Nasopharyngeal carcinoma (NPC) is a form of malignancy at the tissue of the upper section of pharynx behind the nose [1] – the nasopharynx region. Globally, it accounts for 65,000 deaths yearly but also has a regionally varied incidence rate [2]. In endemic regions such as Southern China, Southeast Asia and the Middle East, there are over 20 cases per 100,000 people albeit rare in North America and Europe [3]. Based on World Health Organization (WHO) classification, NPC is histologically categorized as three subtypes, namely Type I: keratinizing differentiated squamous cell carcinoma, Type II (or 2a): non-keratinizing differentiated squamous cell carcinoma, and Type III (or 2b): non-differentiated undifferentiated basaloid squamous cell carcinoma [4]. The more chemo-sensitive type (Type III/2b) is predominant among Asian cases, whereas Types I and II/2a are mostly found in Western countries [5].
Risk factors for NPC include genetic, viral (Epstein–Barr Virus, EBV) infection, environment, lifestyle (smoking), and consumption of certain preserved food [6]. Early stages of malignancy usually involve invasion of NPC cells to surrounding tissue and cervical lymph nodes [7, 8]. Despite the radio-sensitivity of NPC tumors, patients with advanced stages show poor survival rate [9 – 12]. Improved therapeutic techniques such as concurrent chemotherapy with or without neo-adjuvant/adjuvant, intensity-modulated radiation therapy (IMRT), and high resolution magnetic resonance image (MRI) monitoring have been the standard treatment protocol for locally advanced NPC [13 - 15]. Nevertheless, relapse and metastasis still occur in approximately 20-50% of patients [16].
Studies have shown that NPC patients in the same classification present with different prognosis [17, 18]. This suggests that ethnicity consideration [19] and bio-molecular factors associated with survival outcome [20] may be necessary to accurately distinguish NPC patients for individualized and tailored treatment that is more effective. As such, identifying prognostic factors, particular molecular/genetic factors, that correspond closely to the actual clinical outcomes is necessary for improvement of therapies that yield better treatment outcome.
One such candidate biomarker of potential prognostic significance to NPC is the Cyclooxygenase-2 (Cox-2) gene. Its expression has clinical and prognostic significance in cancers of the head and neck [21]. More specifically in NPC, its involvement in carcinogenesis is most probably via participation in the formation of inflammatory microenvironment that has consequence on tumorigenesis and malignancy [22]. Cox-2 overexpression is also associated with metastasis to lymph node in NPC patients [23]. Its most probably mediates metastasis in NPC by promoting interactions between cancer and myeloid-derived suppressor cells [24].
Cox-2, one of the two isoforms of Cox gene and a key enzyme in the conversion of arachidonic acid to prostaglandins, is known to be poorly expressed (if not detectable at all) in most normal tissues but is rapidly induced by pro-inflammatory cytokines, growth factors, carcinogens and tumor promoters [25 - 28]. Its overexpression in various cancers has been linked to angiogenesis, invasion, and apoptotic resistance - suggesting its involvement in inflammation-induced tumorigenesis, and its influence on the outcome and survival of cancer cells [24, 26, 29 - 33]. Interestingly, the functional abrogation of Cox-2 via Cox inhibitor reverses cancer progression [34 - 37]. Actions of Cox inhibitor and non-steroidal anti-inflammatory drugs (NSAIDs) have effects on the reduced incidence and progression of tumors in animal models [38].
To date, a comprehensive review analysis of Cox-2 as per its prognostic value for NPC is lacking. Inferences from existing literature linking its expression to NPC tissues are compounded by the fact that the experimental studies differ in methodology, and each of them was biased by relatively small sample size. As a result, findings have not been consistent. Herein, we report a systematic review and meta-analysis study to established the relationship between Cox-2 expression and survival outcome and treatment response in NPC patients.