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Long non-coding RNA HAND2-AS1 delays cervical cancer progression via its regulation on the microRNA-21-5p/TIMP3/VEGFA axis

Cancer Gene Therapy volume 28, pages 619–633 (2021)Cite this article

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Abstract

Cervical cancer is a common cause of cancer-related mortality in women. Mounting evidence suggests that long non-coding RNAs (lncRNAs) function vitally in many cancers. In this study, we discovered that the regulation of the heart and neural crest derivatives expressed 2-antisense RNA 1 (HAND2-AS1) in cervical cancer. RT-qPCR was conducted to detect the expression of HAND2-AS1 and microRNA-21-5p (miR-21-5p). The relationship of HAND2-AS1 and miR-21-5p was identified by dual-luciferase reporter gene assay. The roles of HAND2-AS1, miR-21-5p and tissue inhibitor of metalloproteinases-3 (TIMP3) in cervical cancer were accessed via gain- and loss-of-function approaches. The expression of related proteins in the vascular endothelial growth factor A (VEGFA) signaling pathway was detected through Western blot analysis. Finally, xenografts of cervical cancer in nude mice were established to assess the effect of HAND2-AS1 on tumorigenesis in vivo. HAND2-AS1 and TIMP3 were downregulated in cervical cancer, which were identified to be associated with a poor prognosis of patients with cervical cancer. Moreover, HAND2-AS1 was upregulated the expression of TIMP3 through competitively binding to miR-21-5p. Overexpressed HAND2-AS1 or downregulated miR-21-5p inhibited cell proliferation, migration, and invasion while promoting cell apoptosis, in association with increased expression of proteins in VEGFA signaling pathway. These changes were reversed by silencing of TIMP3. Overexpressed HAND2-AS1 reduced the tumor formation ability in nude mice. In summary, HAND2-AS1 may exert inhibitory effects on cervical cancer cell growth and cervical cancer development through its regulation on the miR-21-5p/TIMP3/VEGFA axis. This highlights that HAND2-AS1 may serve as a potential target for cervical cancer diagnosis and treatment.

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Fig. 1: HAND2-AS1 is downregulated in cervical cancer tissues and cells.
Fig. 2: HAND2-AS1 suppresses the development of cervical cancer in vitro.
Fig. 3: HAND2-AS1 bindS competitively to miR-21-5p in cervical cancer.
Fig. 4: HAND2-AS1 increases TIMP3 expression by competitively binding to miR-21-5p.
Fig. 5: HAND2-AS1/miR-21-5p/TIMP3 regulates migration and invasion of cervical cancer cells by affecting the VEGFA signaling pathway.
Fig. 6: HAND2-AS1 inhibits the tumorigenic ability of cervical cancer SiHa cells in vivo.
Fig. 7: The mechanism diagram of the HAND2-AS1/miR-21-5p/TIMP3 axis on cervical cancer development.

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All the data obtained and/or analyzed during the current study were available from the corresponding authors on reasonable request.

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Acknowledgements

This study was supported by Youth Fund of Guizhou Provincial People’s Hospital (No. GZSYQN(2019)02). We acknowledge and appreciate our colleagues for their valuable suggestions and technical assistance for this study.

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Authors and Affiliations

  1. Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu, 610041, P.R. China

    Yan Gao & Mingrong Qie

  2. Department of Gynecology, Guizhou Provincial People’s Hospital, Guiyang, 550002, P.R. China

    Yan Gao, Ting Zou, Wentong Liang & Zhijun Zhang

  3. Key Laboratory of Obstetrics and Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, 610041, P.R. China

    Yan Gao & Mingrong Qie

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Contributions

YG conceived and designed the study. YG, TZ, and WTL collected the data, analyzed the data and wrote the manuscript. YG, ZJZ, and MRQ assisted with the data analyses and participated in the writing of manuscript. All authors read and approved the final manuscript.

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Correspondence to Mingrong Qie.

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The authors declare that they have no conflict of interest.

Ethics statement

The study protocols were approved by the Ethic Committee of Guizhou Provincial People’s Hospital and performed in line with the Declaration of Helsinki. Animal experiments were conducted in strict accordance with the Guide for Care and Use of Laboratory Animals issued by the National Institutes of Health (USA). The protocol of animal experiments was approved by the Institutional Animal Care and Use Committee of Guizhou Provincial People’s Hospital.

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Gao, Y., Zou, T., Liang, W. et al. Long non-coding RNA HAND2-AS1 delays cervical cancer progression via its regulation on the microRNA-21-5p/TIMP3/VEGFA axis. Cancer Gene Ther 28, 619–633 (2021). https://doi.org/10.1038/s41417-020-00243-y

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