-019-02217-5

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  • DOI: https://doi.org/10.1007/s12094-019-02217-5

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