Cytoplasmic Expression of Pontin in Renal Cell Carcinoma Correlates with Tumor Invasion, Metastasis and Patients’ Survival

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.

Amygdalin inhibits the growth of renal cell carcinoma cells in vitro

“…During RCC tumor genesis and progression, dedifferentiation accompanied by epithelial mesenchymal transition (EMT) takes place (26,27). During transition the tumor cells lose epithelial (E)-cadherin and gain neural (N)-cadherin (26,28). In all three RCC cell lines used in this study, application of amygdalin for 24 h caused a significant decrease in N-cadherin expression, which indicates re-differentiation.…”

The Role of Pontin and Reptin in Cellular Physiology and Cancer Etiology

“…In the excretory system (Table 1 ), overexpression of the two ATPases was found in renal cell carcinoma (RCC) (Ren et al, 2013 ; Zhang et al, 2015 ). Like in HCC patients, cytoplasmic localization of Pontin and Reptin in RCC was found to be correlated with metastasis and unfavorable outcome (Rousseau et al, 2007 ; Haurie et al, 2009 ; Ren et al, 2013 ; Zhang et al, 2015 ). Whether correlation with localization of the protein can apply to other cancer types where cytoplasmic expression was also shown remains to be investigated.…”

“…Studies in a variety of cancer cell lines have consistently demonstrated that downregulation of either Pontin or Reptin may lead to cell cycle arrest at the G1/S phase checkpoint, resulting in the accumulation of cells in G1 and a reduction of cells in all other phases of the cell cycle (S, G2/M) (Rousseau et al, 2007 ; Haurie et al, 2009 ; Menard et al, 2010 ; Osaki et al, 2013 ; Ren et al, 2013 ; Breig et al, 2014 ; Zhang et al, 2015 ; Yuan et al, 2016 ). G1/S transition is regulated by many proteins and pathways that are normally inactivated until entry into S phase is signaled (Otto and Sicinski, 2017 ).…”

“…Additionally, Pontin and Reptin were shown as interactors of MYC and β-catenin (see section Role of Pontin/Reptin in Mitosis for details), and thus can potentially regulate their transcriptional activity for production of cyclins (Bauer et al, 2000 ; Wood et al, 2000 ). In RCC cells, Pontin knockdown led to a decreased mRNA expression of both MYC and cyclin D1 (Zhang et al, 2015 ). Pontin and Reptin can also regulate the ability of MYC to enhance cell-cycle progression by stimulating its inhibition of the transcription factor MIZ1 (Etard et al, 2005 ).…”

The Emerging Roles of ATP-Dependent Chromatin Remodeling Complexes in Pancreatic Cancer

“…Interacts with oncogene c-MYC and β-catenin. Roles in cell growth and viability [231][232][233][234][235][236][237][238]. In a mouse model of liver cancer, accumulation of E2f1 recruits the RUVBL1/RUVBL2 complex that opens the chromatin conformation at E2f target genes and amplifies the E2f transcriptional response during cancer progression.…”