Tumorigenesis role and clinical significance of DJ-1, a negative regulator of PTEN, in supraglottic squamous cell carcinoma

Zhu et al. Journal of Experimental & Clinical Cancer Research 2012, 31:94 http://www.jeccr.com/content/31/1/94 RESEARCH Open Access Tumorigenesis role and clinical significance of DJ-1, a negative regulator of PTEN, in supraglottic squamous cell carcinoma Xiao-Lin Zhu1,2, Zhang-Feng Wang1,2, Wen-Bin Lei1,2, Hui-Wen Zhuang1,2, Wei-Jian Hou1,2, Yi-Hui Wen1,2 and Wei-Ping Wen1,2* Abstract Background: DJ-1 can induce the tumor cell proliferation and invasion via down-regulating PTEN in many malignant tumors, and correlated to prognostic significance. However, the tumorigenesis role and clinical significance of DJ-1 in supraglottic squamous cell carcinoma (SSCC) is unclear. We aimed to evaluate the DJ-1 the relationship between DJ-1 and clinicopathological data including patient survival. Methods: The expression of DJ-1 and PTEN in SSCCs (52) and adjacent non-cancerous tissues (42) was assessed by immunohistochemistry (IHC), and the relationship between DJ-1 and clinicopathological data was analyzed. Results: DJ-1 was detected mainly in SSCCs (88.5%) and less frequently in adjacent non-cancerous tissues (21.0%). PTEN expression was detected in 46.2% of SSCCs and in 90.5% of adjacent non-cancerous tissues. DJ-1 expression was linked to nodal status (P = 0.009), a highly significant association of DJ-1 expression with shortened patient overall survival (5-year survival rate 88.0% versus 53.9%; P = 0.007; log rank test) was demonstrated. Conclusions: Our data suggested that DJ-1 over-expression was linked to nodal status, and might be an independent prognostic marker for patients with SSCC. Keywords: DJ-1, PTEN, Tumorigenesis, Supraglottic squamous cell carcinoma, Overall survival Background Laryngeal squamous cell carcinoma (LSCC), one of the most common malignancies of the head and neck region, accounts for approximately 2.4% of new malignancies worldwide every year [1,2]. Supraglottic squamous cell carcinoma (SSCC), one advanced type of LSCC, is often accompanied by lymph node metastasis or even systemic metastasis, and usually results in substantial annual morbidity and mortality. Hence, to predict the biology of the tumor and the course of the disease in individual patient is importance for appropriate therapy and patient surveillance. The evaluation of a SSCC patient’s prognosis and predictive markers is primarily based on the clinical tumor- * Correspondence: 1 Department of Otorhinolaryngology Head and Neck surgery, The First Affiliated Hospital, Sun Yat-Sen University, 2nd Zhongshan Road 58#, Guangzhou 510080 Guangdong, P.R. China 2 Otorhinolaryngology Institute, Sun Yat-Sen University, 2nd Zhongshan Road 58#, Guangzhou 510080 Guangdong, P.R. China node-metastasis (TNM) staging [3]. However, patients with SSCC with similar clinical stage classifications usually have different clinical outcomes, suggesting that TNM staging is not sufficient for precisely determining a SSCC prognosis. Therefore, identifying specific biomarkers which have diagnostic and prognostic value for SSCC remains a priority. DJ-1, a mitogendependent oncogene, was firstly reported by Nagakubo in 1997 [4]. Recent studies indicated that DJ-1 is closely related to the proliferation, metastasis, occurrence, and prognosis of the malignant tumors [2,5-13]. In our recent study of glottic squamous cell carcinoma [2], DJ-1 was shown as an independent molecular marker for poor prognosis, and was correlated with pT status and tumor grading. In other LSCC studies [2], DJ-1was also identified as an activator of cell proliferation, and was related to T stage and poor prognosis [14,15]. However, the relationship between DJ-1 and lymph node metastasis of LSCC have not been revealed both in our and others’ studies. © 2012 Zhu et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Zhu et al. Journal of Experimental & Clinical Cancer Research 2012, 31:94 http://www.jeccr.com/content/31/1/94 Phosphatase and tensin homologue (PTEN) is a dualspecific phosphatase that plays an important role in tumorigenesis and reduced PTEN expression is associated with cell survival, proliferation, tumor invasion, and tumornode-metastasis (TNM) stage [14-20]. Furthermore, LSCC studies showed that reduced PTEN expression is also related to cell proliferation, tumor invasion, lymphatic metastasis, and TNM stage [21-23]. Recent studies have showed that PTEN might be regulated by DJ-1 in several cancers, such as renal cell carcinoma, breast cancer, bladder carcinoma, and ovarian carcinoma [8,24-26]. Kim RH [8] found that DJ-1 could activate cell proliferation and transformation by negatively regulating PTEN expression in breast cancer cells. The above evidence suggests that the DJ-1-induced PTEN down-regulation may be involved in LSCC progression and act as activator of the invasion process in LSCC. To date, the relationship between DJ-1 and clinicopathological data including patient survival in SSCC have not been revealed. The aim of this study was to investigate the relationship between DJ-1 and clinicopathological data including patient survival. Page 2 of 6 Table 1 Clinicopathological parameters of the tumor set Gender Age(y) pT status pN status Stage (UICC) Material and methods Patients A total of fifty seven SSCC patients were eligible for this study. 2 and 3 patients were excluded because of insufficient tissue samples and incomplete follow-up data, respectively. 52 subjects with SSCCs and 42 subjects with adjacent non-cancerous tissues were thus examined. These patients underwent surgery in our department from January 1996 to September 2006, and clinical follow-up data were completed. The average observation time for overall survival was 62 months for patients still alive at the time of analysis, and ranged from 7 to 122 months. Twenty-eight patients (53.8%) died during follow-up. Tumor tissues from the resected specimens and adjacent non-cancerous tissues were used as normal control (tumor and adjacent non-cancerous tissues were confirmed by pathologic examination). The tissues used for immunohistochemistry were fixed in 4% polyformaldehyde and embedded in paraffin. All specimens and clinical data in this study were procured, handled, and maintained according to the protocols approved by Institutional Review Board (IRB), and all of the patients who participated in the study provided informed consent. The principal inclusion criteria were primary squamous cell carcinoma of the supraglottis type only, no history of previous malignant disease, and no history of previous radio- or chemotherapy. The main clinical and pathologic characteristics of the patients are presented in Table 1: 49 (94.2%) were male and with a median age was 59.0 years (ranging from 39–81 yea (...truncated)