HYPOXIA induces lncRNA HOTAIR for recruiting RELA in papillary thyroid cancer cells to upregulate miR-181a and promote angiogenesis

• Published in: Journal of endocrinological investigation Vol. 47; no. 11; pp. 2873 - 2884
• Main Authors: Lu, J., Liu, X., Cen, A., Hong, Y., Wang, Y.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01-11-2024
• Subjects: Angiogenesis; Cell Line, Tumor; Cell Movement - genetics; Cell Proliferation; Endocrinology; GATA6 Transcription Factor - genetics; GATA6 Transcription Factor - metabolism; Gene Expression Regulation, Neoplastic; Humans; Hypoxia - genetics; Hypoxia - metabolism; Internal Medicine; Medicine; Medicine & Public Health; Metabolic Diseases; MicroRNAs - genetics; MicroRNAs - metabolism; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - pathology; Original Article; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; Thyroid Cancer, Papillary - genetics; Thyroid Cancer, Papillary - metabolism; Thyroid Cancer, Papillary - pathology; Thyroid Neoplasms - genetics; Thyroid Neoplasms - metabolism; Thyroid Neoplasms - pathology; Transcription Factor RelA - genetics; Transcription Factor RelA - metabolism; Up-Regulation; HOTAIR; GATA6; MiR181a; PTC; RELA; EGFR
• ISSN: 1720-8386; 1720-8386
• DOI: 10.1007/s40618-024-02388-1

Background
Papillary thyroid carcinoma (PTC) is one of the most common subtypes of thyroid carcinoma. Exosomal miR-181a plays an important role in the development of PTC. This study examined the regulatory mechanism of miR-181a under conditions of hypoxia and its impact on angiogenesis.
Methods
A ribonucleoprotein immunoprecipitation (RIP) experiment was conducted to verify the interaction between HOTAIR and RELA. The relationship between RELA and the miR-181a promoter was detected by ChIP-qPCR. Short hairpin (sh) RNA was designed to knock down HOTAIR in TPC cells. The underlying mechanism of miR-181a was verified by use of dual-luciferase assays and rescue experiments. The regulatory effect of GATA6 on angiogenesis was studied using CCK8, EdU, Transwell, and western blot assays.
Results
A RIP assay showed that HOTAIR could bind to RELA under hypoxic conditions. ChIP-qPCR and dual luciferase assays showed RELA could interact with the miR181a promoter and upregulate miR-181a. Knockdown of HOTAIR downregulated miR-181a in TPC-1 cells, and the downregulation could be rescued by RELA overexpression. MiR-181a downregulated GATA6 in HUVEC cells. Overexpression of GATA6 inhibited HUVEC proliferation, migration, tube formation, and EGFR expression. Exosomal miR-181a promoted angiogenesis by downregulating GATA6 expression.
Conclusion
HOTAIR activated RELA to upregulate miR-181a during hypoxia. Exosomal miR-181a promotes tumor angiogenesis by downregulating GATA6.