HIF-1α Promotes the Metastasis of Esophageal Squamous Cell Carcinoma by Targeting SP1

Abstract

Background: In microenvironment of malignant tumors, Hypoxia-Inducible Factors (HIF), most importantly HIF-1α, play an important role in regulation of adaptive biological response to hypoxia, promoting angiogenesis and metastasis. However, the underlying mechanism that HIF-1α regulates metastasis needs to be further clarified. Methods: The expressions of HIF-1α and SP1 were detected in 182 samples of esophageal squamous cell carcinoma (ESCC) and adjacent normal tissues by immunohistochemistry (IHC), and the correlation between the expression levels of HIF-1α and SP1 was analyzed. The expression of HIF-1α in ESCC cell lines TE1 and KYSE30 was then detected using qRT-PCR and western blot. The potential binding sites of HIF-1α on the SP1 promoter were analyzed using UCSC and JASPAR databases, verified by chromosomal immunoprecipitation (ChIP) assay and qRT-PCR. The effects of HIF-1α and SP1 on ESCC cell migration and invasion were then tested with Transwell and Matrigel experiments. Results: The expression of HIF-1α in cancer tissues is higher than adjacent normal tissues, and is correlated with metastasis, recurrence and poor prognosis. Upon silencing HIF-1α by siRNA, the invasion and migration ability of ESCC cells were significantly inhibited, which could be restored by the overexpression of SP1. Hypoxic conditions significantly increased the expression of HIF-1α and SP1 at both protein and mRNA levels in ESCC cells. HIF-1α enhanced SP1 transcription through binding to the promoter region. The expression of protein and mRNA levels of SP1 was decreased by silencing HIF-1α in cells. In contrast, overexpression of HIF-1α significantly increased the mRNA and protein levels of SP1. The expression of SP1 in ESCC was positively correlated with the protein expression of HIF-1α and poor prognosis. Conclusion: The results of our study indicate that HIF-1α promotes metastasis of ESCC by targeting SP1 in a hypoxic microenvironment. Further study on this mechanism may elucidate the possibility of HIF-1α and SP1 as new targets for the treatment of ESCC.

Cartilage Endplate Stem Cells Transdifferentiate Into Nucleus Pulposus Cells via Autocrine Exosomes

“…These factors activate signal transduction pathways that lead to cell proliferation by binding to their cognate receptors ( Semenza, 2003 ). Furthermore, previous studies suggested that HIF-1α was associated with tumor metastasis, promoting cell migration and invasion ( Liu et al, 2016 ; Hu et al, 2020 ). Our immunofluorescence results revealed that the expression level of HIF-1α increased in CESCs after treatment with exosomes, indicating that HIF-1α played important roles in CESC transdifferentiation.…”

Activation of PGK1 under hypoxic conditions promotes glycolysis and increases stem cell‑like properties and the epithelial‑mesenchymal transition in oral squamous cell carcinoma cells via the AKT signalling pathway

“…Hypoxic environments can be readily found in solid malignant tumors and can lead to alterations in the expression of a number of molecular biomarkers, including HIF, carbonic anhydrase, glucose-transporter-1 and vascular endothelial growth factor ( 49 ). HIF-1α, which is activated under hypoxic conditions, is involved in the regulation of tumor cell propagation, migration, glucose metabolism and angiogenesis ( 50 ).…”

“…It allows cells to adapt to hypoxic environments, contributing to invasion and metastasis. It was previously found that HIF-1α can promote the malignant progression of esophageal squamous cell carcinoma by regulating the expression specificity protein 1 ( 49 ). In the present study, it was found that both HIF-1α and PGK1 expression were upregulated due to hypoxia, suggesting an association between these two proteins.…”

<p>Esophageal Microenvironment: From Precursor Microenvironment to Premetastatic Niche</p>

“…For example, it can bind to the SP1 promoter and regulate its transcription program in order to enhance the ability of ESCC cells to migrate and invade and promote tumor recurrence and metastasis. 55 Other studies have mentioned that it also could bind to the hypoxic response element, which located at the upstream of the Insulin-like growth factor binding protein 3 (IGFBP3) transcription initiation site, and then induce continuous translation of IGFBP3 mRNA 44 and promote ESCC cell growth and proliferation through the insulin-like growth factor-independent pathway. 56 Finally, it can also directly bind to the promoter-specific hypoxic response element of ECM metalloproteinase inducer (EMMPRIN), and further promote EC cell migration and epithelial-mesenchymal transition (EMT).…”