Potential Role of p27, PTEN, Cks1 and Skp2 Expression in Hepatocellular Carcinoma.
Dimitrios Karavias, John Maroulis, Charalabos Gogos, Vassiliki Zolota, Dionissios Karavias, Chrisoula Scopa, Athanassios Tsamandas. Patras University Medical School, Greece
Background: p27Kip1 is a cell-cycle inhibitory protein and its downregulation is mediated by its specific ubiqitin subunits Cks1 and Skp2. PTEN is a tumor suppressor gene which upregulates p27. This study investigates p27, PTEN, Cks1 and Skp2 expression in hepatocellular carcinoma (HCC).
Design: Formalin-fixed, paraffin-embedded 4 m sections, obtained from 117 HCC hepatectomy specimens with matched non-neoplastic liver, were subjected to immunohistochemistry using antibodies for p27, PTEN, Cks1 and Skp2. Nuclear staining was considered as positive. Results were correlated with pathologic data and patients survival. Mean follow up time was 42.17 months (range 1-102 months).
Results: Expression of p27, PTEN, Cks1 and Skp2 was recorded in: 88/117(76%), 109/117(94%), 28/117(24%) and 26/117(34%) cases, respectively. PTEN was also expressed in cirrhotic and non-cirrhotic non-neoplastic livers; however its expression was significantly lower compared to that of tumors (HCC: 72.84 38.32, cirrhotic livers: 33.55 14.12, non-cirrhotic livers: 12.13 8.64-p<0.001). Mean values for Cks1, Skp2 and p27 expression in HCC were: 9.2 14.3, 4.33 7.6, 16 8.2 respectively. Cks1, Skp2 and p27 expression in cirrhotic and non-cirrhotic livers was observed in rare instances. Statistical analysis revealed a loss of PTEN and p27 expression in HCC grade 3: [PTEN: grade 1: 96.4 2.3, grade 2: 70.8 21.8, grade 3: 9.1 3.4-p<0.0001. p27: grade 1+2: 20.4 12.4, grade 3: 6.1 4.2-p=0.031]. Loss of PTEN and p27 expression was also related to presence of vascular invasion (VI): [PTEN: VI(-): 92.1 5.6, VI(+): 12.4 1.2-p=0.0012. p27: VI(-): 23.1 4.5, VI(+): 5.2 2.7-p=0.013]. No association was recorded between Cks1 and Skp2 expression and tumor grade or stage. PTEN and p27 expression were reversibly correlated with disease free survival (r=- 0.63, p=0.0041 and r=- 0.45, p=0.014). Cox regression analysis revealed that vascular invasion (CI:1.233-5.402, p=0.017), tumor stage (CI:0.057-0.630, p=0.015) and PTEN expression (CI: 1.059-42.065, p=0.031), were independent prognostic factors.
Conclusions: This study demonstrates that loss of PTEN and p27 expression is associated with adverse pathological parameters and increased risk for tumor recurrence. These results support the importance of PTEN and p27 loss for the progression of HCC in humans. PTEN increased expression in cirrhotic non-neoplastic livers may reflect an effort for control of hepatocyte regeneration associating liver cirrhosis.
Category: Liver & Pancreas
Tuesday, March 1, 2011 9:30 AM
Poster Session III # 257, Tuesday Morning