Abstract
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.
Highlights
Malignant pleural mesothelioma originates from pleural mesothelial cells
Comparison of Im index showed a greater expression of NANOG and SOX2 proteins in mesothelioma than in mesothelium, indicting a dedifferentiation of mesothelioma compared to mesothelial cells from which mesothelioma originates
The expression of SOX2 protein showed no difference among different histological subtypes, while NANOG protein was significantly more expressed in the pleomorphic than in the tubulopapillary mesothelioma
Summary
Malignant pleural mesothelioma originates from pleural mesothelial cells. It is notorious for its resistance to various types of therapy and poor survival. Especially cancer stem cells may recapitulate some of these features of undifferentiated cells, which could be responsible for local and distal spreading of the tumor, and even resistance to therapy [3]. Pluripotency factors, such as OCT4 or NANOG, are master regulators of dedifferentiation, and may be critical for the clinical outcome of malignant tumors. Cancer stem cells exhibit high expression of OCT4, NANOG and SOX2, which represent their markers [9,10]. Reactive oxygen species (ROS), produced by mitochondria regulate expression of numerous genes and cellular functions, including the expression of pluripotency genes and the differentiation status [12]
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