Expression Of CIP2A In Clear Cell Renal Cell Carcinoma And Its Clinical Significance

Background:Cancerous inhibitor of protein phosphatase2A (CIP2A) was a newly characterized oncoprotein in2007that inhibits protein phosphatase2A(PP2A) activity toward c-Myc, prevents c-Myc proteolytic degradation and thereby leads to cell proliferation and tumor formation. Overexpression of CIP2A was identified in a series of human malignancies recently and is associated with clinicopathological characteristics and survival. Clear cell renal cell carcinoma (ccRCC) is a common malignancy in urologic cancers while c-Myc overxepression is essential for the formation and proliferation of ccRCC. Although CIP2A mediated c-Myc stabilization was already identified, the role of CIP2A in ccRCC has not yet been demonstrated.Objectives:The aim of this study is to investigate the expression of CIP2A in ccRCC and its clinical significance.Materials and Methods:Clinical data of patients (n=56) who underwent radical nephrectomy or palliative surgery for ccRCC at the Department of Urology, Huashan Hospital, Fudan University, between Mar2001and Aug2006were entered into a prospective database. The histological diagnosis was confirmed by the Department of Pathology of the same center. All the patients were diagnosed without other malignancies within one month before and after surgery. Patient information of gender, age at surgery, tumor size, TNM stage, Fuhrman grade and survival time were recorded. Expression of CIP2A was examined by immunohistochemistry in malignant tissues from56ccRCC patients and20corresponding benign tissues (>0.5cm away from the margin of the primary tumor) from those patients. Immunoreactivity was scored semi-quantitatively by the intensity of staining and the percentage of positive cells. Statistical analysis was performed using SPSS13.0to compare the expression of CIP2A with clinicopathological parameters and survival status.Results:The positive rate of CIP2A protein in ccRCC tissues was80.4%(45/56), while that in corresponding benign tissues was30.0%(6/20), the difference is of statistical significance (x2=16.9, P﹤0.001). CIP2A displayed a coarse granular cytoplasmic staining of moderate or strong intensity in the ccRCC tissue; in contrast, CIP2A was mainly negative in the corresponding benign tissues, except for weak non-specific staining in the cytoplasmic area of the tubular epithelial cells. Overexpression of CIP2A was associated with large tumor size (rs=0.463, P﹤0.01), high pathological T-class (pT3/pT4vs pTl/2, P=0.021), distant metastasis (M+vs MO, P=0.022) and high Fuhrman grade (G3/G4vs G1/G2, P=0.040). However, no correlation was found between gender, age at surgery, N-class and CIP2A expression. Overexpression of CIP2A was associated with reduced overall survival (log-rank test, P=0.040) and cancer specific survival (log-rank test, P=0.010). In the multivariate analysis, CIP2A was an independent prognostic factor for overall survival of ccRCC patients (HR=2.97,95%CI1.23-7.17, P=0.016).Conclusions:CIP2A is overexpressed in ccRCC and associates with clinical aggressivity of the disease. Immunoreactivity of CIP2A may serve as a novel independent prognostic marker for ccRCC patients.