International Journal of Radiation Oncology*Biology*Physics
Clinical InvestigationEffect of S-Phase Kinase-Associated Protein 2 Expression on Distant Metastasis and Survival in Nasopharyngeal Carcinoma Patients
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.
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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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Cited by (32)
Silencing of S-phase kinase-associated protein 2 enhances radiosensitivity of esophageal cancer cells through inhibition of PI3K/AKT signaling pathway
2020, GenomicsCitation Excerpt :The in vitro experiments in our study revealed that SKP2 knockdown decreased mRNA and protein expression of PI3K, AKT and Bcl-2 while increasing p27 protein expression. Overexpressed SKP2 is correlated with many human cancers, including nasopharyngeal carcinoma, colorectal carcinoma, and breast cancer [30–32]. Furthermore, PI3K/AKT signaling pathway is constitutively activated in cancers, and is correlated with cell viability, drug resistance and tumor growth in cancer cells [13].
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2016, Biochimica et Biophysica Acta - Reviews on CancerCitation Excerpt :On the other hands, overexpression of Skp2 in mice led to tumor development including lymphoma [116], prostate cancer [114], and mammary gland tumor [113]. Consistently, overexpression of Skp2 has been frequently observed in a variety of human cancers such as lymphomas [117,118], pancreatic cancer [119], breast carcinomas [120–124], prostate cancer [125,126], melanoma [127–129], and nasopharyngeal carcinoma [130,131]. Importantly, Skp2 expression is associated with histological grade and tumor size in hepatocarcinoma [132].
E2F transcription factor 1 overexpression as a poor prognostic factor in patients with nasopharyngeal carcinomas
2013, Biomarkers and Genomic MedicineCitation Excerpt :The advances in diagnostic imaging, radiation therapy, and adjuvant chemotherapy of NPC have achieved better locoregional control, whereas it appears less satisfactory in final treatment outcomes.4,5 Despite being an important parameter, tumor size, nodal status, and metastasis (TNM) staging still has space to improve in terms of providing the optimal prognostication to the patients.1,4−6 Therefore, to identify potential biomarkers with better correlation to tumor growth and/or treatment outcomes in patients with NPC, subsequently, to aid in risk stratification and perhaps development of therapeutic targets, is indispensable.
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.