Background: It is important to properly understand the molecular mechanisms of aggressive
tumors among
papillary thyroid carcinomas (PTCs) that are often the most indolent.
Hypoxia inducible factor-1α (HIF-1α), induced by
hypoxia, plays pivotal roles in the development and
metastasis of the many
tumors, including PTCs. Upregulation of
telomerase reverse transcriptase (TERT) activity is found in highly invasive PTCs. Further, previous studies have reported that autophagy serves as a protective mechanism to facilitate PTC cell survival. We, therefore, hypothesized that there was a link between HIF-1α, TERT, and autophagy in promoting PTC progression. Methods: Immunohistochemistry staining was conducted to evaluate the expressions of HIF-1α, TERT, and autophagy marker, LC3-II, in matched PTC
tumors and corresponding nontumor tissues. Two PTC cell lines (TPC-1 and BCPAP) were used in subsequent cytological function studies. Cell viability, proliferation, apoptosis, migration, and invasion were assessed during
hypoxia, genetic enhancement and inhibition of TERT, and chemical and genetic inhibition of autophagy. The
protein expression levels of the corresponding
biomarkers were determined by Western blotting, and autophagy flow was detected. We characterized the molecular mechanism of PTC cell progression. Results: The
protein expression levels of HIF-1α, TERT, and LC3-II were upregulated in PTCs and were significantly correlated with high
tumor-node-
metastasis stage. Further, an in vitro study indicated that HIF-1α induced by
hypoxia functioned as a transcriptional activator by binding with sequences potentially located in the TERT promoter and was positively correlated with the malignant behavior of PTC cell lines. Overexpression of TERT inhibited the
kinase activity of
mammalian target of rapamycin (mTOR), resulting in the activation of autophagy. Functionally, TERT-induced autophagy provided a survival advantage to PTC cells during
hypoxia stress. Conclusions: We identified a novel molecular mechanism involving the HIF-1α/TERT axis, which promoted PTC progression by inducing autophagy through mTOR during
hypoxia stress. These findings may provide a basis for the new treatment of aggressive PTCs.