Abstract
Budding at the tumor invasive front has been correlated with the malignant properties of many cancers. Malic enzyme 1 (ME1) promotes the Warburg effect in cancer cells and induces epithelial–mesenchymal transition (EMT) in oral squamous cell carcinoma (OSCC). Therefore, we investigated the role of ME1 in tumor budding in OSCC. Tumor budding was measured in 96 human OSCCs by immunostaining for an epithelial marker (AE1/AE3), and its expression was compared with that of ME1. A significant correlation was observed between tumor budding and ME1 expression. The correlation increased with the progression of cancer. In human OSCC cells, lactate secretion decreased when lactate fermentation was suppressed by knockdown of ME1 and lactate dehydrogenase A or inhibition of pyruvate dehydrogenase (PDH) kinase. Furthermore, the extracellular pH increased, and the EMT phenotype was suppressed. In contrast, when oxidative phosphorylation was suppressed by PDH knockdown, lactate secretion increased, extracellular pH decreased, and the EMT phenotype was promoted. Induction of chemical hypoxia in OSCC cells by CoCl2 treatment resulted in increased ME1 expression along with HIF1α expression and promotion of the EMT phenotype. Hypoxic conditions also increased matrix metalloproteinases expression and decreased mitochondrial membrane potential, mitochondrial oxidative stress, and extracellular pH. Furthermore, the hypoxic treatment resulted in the activation of Yes-associated protein (YAP), which was abolished by ME1 knockdown. These findings suggest that cancer cells at the tumor front in hypoxic environments increase their lactate secretion by switching their energy metabolism from oxidative phosphorylation to glycolysis owing to ME1 overexpression, decrease in extracellular pH, and YAP activation. These alterations enhance EMT and the subsequent tumor budding. Tumor budding and ME1 expression are thus considered useful markers of OSCC malignancy, and ME1 is expected to be a relevant target for molecular therapy.
Highlights
Tumor budding refers to a small undifferentiated cancer cell cluster consisting of up to five cancer cells or a solitary cancer cell in the invasive front [1]
We investigated the role of Malic enzyme 1 (ME1) in tumor budding in oral squamous cell carcinoma (OSCC), in which we had found a significant role for ME1 in tumor progression and epithelial–mesenchymal transition (EMT) [11]
When the correlation between tumor budding and ME1 expression was compared with T factor, N factor, and stage, a stronger correlation was observed in cases that progressed with respect to all factors
Summary
Tumor budding refers to a small undifferentiated cancer cell cluster consisting of up to five cancer cells or a solitary cancer cell in the invasive front [1] These cells are thought to acquire metastatic potential through the acquisition of an epithelial–mesenchymal transition (EMT) phenotype, characterized by decreased cell adhesion and enhancement of stemness [2]. Reprogramming of energy metabolism in a hypoxic environment, that is, suppression of oxidative phosphorylation and promotion of glycolysis and lactate fermentation, alter the properties of cancer [10]. ME1 expression in cancer cells leads to energy metabolism reprogramming from oxidative phosphorylation to glycolysis, resulting in decreased oxygen consumption and increased lactate production, promoting tumorigenicity and tumor growth [11,15]. The above findings suggest that ME1 might play an important role in tumor budding
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
