Esophageal cancer is one of the most aggressive and lethal malignancies, and esophageal squamous cell carcinoma (ESCC) is the major histologic form of esophageal cancer . Surgery is still the mainstay treatment for patients with esophageal cancer, however, the five-year risk of the operable recurrence is 70% to 80% [2, 3]. Postoperative radiotherapy as an adjuvant therapy is being used more often to improve the outcome of ESCC patients after surgery . However, not all patients with ESCC benefit from radiotherapy, and there are individual differences in response to postoperative radiotherapy. The outcomes vary greatly and unpredictably, and the survival of responders has been reported to be better than that of non-responders [4, 5]. It is important to recognize the probable treatment response in these tumors. The main obstacle to this approach is the lack of availability of prognostic biomarkers. Pretreatment clinical parameters such as gender, age, TNM classification, and tumor differentiation are not effective in predicting the biologic behavior of ESCC patients who receive postoperative radiotherapy. Thus, it is necessary to identify available biomarkers for predicting response and treatment outcomes of postoperative radiotherapy in ESCC patients.
Among the molecular pathways potentially involved in generating the differential response to radiotherapy, an association has consistently been observed between the apoptotic pathway and the tumor radiosensitivity [4, 5]. Inhibitor of apoptosis (IAP) proteins are a family of endogenous antiapoptotic proteins . Among the eight human IAP proteins, X-chromosome-linked IAP (XIAP) has been reported to exert the most pronounced antiapoptotic function, which has been linked to its ability to bind to caspase-3, -7 and -9 . Firstly, a number of studies have demonstrated that elevated expression levels of XIAP in many types of tumors correlates with a poor prognosis . Secondly, both in vitro and in vivo studies have further demonstrated that down-regulation of XIAP expression, either by RNA interference (RNAi) or antisense oligonucleotides, results in stimulation of sensitization to gamma-irradiation and chemotherapeutic-induced apoptosis in tumor cells [9–12]. Likewise, XIAP has been found to be highly expressed in ESCC, and its downregulation by RNAi sensitizes ESCC cell lines to chemotherapeutics . Additionally, more and more research has shown that XIAP acts as a radioresistance factor for radiotherapy in human cancers [14–19]. However, whether XIAP can play a role as a prognostic marker for radiotherapy in ESCC patients has not been extensively investigated to date.
Moreover, aberrant nuclear factor-κB (NF-κB) expression has been detected in many human malignancies. NF-κB is a transcription factor that regulates the expression of genes linked to inflammation, apoptosis, survival, proliferation, invasion, angiogenesis, metastasis, chemoresistance, tumor cell transformation, and radioresistance . NF-κB may activate the expression of several genes or proteins that are involved in the apoptotic regulation, such as IAPs . Furthermore, XIAP has also been implicated in the regulation of NF-κB activation . On the other hand, NF-κB may be responsible for blocking the efficacy of chemotherapy and radiation in some types of tumor cells. The positive correlation between NF-κB expression in ESCC and their resistance to chemoradiation therapy has been previously reported , but more specific studies are required to confirm the significance of NF-κB in predicting disease progression in postoperative radiotherapy of ESCC.
The aim of this study was to determine the prognostic significance of XIAP and NF-κB in terms of overall survival in ESCC treated with surgery followed by radiotherapy. This was done by using immunohistochemical staining to explore the potential markers in 78 ESCC patients who underwent a surgical resection and postoperative radiotherapy. We also investigated whether the expression levels of XIAP correlate with that of NF-κB in this patient population.