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Skp2 Is an Independent Prognosticator of Gallbladder

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Skp2 Is an Independent Prognosticator of Gallbladder Modern Pathology (2007) 20, 497–507 & 2007 USCAP, Inc All rights reserved 0893-3952/07 $30.00 www.modernpathology.org Skp2 is an independent prognosticator of gallbladder carcinoma among p27Kip1-interacting cell cycle regulators: an immunohistochemical study of 62 cases by tissue microarray Shau-Hsuan Li1, Chien-Feng Li2, Ming-Tse Sung3, Hock-Liew Eng3, Ching-Yeh Hsiung4, Wen-Wei Huang5, Ching-Nan Lin2, Shih-Chen Yu3 and Hsuan-Ying Huang3 1Division of Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan; 2Department of Pathology, Chi-Mei Foundation Medical Center, Tainan, Taiwan; 3Department of Pathology, Chang Gung Memorial Hospital- Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan; 4Department of Radiation Oncology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan and 5Department of Family Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan Despite improvement in surgical techniques, prognosis of gallbladder carcinoma remains poor. It is desirable to identify prognostic biomarkers to aid in the development of targeted therapeutic strategies. Two SCFSkp2 ubiquitin ligase-related proteins, Skp2 and cyclin-dependent kinase subunit 1 (Cks1), are involved in post- transcriptional degradation of p27Kip1 tumor suppressor, which inhibits both cdk2/cyclin E and cdk2/cyclin A complexes and thus prevents transition to the S phase. However, the prognostic utility of p27Kip1-interacting cell cycle regulators has not been systematically assessed in gallbladder carcinoma. Immunohistochemistry was performed for p27Kip1, Skp2, Cks1, cyclin E, cyclin A, and Ki-67 in tissue microarrays of 62 gallbladder carcinomas with follow-up. The data were correlated with clinicopathological features and overall survival (OS). The cumulative OS rate for all 62 cases was 42.9% at 3 years. Aberrant labeling indices (LIs) of p27Kip1 (o20%), cyclin E (Z5%), cyclin A (Z5%), Cks1 (Z40%), and Skp2 (Z10%) were identified in 29, 58, 66, 21, and 57% of gallbladder carcinomas, respectively. By log-rank tests, downregulation of p27Kip1 (P ¼ 0.0319) and high LIs of Skp2 (P ¼ 0.0006), Cks1 (P ¼ 0.0460), cyclin E (P ¼ 0.0070), and Ki-67 (P ¼ 0.0037) were predictive of inferior OS. Furthermore, the combined expression status of Skp2 and Ki-67 robustly defined three prognostically different groups (P ¼ 0.0001). In multivariate comparison, Skp2 overexpression represented the strongest independent adverse prognosticator (P ¼ 0.004, risk ratio (RR): 5.538), followed by Ki-67 LI Z50% (P ¼ 0.016, RR: 3.254) and American Joint Committee on Cancer stages II–IV (P ¼ 0.013, RR: 3.163). In conclusion, aberrations of p27Kip1- interacting cell cycle regulators are common in gallbladder carcinomas. Skp2 overexpression is highly representative of biological aggressiveness and independently associated with poor OS, suggesting that it is a promising novel target for therapeutic intervention in aggressive cases. The combined assessment of Skp2 and Ki-67 LIs effectively risk-stratifies gallbladder carcinomas with different prognosis, which is worth being prospectively validated in future study. Modern Pathology (2007) 20, 497–507. doi:10.1038/modpathol.3800762; published online 2 March 2007 Keywords: cell cycle; gallbladder carcinoma; Skp2; p27kip1; proteolysis Despite improvement in surgical techniques, prog- Correspondence: Dr H-Y Huang, MD, Department of Pathology, nosis of gallbladder carcinoma generally remains Chang Gung Memorial Hospital-Kaohsiung Medical Center, poor.1,2 Among various clinicopathologic para- Chang Gung University College of Medicine, 123 Ta-Pei Road, meters, tumour, node, metastasis (TNM) stage is Niao-Sung Township, Kaohsiung County, Taiwan. indisputably accepted as an adverse prognosticator E-mail: [email protected] 1–3 Received 04 October 2006; revised and accepted 19 December in patients with gallbladder carcinoma. The 2006; published online 2 March 2007 effective therapy to cure gallbladder carcinoma is Skp2 as a prognosticator of gallbladder carcinoma S-H Li et al 498 complete surgical resection at the early stage, have been separately substantiated in colorectal, whereas most patients present with advanced dis- gastric, and head and neck carcinomas, etc.21,27–29 ease and have few therapeutic options.1,2 In this Nevertheless, Skp2 or Cks1 did not correlate with context, the survival rate is as high as 85–100% at low p27Kip1 in some malignancies, implying that 5 years for lesions limited to the muscle layer.2 additional factors may be implicated in p27Kip1 Nevertheless, even after extensive surgery, a con- degradation.22,30,31 siderable number