Abstract
BackgroundAngiogenic placental growth factor (PlGF) plays a role in hypoxia-induced angiogenesis. Here, we aimed to investigate the biological roles of PlGF in cell proliferation and glycolysis of lung adenocarcinoma (LUAD) and the underlying molecular mechanisms.MethodsPlGF was knocked down in H358 and H1975 cells by lentiviruses, which were then cultured under hypoxia (90% N2, 5%CO2 and 5%O2) for 24 h. PlGF was overexpressed in PC9 cells treated with XAV939, inhibitor of Wnt/β-catenin signaling pathway. PlGF-silencing H1975 cells were implanted into mice, and tumor xenografts were harvested and analyzed.ResultsHypoxia treatment led to up-regulation of PlGF, C-myc, lactate dehydrogenase A (LDHA), and β-catenin, promotion of cell proliferation and glycolysis in H358 and H1975 cells, which were obviously reversed by knocking down PlGF. In tumors, PlGF knockdown significantly prohibited cell proliferation and glycolysis, and decreased expression of C-myc, LDHA, and β-catenin. PlGF overexpression markedly strengthened cell proliferation, which was inhibited by β-catenin knockdown. Consistently, XAV939, inhibitor of Wnt/β-catenin pathway, also inhibited PlGF-induced cell proliferation, glycolysis, and β-catenin expression in PC9 cells.ConclusionPlGF knockdown inhibited the stimulatory effect of hypoxia on cell proliferation and glycolysis of LUAD through deactivating Wnt/β-catenin pathway.
Highlights
Angiogenic placental growth factor (PlGF) plays a role in hypoxia-induced angiogenesis
PlGF was up‐regulated in primary tumor tissues and in lung cancer cells Using gene expression data of 515 primary lung adenocarcinoma (LUAD) samples and 59 paired normal lung samples downloaded from The Cancer Genome Atlas (TCGA) database, we found that PlGF expression was remarkably higher in LUAD tissues relative to the paired normal lung tissue (Fig. 1a)
Knockdown of PlGF abrogated the impact of hypoxia on H358 and H1975 cells We further investigated the effect of PlGF on hypoxiainduced cell proliferation, Oxygen consumption rates (OCR) and extracellular acidification rate (ECAR) levels by
Summary
Angiogenic placental growth factor (PlGF) plays a role in hypoxia-induced angiogenesis. We aimed to investigate the biological roles of PlGF in cell proliferation and glycolysis of lung adenocarcinoma (LUAD) and the underlying molecular mechanisms. To adapt to hypoxic microenvironment, oxidative phosphorylation is switched to glycolysis in tumor cells, which provide cellular energy, and foster macromolecular biosynthesis by the production of metabolic intermediates, thereby promoting tumor growth, and facilitating immune escape [9, 10]. Previous studies have made considerable efforts to unravel the physiological and molecular mechanisms behind glycolysis enhancement in tumor and have unveiled a few transcription factors as central regulators, such as HIF-1 and C-myc [15, 16]. Oncogene MYC encodes C-myc of the Myc family, which is a transcription factor involved in cell proliferation, apoptosis and metabolism, contributing to tumorigenesis [17]. C-myc is a key regulator of glycolysis and can transcriptionally elevate expression of lactate dehydrogenase A (LDHA), hexokinase 2 and pyruvate kinase isoform 2, which are important players in glycolysis [19]
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