Abstract
Phosphoglycerate kinase 1 (PGK1) has complicated and multiple functions in cancer occurrence, tumor progression and drug resistance. Sorafenib is the first-line treatment targeted drug for patients with kidney renal clear cell carcinoma (KIRC) as a tyrosine kinase inhibitor, but sorafenib resistance is extremely common to retard therapy efficiency. So far, it is unclear whether and how PGK1 is involved in the pathogenesis and sorafenib resistance of KIRC. Herein, the molecular mechanisms of PGK1-mediated KIRC progression and sorafenib resistance have been explored by comprehensively integrative studies using biochemical approaches, mass spectrometry (MS) identification, microarray assay, nude mouse xenograft model and bioinformatics analysis. We have confirmed PGK1 is specifically upregulated in KIRC based on the transcriptome data generated by our own gene chip experiment, proteomics identification and the bioinformatics analysis for five online transcriptome datasets, and PGK1 upregulation in tumor tissues and serum is indicative with poor prognosis of KIRC patients. In the KIRC tissues, a high expression of PGK1 is often accompanied with an increase of glycolysis-related enzymes and CXCR4. PGK1 exhibits pro-tumorigenic properties in vitro and in a xenograft tumor model by accelerating glycolysis and inducing CXCR4-mediated phosphorylation of AKT and ERK. Moreover, PGK1 promotes sorafenib resistance via increasing CXCR4-mediated ERK phosphorylation. In conclusion, PGK1-invovled metabolic reprogramming and activation of CXCR4/ERK signaling pathway contributes to tumor growth and sorafenib resistance of KIRC.
Highlights
In recent years, the incidence of kidney cancer has been increasing year by year, reaching to proximate 2.2% of all new cancer cases and 1.8% of the total cancer deaths [1]
The differences in gene expression between Kidney renal clear cell carcinoma (KIRC) tissues and paired normal adjacent tissues (NATs) were visualized by Volcano plots (Fig. 1B)
With a threshold defined by a | log2FC | >0.75 and an adjusted P value < 0.05, a total of 6092 differentially expressed genes (DEGs) were identified from gene chip experiment results, including 3082 downregulated genes and 3010 up-regulated genes in the KIRC tissues
Summary
The incidence of kidney cancer has been increasing year by year, reaching to proximate 2.2% of all new cancer cases and 1.8% of the total cancer deaths [1]. The development of diagnosis and treatment technology has prolonged the survival of RCC patients in recent years, tumor metastasis and chemoresistance still remain the main limiting factors for prognosis of patients. 25–30% of RCC patients present with a locally advanced or metastatic stage at the time of initial diagnosis [2]. Kidney renal clear cell carcinoma (KIRC) is the most common and fatal subtype of RCC, accounting for ~70–75% of RCC, and the other two subtypes including kidney chromophobe cell carcinoma and kidney renal papillary cell carcinoma account for about 25% of the remaining RCC [3]. KIRC is a highly vascularized malignant tumor, and several anti-angiogenesis tyrosine kinase inhibitors (TKIs), such as sorafenib, exhibit initially effective in tumor regression, but the acquired drug resistance will occur gradually and render sorafenib treatment ineffective for some patients [5]. Exploring new therapeutic targets and strategies to impede tumor progression and drug resistance are urgently needed concerns for RCC therapy
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