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LncRNA PVT1 induces aggressive vasculogenic mimicry formation through activating the STAT3/Slug axis and epithelial-to-mesenchymal transition in gastric cancer

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Abstract

Purpose

Vasculogenic mimicry (VM), a vessel-like network formed by highly aggressive tumor cells, plays an important role in accelerating cancer progression. This special vascularization pattern is closely associated with a poor prognosis in various cancers. As yet, however, the regulatory mechanism of VM formation is largely unknown. In this study, we assess whether the long noncoding RNA PVT1 is involved in VM generation in gastric cancer.

Methods

VM formation was determined by immunohistochemistry using PAS/CD31 double staining in gastric cancers and Matrigel tube formation in vitro. qRT-PCR and Western blotting were used to assess mRNA and protein expression. Interaction between PVT1 and STAT3 was determined using a RNA pull-down assay. Luciferase reporter and chromatin immunoprecipitation assays were performed to evaluate transcriptional activity of STAT3 on the Slug gene promoter.

Results

We found that PVT1 can induce VM generation both in vitro and in vivo. Mechanistically, we found that PVT1 interacted with and activated STAT3 through a 850–1770 nt fragment. PVT1 facilitated STAT3 recruitment to the Slug promoter and transcriptionally enhanced Slug expression, thereby triggering epithelial-to-mesenchymal transition (EMT) and VM capillary formation. STAT3 inhibition effectively blocked PVT1-mediated VM. In primary gastric cancer samples, a positive correlation was found between PVT1 and Slug upregulation, and patients with a high PVT1 and Slug expression exhibited markedly shorter survival times.

Conclusion

Our results shed light on the role of PVT1 in gastric cancer cell-dependent VM formation. Our findings provide valuable clues for the design of new anti-angiogenic therapeutic strategies. The PVT1/STAT3 axis may serve as a potential target in gastric cancer treatment.

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Acknowledgments

This study was supported by the Natural Science Foundation of China (81672378 and 81201521).

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Authors and Affiliations

  1. Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, 200040, People’s Republic of China

    Jing Zhao, Yunyun Qin, Guangjian Huang & Lunxiu Qin

  2. Cancer Metastasis Institute, Fudan University, Shanghai, 200040, People’s Republic of China

    Jing Zhao & Lunxiu Qin

  3. Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, People’s Republic of China

    Jing Wu & Wenhong Zhang

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  1. Jing Zhao
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Contributions

Lunxiu Qin, Guangjian Huang and Wenhong Zhang designed the study. Material preparation, experiment operation and data analysis were mainly performed by Jing Zhao, Jing Wu and Qin Yunyun. The first draft of the manuscript was written by Jing Zhao, Wenhong Zhang Guangjian Huang and Lunxiu Qin. All authors commented on previous versions of the manuscript and approved the final manuscript.

Corresponding authors

Correspondence to Wenhong Zhang, Guangjian Huang or Lunxiu Qin.

Ethics declarations

Each of the enrolled patients has provided written informed consent. The study protocol was approved by the Human Research Ethics Committee of Huashan Hospital of Fudan University. The animal experiments were approved by the Institutional Animal Care and Use Committee at Huashan Hospital of Fudan University, and performed in line with the USA NIH laboratory animal care and usage guidelines.

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The authors declare no conflict of interest.

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Zhao, J., Wu, J., Qin, Y. et al. LncRNA PVT1 induces aggressive vasculogenic mimicry formation through activating the STAT3/Slug axis and epithelial-to-mesenchymal transition in gastric cancer. Cell Oncol. 43, 863–876 (2020). https://doi.org/10.1007/s13402-020-00532-6

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