of patients with stage II–IV To date, very few studies have systematically gallbladder carcinoma develop distant or intra- addressed the prognostic utility of p27Kip1-interact- abominal metastases that are resistant to conven- ing cell cycle regulators in gallbladder carcinoma. tional chemotherapy.2 By using tissue microarray (TMA), we therefore Sequential morphological alterations from pre- aimed at analyzing the immunohistochemical ex- cancerous dysplasia or adenoma to carcinoma have pression patterns, associations with clinicopatholo- been regarded as models implicated in tumorigen- gic factors and proliferative index, and prognostic esis of gallbladder carcinoma.4 However, owing to implications of cyclin E, cyclin A, p27Kip1, Skp2, the rarity of gallbladder carcinoma, the molecular and Cks1 proteins in 62 cases of gallbladder mechanisms underlying its initiation and progres- carcinoma with follow-up information. sion are not fully elucidated. During multistep carcinogenesis, deregulation of multiple cell-cycle regulators represents a common mode of genetic Materials and methods alterations that promote progression in aggressive tumor subsets, thereby conferring an adverse impact Patients and Tumor Material 5 on patient survival. Prior studies have character- Ninety-eight cases of gallbladder carcinoma under- ized genetic aberrations of K-ras oncogene and p53 going primary surgery between 1994 and 2004 were tumor-suppressor gene as early events in evolution retrieved from the databases of two tertiary medical of gallbladder carcinoma, whereas these alterations centers in Southern Taiwan. Of these, 62 cases with are not associated with tumor progression and 6,7 available paraffin blocks and follow-up were retro- prognosis. Accordingly, identification of prognos- spectively classified for histological types and tic biomarkers by better elucidating the molecular tumor grading according to the latest World Health basis of gallbladder carcinoma may provide a useful Organization classification.1 Other histopathological insight that aid in the development of novel targeted features evaluated included the presence or absence therapeutic strategies. of spontaneous tumor necrosis and vascular inva- Physiologically, cyclin E levels determine the time 8,9 sion. In addition, pathological staging was deter- point when cells enter S phase, and its critical mined based on the 6th edition of American Joint oncogenic role is also shown by its overexpression Committee on Cancer (AJCC) system.32 Institutional and profound prognostic impact in breast, ovarian, 10–15 review boards of the participating hospitals ap- and non-small cell pulmonary carcinomas, etc. proved retrospective clinical data collection and Cyclin A is not only required for DNA replication procurement of archival tissues. Surgical proce- during S-phase progression but also active in the 15,16 dures were cholecystectomy in 54 patients and initiation of mitosis. Increased cyclin A level has extended operation in the remaining 10 patients. been linked to accelerated cell proliferation and The former procedure comprised single cholecys- associated with shorter survival in several types of 15–18 Kip1 tectomy or cholecystectomy with resection of less cancers. P27 is a new tumor suppressor that than 2 cm depth of the liver bed, whereas extended specifically inhibits the activity of both cyclin operation included resection of adjacent organs in E/CDK2 complex in G1/S transition and cyclin addition to the gallbladder. The median period of A/CDK2 complex in S phase to control cell cycle 9,13 Kip1 follow-up was 29 months (range, 1–186) for all 62 progression. Reduced expression of p27 pro- patients. For 28 survivors, the minimal and median tein was recently found correlated with tumor durations of follow-up were 6 and 31 months, progression and prognosis in gallbladder carcino- respectively. ma.19,20 However, downregulation of p27Kip1 mRNA is rarely observed in human malignancies.9 Instead, Kip1 it becomes apparent that aberrant loss of p27 Construction of TMA Blocks and protein in malignant diseases results mainly from Immunohistochemistry enhanced ubiquitin-mediated proteolysis regulated by Skp2, a member of the F-box protein family, Recut hematoxylin and eosin-stained sections were which targets Thr187-phosphorylated p27Kip1 for examined to define representative tumor and non- degradation.21–25 More recently, human cyclin-de- neoplastic tissues. Corresponding paraffin blocks pendent kinase subunit 1 (Cks1) has been identified were then precisely aligned with the marked slides. as a cofactor in the ubiquitination and degradation To circumvent the problem of tissue heterogeneity, of p27Kip1, which increases the affinity of SCFSKP2 six tissue
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