Journal of Experimental & Clinical Cancer Research 2008, 27:51 http://www.jeccr.com/content/27/1/51 Table 1: Expression of p27Kip1, Skp2, and Cks1 in relation to clinicopathological parameters Variables Age, years Mean Gender Men Women Metastasis Negative Positive Histology Clear cell Papillary Chromophobe pT stage 1 2 3+4 Tumor size ≤ 7.0 >7.0 Grade 1 2 3 4 Necrosis Absent Present ECOG-PS = 0 >0 No. 329 153 437 45 384 81 17 255 103 124 324 158 78 250 121 33 432 50 388 94 Low 62.5 213 101 279 35 239 61 14 141 78 95 188 126 46 159 86 23 271 43 250 64 P27 High 61.3 116 52 158 10 145 20 3 114 25 29 136 32 32 91 35 10 161 7 138 30 p-value 0.904 0.785 0.062 0.008a 0.002b <0.001 0.075c 0.001 0.505 N 62.0 281 130 376 35 316 78 17 243 83 85 298 113 68 215 102 26 376 35 335 76 Skp2 65.1 P 48 23 61 10 68 3 0 12 20 39 26 45 10 35 19 7 56 15 53 18 p-value 0.723 0.898 0.136 <0.001a <0.001b <0.001 0.361c 0.001 0.178 N 60.0 272 120 359 33 302 73 17 217 78 97 273 119 60 201 103 28 352 40 313 79 Cks1 62.3 P 57 33 78 12 82 8 0 38 25 27 51 39 18 49 18 5 80 10 75 15 p-value 0.630 0.266 0.148 0.003a 0.304b 0.018 0.149c 0.799 0.452 Note: N indicates negative; P indicates positive; a Histology, clear cell vs. others. bStage, Stages I and II vs. Stages III and IV. c Grade, Grade1/2 vs. Grade3/4. In the univariate analysis, the Kaplan-Meier survival curves showed that high Skp2 and Cks1 expression and low p27Kip1 expression related to a poor survival with sta- tistical significance, regardless of endpoints (Table 2, Fig. 2). The Cox's proportional hazards regression model proved that tumor stage, tumor size and low p27Kip1 expression or lack of p27Kip1 immunoreactivity were inde- pendent prognostic factors for different endpoints in patients with RCC (Table 2). Discussion To our knowledge, the current study presents the largest samples for investigating the expression of p27Kip1 and its interacting cell cycle regulators: Skp2 and Cks1. This is also the first article to analyse Cks1 expression in renal cell carcinoma, with respect to possible associations with clin- icopathological data as well as patients' prognosis. Fur- thermore, for the first time, the possible relation between levels of p27Kip1 and of its specific ubiquitin ligase subunit Skp2 and Cks1 was assessed in renal cell carcinoma. p27Kip1 is a member of the Cip/Kip family of CDK inhibi- tory proteins and serves as an important regulator for both cellular proliferation and tissue differentiation. Till now, the significant association between low p27Kip1 expression and adverse pathologic features or poor survival has been found in patients with a variety of neoplasms, including carcinoma of the gastrointestinal system [17], prostate [18,19], breast [11], and lung [12]. However, previous studies on p27Kip1 expression in RCCs presented contra- dictory results. The low p27Kip1 expression was found to be related to high-stage and high-grade RCCs by Langner C et al. [13] and Hedberg et al. [20]. Yet, other studies reported that the p27Kip1 level only was only related to the TNM stage [21] or no associations at all [22]. Further- more, although Hedberg et al. [20] reported the different Page 5 of 8 (page number not for citation purposes)