Abstract
PIN2/TRF1-interacting telomerase inhibitor 1 (PinX1) is a novel cloned gene which has been identified as a major haploinsufficient tumor suppressor essential for maintaining telomerase activity, the length of telomerase and chromosome stability. This study explored the clinical significance and biological function of PinX1 in human clear cell renal cell carcinoma (ccRCC). The clinical relevance of PinX1 in ccRCC was evaluated using tissue microarray and immunohistochemical staining in two independent human ccRCC cohorts. Our data demonstrated that PinX1 expression was dramatically decreased in ccRCC tissues compared with normal renal tissues and paired adjacent non-tumor tissues. Low PinX1 expression was significantly correlated with depth of invasion, lymph node metastasis and advanced TNM stage in patients, as well as with worse overall and disease-specific survival. Cox regression analysis revealed that PinX1 expression was an independent prognostic factor for ccRCC patients. Moreover, PinX1 inhibited the migration and invasion of ccRCC by suppressing MMP-2 expression and activity via NF-κB-dependent transcription in vitro. In vivo studies confirmed that PinX1 negatively regulated ccRCC metastasis and the expression of MMP-2 and NF-κB-p65. These findings indicate that PinX1 suppresses ccRCC metastasis and may serve as a ccRCC candidate clinical prognostic marker and a potential therapeutic target.
Highlights
Kidney cancer is estimated to have been diagnosed about 63, 920 new cases in 2014 in the United States [1]
Immunohistochemistry staining was utilized in tissue microarray (TMA) slides to evaluate the PinX1 expression in normal renal tissues, clear cell renal cell carcinoma tissues and paired adjacent non-tumor tissues
Because 5-year patients’ survival is widely used to predict outcome in clear cell renal cell carcinoma (ccRCC) patients, our results clearly indicated that low PinX1 expression is associated with poor prognosis, suggesting that PinX1 may serves as a molecular prognostic marker for this aggressive disease
Summary
Kidney cancer is estimated to have been diagnosed about 63, 920 new cases in 2014 in the United States [1]. Most kidney tumors are renal cell carcinomas (RCC), and 70% are the clear cell type (ccRCC) [2]. There has been a steady decline in the cancer death rate over the past 2 decades (it depends on the prevention, early detection, and treatment) [1], but once ccRCC happens metastatic, it remains largely incurable [3], median survival of the patient is only about 13 months [4]. The molecular mechanism contributes to regulating the invasion and metastasis of ccRCC remains unclear. Any insight into the mechanisms of ccRCC metastasis may contribute to the development of more effective and specific strategies to interfere with www.impactjournals.com/oncotarget ccRCC progression. Novel diagnosis, prognosis and individualized medication biomarkers are strongly needed for ccRCC
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