Clinical Investigation
Effect of S-Phase Kinase-Associated Protein 2 Expression on Distant Metastasis and Survival in Nasopharyngeal Carcinoma Patients

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Purpose

The S-phase kinase-associated protein 2 (Skp2) oncoprotein is an E3 ubiquitin ligase targeting the p27Kip1 tumor suppressor for degradation. We evaluated the prognostic utility of Skp2 in nasopharyngeal carcinoma (NPC), with an emphasis on distant metastasis-free (DMF) survival.

Methods and Materials

Immunohistochemical expression of Skp2 was assessed by H-score for 233 NPC patients without initial distant metastasis and correlated with the clinicopathologic features, therapeutic modalities, locoregional control rate, DMF survival, and overall survival (OS). No selection bias in essential parameters was shown between these and another 113 control patients.

Results

Skp2 was detectable in most patients (95%) but displayed a wide range of expression. Despite no correlation between Skp2 and any clinicopathologic factor, greater Skp2 expression (H-score >80) significantly portended inferior DMF survival (p = 0.01) and OS (p = 0.02) when categorically dichotomizing the study cohort. The associations with DMF survival (p = 0.003) and OS (p = 0.003) became even stronger when the H-score was expressed as a continuous variable. In the multivariate model, greater Skp2 expression remained significantly predictive of poorer DMF survival and OS (p = 0.01 for both), along with T stage (p = 0.04 for DMF survival; p = 0.005 for OS), N stage (p = 0.008 for DMF survival; p = 0.02 for OS), and/or age (p = 0.001 for OS). In contrast, T stage (p = 0.01) was the single independent prognosticator of LCR.

Conclusions

The results of our study have shown that Skp2 expression is frequent in NPC and has a wide range of distribution in H-score. Skp2 overexpression is significantly predictive of DMF survival and OS, independent of the T stage and/or older age. Therefore, Skp2 might represent a useful prognostic adjunct to risk stratify NPC patients for appropriate allocation of adjuvant therapy.

Introduction

Nasopharyngeal carcinoma (NPC) is an endemic head-and-neck epithelial malignancy in Taiwan (1). The advances in diagnostic imaging, radiotherapy, and adjuvant chemotherapy have achieved improved locoregional control (LRC) 2, 3. To date, distant metastasis is still the major cause of mortality in NPC patients, and the underlying molecular aberrations contributing to the metastatic propensity in aggressive NPC remains to be further elucidated 2, 3. Accordingly, the identification of an effective biomarker that better correlates with metastasis-free survival in patients with NPC is of paramount importance in treatment decisions.

During stepwise tumorigenesis, deregulation of cell cycle regulators represents a common mode of promoting progression and the survival advantage of aggressive tumor subsets, thereby conferring an adverse prognostic effect on patient survival 4, 5, 6. Of the cyclin-dependent kinase inhibitors, we had previously reported the value of aberrant loss of p27Kip1 expression in predicting for inferior LRC (7). However, the correlation of p27Kip1 expression with metastatic disease was not well elaborated owing to the small number of cases. It has become clear that the expression of p27Kip1 protein is primarily regulated at the post-transcriptional level by S-phase kinase-associated protein 2 (Skp2), a substrate-recognizing E3 ubiquitin ligase that targets p27Kip1 for degradation by 26S proteasome (8). Several lines of evidence have documented a significant correlation of Skp2 overexpression with decreased p27Kip1 expression and aggressive clinical behavior in a variety of caners, such as head-and-neck squamous cell carcinoma (5), malignant lymphoma (9), and common types of sarcoma 10, 11. Nevertheless, thus far, no systematic study has specifically addressed the prognostic role of Skp2 expression in NPC. With special attention given to metastasis-free survival, we aimed to analyze the expression status and prognostic significance of Skp2 using immunohistochemistry in a well-defined, large cohort of NPC patients.

Section snippets

Study population

Between January 1996 and December 1999, 346 patients presented with NPC without distant metastasis at diagnosis, underwent radiotherapy (RT) alone at Kaohsiung Chang Gung Memorial Hospital, and had sufficient clinical follow-up. In this cohort, immunohistochemical study for Skp2 expression could be performed for 233 patients (68%) with available paraffin-embedded blocks of pretreatment biopsy. These patients formed the study group in this series. To exclude a potential selection bias, the

Results

In most NPC patients, Skp2 was detectable, albeit with a wide variation in expression. Among the 233 patients tested, Skp2 displayed a wide range of H-scores, from 0 to 370 (median, 85.0; mean, 95.9 ± 81.8, Fig. 1), and its expression was found in the vast majority of patients (n = 218, 95%).

Discussion

Despite its high radiosensitivity, a subset of aggressive NPC is characterized by considerable metastatic potential, an essential cause leading to the disease-related mortality 2, 3, 15. Approximately 30% of patients with NPC developed distant failure after initial RT in our institution. With an increasing need for patient-tailored strategy to treat high-risk cases, the identification of a biomarker that can independently correlate with metastatic behavior might allow for clinical outcome

Conclusions

We systematically analyzed the prognostic utility of Skp2 expression in a well-characterized, large series of NPC. Skp2 is detectable by immunohistochemistry in the vast majority of NPC cases but shows a wide range of distribution in expression, as assessed by H-score. Along with greater T stage and/or older age, Skp2 overexpression is independently predictive of DMF survival and OS. Accordingly, it might represent a useful prognostic adjunct to better stratify NPC patients at differing risks

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    F.-M. Fang and C.-Y. Chien contributed equally to this work.

    Supported by Grant NSC95-2314-B-182A-185 from the National Science Council, Taiwan.

    Conflict of interest: none.

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