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

• Published in: Cancer gene therapy 2021-06, Vol.28 (6), p.619-633
• Main Authors: Gao, Yan, Zou, Ting, Liang, Wentong, Zhang, Zhijun, Qie, Mingrong
• Format: Article
• Language: English
• Subjects: 13/31; 13/51; 692/308/53; 692/699/67/68; Adult; Aged; Animals; Antisense RNA; Apoptosis; Biomedical and Life Sciences; Biomedicine; Care and treatment; Cell growth; Cell migration; Cell Movement - genetics; Cell proliferation; Cell Proliferation - genetics; Cervical cancer; Cervix; Development and progression; Diagnosis; Disease Progression; Female; Gene Expression; Gene Expression Regulation, Neoplastic - genetics; Gene targeting; Gene Therapy; Health aspects; Heart; Heterografts; Humans; Mice; MicroRNA; MicroRNAs; MicroRNAs - genetics; Middle Aged; miRNA; Neoplasm Invasiveness - genetics; Neoplasm Invasiveness - pathology; Neural crest; Non-coding RNA; Reporter gene; RNA, Long Noncoding - genetics; Signal transduction; Tissue inhibitor of metalloproteinase 3; Tissue Inhibitor of Metalloproteinase-3 - genetics; Tumorigenesis; Uterine Cervical Neoplasms - genetics; Uterine Cervical Neoplasms - pathology; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - genetics; Xenografts
• ISSN: 0929-1903; 1476-5500
• DOI: 10.1038/s41417-020-00243-y

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.