Abstract
Wild-type p53-induced phosphatase (Wip1 or PPM1D) has been reported to be aberrantly expressed in various cancers and correlated with the malignant behavior of cancer cells. However, the function of Wip1 in RCC remains unclear. The present study investigated its abnormal expression and dysfunctions in clear cell renal cell carcinoma (ccRCC) in vitro. With the combination of immunohistochemistry, western blotting, immunofluorescence, qRT-PCR, and cell proliferation, migration and invasion assays, we found that levels of Wip1 mRNA and protein were dramatically increased in human ccRCC tissues (P<0.001 for both), and upregulation of Wip1 was significantly associated with depth of invasion (P<0.001), Distant metastasis (P = 0.001), lymph node status (P<0.001) and Fuhrman grade (P<0.001). Wip1 knockdown inhibited the proliferation, migration and invasion of 786-O and RLC-310 cells, whereas Wip1 overexpression promoted the growth and aggressive phenotype of 786-O and RLC-310 cells in vitro. The uni- and multivariate analyses indicated that expression of Wip1 was an independent predictor for survival of ccRCC patients (P = 0.003, P = 0.027 respectively). Wip1- negative patients had a higher tumor-free/overall survival rate than patients with high Wip1 expression (P = 0.001, P = 0.002 respectively). Overexpression of Wip1 is useful in the prediction of survival in ccRCC patients.
Highlights
Renal cell carcinoma (RCC) is the most prevalent malignancy of the adult kidney, accounting for approximately 90–95% of all kidney neoplasms [1], with annual estimations of 209,000 new cases and 102,000 cancer-related deaths in the world [2]
To further confirm these observations, we investigated the expression of Wip1 in Clear cell renal cell carcinoma (ccRCC) tissues and paired tissues using western blotting
The expressions of both Wip1 mRNA and protein were significantly upregulated in RCC cell lines as compared with that in the immortalized normal human proximal tubule epithelial cell line HK-2 (Fig. 2E–F), which indicated Wip1 expression was associated with the aggressive phenotypes of RCC cells
Summary
Renal cell carcinoma (RCC) is the most prevalent malignancy of the adult kidney, accounting for approximately 90–95% of all kidney neoplasms [1], with annual estimations of 209,000 new cases and 102,000 cancer-related deaths in the world [2]. Clear cell renal cell carcinoma (ccRCC) represents the predominant subtype of RCC and constitutes for approximately 75–80% of all cases [3]. Approximately a quarter of RCC clinic patients will develop a metastatic disease despite curative surgical removal of the primary tumor [4]. Identification of novel biomarkers associated with disease progression and metastasis of RCC and combination of their application with traditional diagnostic and prognostic parameters would contribute to development of effective strategies for the prevention, early diagnosis and treatment of RCC
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