NPC is a malignant neoplasm arising from the mucosal epithelium of the nasopharynx, most often within the lateral nasopharyngeal recess, and is thought to be closely associated with Epstein-Barr virus infection, dietary, and genetic factors. The majority of NPC-related deaths are attributed to tumor metastasis rather than to the primary tumor. However, the molecular mechanisms underlying NPC invasion and metastasis are not completely understood. Thus, novel molecular markers that can identify tumor metastasis and aid in prognosis assessment are urgently needed.
Immunohistochemistry is an indispensable research tool frequently used to study tumor progression and prognosis. Here, we evaluated SPARC protein expression detected by immunohistochemical techniques in a large and well-documented cohort of primary NPC samples, and correlated the results with clinicopathological characteristics and patient survival. In many NPC specimens, over expression of SPARC was frequently detected. We also demonstrated that SPARC was highly expressed at both the mRNA and protein levels in NPC cell lines as compared with NPEC2 Bmi-1. The expression of SPARC in all normal nasopharyngeal epithelium detected by IHC was absent, suggesting that SPARC is a common feature in NPC that might play an important role in its prognosis and metastasis.
Over-expression of SPARC was frequently observed in the tumor specimens analyzed, and showed statistically significant association with high tumor metastasis and poor prognosis. In the patients here, higher SPARC expression was significantly associated with tumor progression (metastasis and poor prognosis) and the advanced stages of NPC. In addition, patients with lower SPARC expression had an improved prognosis. These observations between SPARC expression and tumor progression are consistent with other malignancies, such as gastric cancer  and renal carcinoma . The expression of SPARC has been positively correlated with the histological grade of tumor cells in bladder cancer , thyroid cancer , glioma  and HCC . In the present study, SPARC expression still remained a significant predictor in the advanced stage. Radiotherapy has become the standard treatment for NPC patients with earlier stage. Although chemo-radiotherapy is a popular therapy for advanced NPC, improving the survival of these patients still remains a significant challenge . SPARC may be a marker for advanced NPC as a potential therapy agent. Advanced NPC patients with low SPARC expression may accept the mild treatment without the radical therapy. By contrast, advanced NPC patients with higher SPARC expression may benefit from higher-dose radiation, adjuvant therapy, or molecular target therapy. Multivariate Cox proportional hazards survival analysis suggested that SPARC over-expression had a significantly worse prognostic impact (P < 0.001) on survival of NPC patients. Consistent with the findings reported by the previous studies, we confirmed that the independently significant negative predictive factors for survival included advanced increased age (P < 0.001) and advanced clinical stage (P < 0.001) [40–42]. These results indicate that as an independent risk factor, SPARC may serve as a prognostic marker for survival of NPC patients.
SPARC functions as a regulator of cell-matrix interaction, and is generally recognized to mediate de-adhesion thereby promote cell migration . It has a profound influence on cancer progression . However, a previous study  revealed that SPARC expression was higher in NPEC than in NPC cell lines. With the results of the current study, we speculated that endogenous SPARC expression was higher in NPC cell lines than in the NPEC2 Bmi-1. This seems to contradict our current study. One possible reason is that the current results here were showed in a large retrospective cohort. Another reason may be the difference in the distribution of NPC patients and NPC cell types. Especially, high levels of SPARC often correlated with the lymph node metastasis, enhanced invasion, metastasis, and poor prognosis [13, 17, 46, 47], for example, metastasis to the colon, lung, esophagus and pancreas . Previous studies [49–51] using prostate cancer tissue samples reported that SPARC expression was higher in metastatic sites than in the primary site. These phenomena suggest that SPARC plays different roles in cancer progression in different tumor cell types and acts via different signal transduction pathways .
Our study may have suffered from the limitation: as discussed above the difference of SPARC expression between the NPEC2 Bmi-1 cell line and NPEC was not objectively verified. However, we chosen the NPEC2 Bmi-1 cell line as a control because it is the immortalized cell line closest to normal nasopharyngeal epithelium. Furthermore, the immortal NPEC cell line (NPEC2 Bmi-1) is a pre-malignant nasopharyngeal epithelial cell model and maintains a normal P53 checkpoint . Compared with nasopharyngeal carcinoma cell lines, NPEC2 Bmi-1 cell line as a control may be feasible.
While a High SPARC level indicates poorer prognosis in some tumors, SPARC expression in neuroblastoma inhibits angiogenesis and impairs tumor growth . For example, the increased SPARC expression in prostate cancer, bladder cancer , melanoma  and non-small cell lung cancer indicated a higher malignancy and invasion of tumors with poor prognosis. In contrast, in ovarian cancer, elevated SPARC expression inhibited the invasion and metastasis of tumor cells . Thus, the varying influence of SPARC in different tumors reflects that the function of SPARC may be tissue-specific.