Abstract
Renal cell carcinoma (RCC) is the most lethal of all genitourinary malignancies. Distant metastasis represents the major cause of death in patients with RCC. Recent studies have implicated the AAA+ ATPase pontin in many cellular activities that are highly relevant to carcinogenesis. In this study, we demonstrate for the first time that pontin was up-regulated in RCC, and plays a previously unknown pro-invasive role in the metastatic progression of RCC through epithelial-to-mesenchymal transition (EMT) pathway. 28 pairs of freshly frozen clear cell RCC samples and the matched normal renal tissues analyzed by quantitative RT-PCR and western blotting demonstrated that pontin was up-regulated in clear cell RCC tissues than in normal renal tissues. In addition, immunohistochemistry was used to evaluate subcellular pontin expression in 95 RCC patients, and found that overexpression of pontin in cytoplasm positively correlated with the metastatic features, predicting unfavorable outcomes of RCC patients. Furthermore, in vitro experiments show pontin was predominantly expressed in cytoplasm of RCC cell lines, and a significant suppression of cell migration and invasion in pontin siRNA treated RCC cell lines was observed. Mechanistic studies show that pontin depletion up-regulated the E-cadherin protein and down-regulated vimentin protein, and decreased nuclear β-catenin expression, suggesting the involvement of EMT in pontin induced metastatic progression. Together, our data suggest pontin as a potential prognostic biomarker in RCC, and provide new promising therapeutic targets for clinical intervention of kidney cancers.
Highlights
Renal cell carcinoma (RCC) is the most common malignances of adult kidneys
Pontin mRNA was significantly up-regulated in ccRCC tissues than in matched normal renal tissues levels determined by qRT-PCR. (B and C) Relative pontin and E-cadherin protein levels determined by western blotting analyses. (D) Western blotting analyses from 4 representative pairs of matched ccRCC and normal renal tissues. β-actin was used as a loading control. **P
Recent studies have implicated the AAA+ superfamily member pontin and its homology reptin are involved in many cellular processes that are highly relevant to cancer
Summary
Renal cell carcinoma (RCC) is the most common malignances of adult kidneys. Due to the asymptomatic nature of early stage RCC, more than one third of the patients present with locally advanced or metastatic disease at the time of diagnosis. Pontin and reptin are usually co-expressed [2] Both of them are found in several multi-protein complexes, where they are thought to participate notably in chromatin remodeling [3], transcriptional regulation [4], DNA damage repair [5], and small nucleolar RNA biogenesis [6], but they can function independently from each other. The present study was performed to examine the postulated oncogenic role of pontin in RCC In this respect, we examined pontin expression in RCC surgical samples, and explored the potential effects of pontin on RCC metastatic progression and patients’ survival. We applied siRNA to knockdown pontin in RCC cell lines to examine its biological functions and the possible molecular mechanisms
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