Mitochondrial ROS Induce Partial Dedifferentiation of Human Mesothelioma via Upregulation of NANOG

The expression of pluripotency factors is a key regulator of tumor differentiation status and cancer stem cells. The purpose of this study was to examine the expression of pluripotency factors and differentiation status of human mesothelioma and the role of mitochondria in their regulation. We teste...

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Bibliographic Details
Published in:Antioxidants 2020-07, Vol.9 (7), p.606
Main Authors: Sedlic, Filip, Seiwerth, Fran, Sepac, Ana, Sikiric, Suncana, Cindric, Marina, Milavic, Marija, Batelja Vuletic, Lovorka, Jakopovic, Marko, Seiwerth, Sven
Format: Article
Language:English
Subjects:
1-Phosphatidylinositol 3-kinase
AKT protein
Antibodies
Cell culture
Cell differentiation
Cloning
Gastric cancer
Gene expression
Health aspects
Kinases
Membrane potential
Mesothelioma
Mesothelium
Metastasis
Mitochondria
Oct-4 protein
Pluripotency
pluripotency factors
Protein expression
Proteins
Reactive oxygen species
reprogramming
Software
Stem cells
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Summary:The expression of pluripotency factors is a key regulator of tumor differentiation status and cancer stem cells. The purpose of this study was to examine the expression of pluripotency factors and differentiation status of human mesothelioma and the role of mitochondria in their regulation. We tested the expression of OCT4/POU5F1, NANOG, SOX2, PI3K-AKT pathway and BCL2 genes and proteins in 65 samples of human mesothelioma and 19 samples of normal mesothelium. Mitochondrial membrane potential, reactive oxygen species (ROS) generation and expression of pluripotency factors were also tested in human mesothelioma cell line. Human mesothelium and mesothelioma expressed SOX2, NANOG, PI3K and AKT genes and proteins and POU5F1 gene, whereby NANOG, SOX2 and phosphorylated (activated) AKT were upregulated in mesothelioma. NANOG protein expression was elevated in less differentiated samples of human mesothelioma. The expression of genes of PI3K-AKT pathway correlated with pluripotency factor genes. Mesothelioma cells had functional, but depolarized mitochondria with large capacity to generate ROS. Mitochondrial ROS upregulated NANOG and mitoTEMPO abrogated it. In conclusion, human mesothelioma displays enhanced expression of NANOG, SOX2 and phosphorylated AKT proteins, while elevated NANOG expression correlates with poor differentiation of human mesothelioma. Mitochondria of mesothelioma cells have a large capacity to form ROS and thereby upregulate NANOG, leading to dedifferentiation of mesothelioma.
ISSN:2076-3921
2076-3921
DOI:10.3390/antiox9070606