ATF2-Induced lncRNA GAS8-AS1 Promotes Autophagy of Thyroid Cancer Cells by Targeting the miR-187-3p/ATG5 and miR-1343-3p/ATG7 Axes

Abstract

Long non-coding RNAs (lncRNAs) play an essential regulatory role in multiple cancers. However, the role of lncRNAs in papillary thyroid carcinoma (PTC) is still unknown. Here, GAS8-AS1, a novel lncRNA that is significantly downregulated in PTC, was selected for further investigation. The roles of GAS8-AS1 in PTC cells were verified by gain- and loss-of-function experiments. The functional mechanism of GAS8-AS1 on the microRNA (miR)-187-3p/ATG5 axis and miR-1343-3p/ATG7 axis in PTC cells was evaluated using bioinformatics analysis, luciferase reporter assay, Cell Counting Kit-8 (CCK-8) assay, immunohistochemistry analysis, transmission electron microscopy, and immunofluorescence. We found that GAS8-AS1 was downregulated in PTC tissues and cell lines. In patients with PTC, low GAS8-AS1 expression was associated with higher tumor-node-metastasis (TNM) stage and lymph node metastasis (LNM). Functionally, GAS8-AS1 significantly promoted autophagy and inhibited PTC cell proliferation in vitro and promoted tumorigenesis in vivo. Mechanistically, GAS8-AS1 acted as a sponge of miR-187-3p and miR-1343-3p and upregulated ATG5 and ATG7 expression, respectively. The transcription factor ATF2 regulated GAS8-AS1 by binding to the GAS8-AS1 promoter. In conclusion, upregulation of ATF2 activated GAS8-AS1–promoted autophagy of PTC cells by sponging oncogenic miR-187-3p and miR-1343-3p and upregulating the expression of ATG5 and ATG7, respectively, making GAS8-AS1 a potential prognostic biomarker and therapeutic target for PTC.

Keywords

• GAS8-AS1
• lncRNA
• thyroid cancer
• autophagy
• transcription factor