Pyruvate kinase M2 deregulation enhances the metastatic potential of tongue squamous cell carcinoma.

Wei Wang,Anxun Wang,Jingjing Sun,Luodan Zhao,Xiaofeng Zhou,Zhonghua Liu,Zhiyuan Lu,Qianting He

doi:10.18632/oncotarget.19291

Wei Wang, Anxun Wang + Show 6 more

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https://doi.org/10.18632/oncotarget.19291

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Abstract

Pyruvate kinase M2 (PKM2) has been verified to correlate with the prognosis of many types of cancer. However, its role in the development and metastasis of tongue squamous cell carcinoma (TSCC) remains unclear. The immunohistochemistry (IHC) results confirmed that PKM2 is overexpressed in patients with TSCC. PKM2 up-regulation was related to lymph node metastasis and associated with reduced overall survival. According to the microarray analysis and Western blots, PKM2 expression was up-regulated in TSCC cells with enhanced metastatic potential. PKM2 knockdown inhibited cell migration and invasion, reduced SOD2 (manganese superoxide dismutase) activity and the intracellular H2O2 level, and inhibited tumour growth and lung metastasis in vivo. PKM2 overexpression promoted cell migration and invasion, and increased SOD2 activity and the intracellular H2O2 level. Moreover, miR-138 directly targeted PKM2 and inhibited PKM2 expression. Thus, PKM2 deregulation plays an important role in TSCC and may serve as a biomarker of metastatic potential or as a therapeutic target in patients with TSCC. PKM2, a miR-138 target gene, enhances the metastatic potential of TSCC through the SOD2-H2O2 pathway.

Highlights

In contrast to normal cells, which rely primarily on mitochondrial oxidative phosphorylation to generate energy, most cancer cells rely on glycolysis, even in conditions of normal oxygen concentration; this metabolic condition is termed the Warburg effect [1]
To elucidate the prognostic role of Pyruvate kinase M2 (PKM2) expression in patients with tongue squamous cell carcinoma (TSCC), we examined the relationship between PKM2 expression and patient outcome using long-term follow-ups
Many studies have revealed high PKM2 expression levels in cancer cells, which were associated with metastasis and poor prognosis in cancer patients [9, 24, 25]

Summary

Introduction

In contrast to normal cells, which rely primarily on mitochondrial oxidative phosphorylation to generate energy, most cancer cells rely on glycolysis, even in conditions of normal oxygen concentration; this metabolic condition is termed the Warburg effect [1]. PKM2 is encoded by the PKM gene and is expressed in embryonic cells, adult stem cells, and cancer cells [3]. PKM2 gene transcription is controlled by many factors [4,5,6,7,8]. Hypoxia-inducible factor (HIF)-1 activates PKM2 gene transcription in hypoxic cells by binding to a hypoxia response element located within the first intron of the PKM2 gene [4]. Myc regulates PKM2 expression both directly, by binding to a Myc response element located in the promoter of the PKM2 gene, and indirectly, by activating the transcription of genes encoding hnRNPI, hnRNPA1, and hnRNPA2, which facilitate the alternative splicing that generates PKM2 mRNA [5, 6]. Some microRNAs (miRNAs), such www.impactjournals.com/oncotarget as miR-326 [7], miR-133a and miR-133b [8], have been found to directly target and regulate the synthesis of PKM2 protein [7, 8]

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