HIF-1α-Mediated Telomerase Reverse Transcriptase Activation Inducing Autophagy Through Mammalian Target of Rapamycin Promotes Papillary Thyroid Carcinoma Progression During Hypoxia Stress

Abstract

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-1a (HIF-1a), 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-1a, TERT, and autophagy in promoting PTC progression. Methods: Immunohistochemistry staining was conducted to evaluate the expressions of HIF-1a, 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-1a, 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-1a 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-1a/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.

Sex Bias in Differentiated Thyroid Cancer

“…Autophagy is a mechanism by which cells eliminate some toxic products and recycle others to sustain vital function. It is induced in condition of hypoxia, and Hif-1 (hypoxia induced factor) has been shown to participate to this activation [ 123 ], as well as during starvation. It is associated with higher cell survival, less apoptosis, and could contribute to thyroid cancer cell proliferation.…”

HIF-1 recruits NANOG as a coactivator for TERT gene transcription in hypoxic breast cancer stem cells

“…Expression of TERT is repressed in most adult somatic cells but is reactivated in 90% of all human cancers (Shay and Bacchetti, 1997). Hypoxia-induced TERT expression has been observed in human choriocarcinoma, papillary thyroid carcinoma, and cervical cancer cell lines (Nishi et al, 2004;Song et al, 2021;Yatabe et al, 2004). Further study Cell Reports 36, 109757, September 28, 2021 7 Report ll OPEN…”

“…BCSC specification is induced by hypoxia via multiple HIF-1-dependent pathways (Conley et al, 2012;Mimeault and Batra, 2013;Xiang and Semenza, 2019). Hypoxia-induced TERT expression mediated by HIF-1 has been reported in choriocarcinoma (Nishi et al, 2004), cervical cancer (Yatabe et al, 2004), and papillary thyroid carcinoma (Song et al, 2021) cell lines, as well as in ESCs (Coussens et al, 2010), but the mechanism that restricts HIF-1-dependent TERT expression to stem cells is unknown. In the present study, we demonstrate that HIF-1a is required for NANOG-mediated BCSC specification.…”

Hypoxia in Cell Reprogramming and the Epigenetic Regulations

“…Moreover, the TERT transcription can be enhanced by DNA methylation at the TERT-DMR via binding to nuclear lamina during cellular reprogramming (Takasawa et al, 2018). Hypoxia can promote telomerase TERT expression and HIF-1α mediates upregulation of TERT (Yu et al, 2006;Song et al, 2020). This has a significant impact on cellular reprogramming from somatic cells into pluripotent stem cells.…”