Over the past 50 years, the worldwide incidence of lung cancer has significantly increased. In developed countries and large cities, lung cancer has become the most common type of cancer among males. In many countries, the number of mortalities due to lung cancer has surpassed the combined numbers from prostate cancer, breast cancer and gastrointestinal tumors (1,2). The majority of patients with lung cancer are males over the age of 40; however, the number of female patients has also increased significantly in recent years. Typically, lung cancer is divided into two categories: Small cell lung cancer (SCLC) and non-SCLC (NSCLC). As SCLC is distinct from NSCLC with respect to its biological behavior, treatment, prognosis and other features, the present study focused on the associations between NSCLC prognosis and the uPA system. Although there has been considerable progress in the diagnosis and treatment of NSCLC in recent years, the majority of cases are diagnosed only at an advanced stage. Consequently, the 5-year survival rate for NSCLC is ~15% (3). The invasion and distant metastasis of NSCLC cells are the most important biological characteristics of malignant lung tumors; these phenomena result in the associated low survival rates of patients with NSCLC (4). Thus, a biomarker that facilitates the recognition of NSCLC invasion, metastasis and prognosis would aid thoracic surgeons in treatment regimen selection.

The uPA system includes urokinase plasminogen activator (uPA), uPA receptor (uPAR), and two inhibitors, PA inhibitor type 1 (PAI-1) and PAI type 2 (PAI-2). uPA can be produced by fibroblasts, monocytes, neutrophils, epithelial cells and tumor cells, among others. The specific receptor for uPA, uPAR, is a multifunctional receptor able to mediate the activation of PA, signaling pathways, cell adhesion and metastasis following the binding of uPA (5–8). uPAR is composed of 283 amino acid residues and has a molecular weight of 55–60 kDa. The receptor is a glycoprotein that is anchored to the membrane by a glycosylated phosphatidylinositol. This glycoprotein regulates proteolysis at the invading edge of tumors (9). uPAR serves a critical function in cancer progression through its interaction with integrins and vitronectin, and its role as a regulator of angiogenesis. PAI-1 and PAI-2 are specific inhibitors of uPA; PAI-1 exhibits increased activity in comparison with PAI-2, and is the primary inhibitor of uPA. PAI-1 is predominantly produced by blood platelets, epithelial cells, granulosa cells and tumor cells. PAI-2 is produced by tumor cells, trophoblasts and monocytes, and exhibits increased expression levels in the plasma of pregnant females. PAI combines with uPA (1:1 ratio) to generate a stable complex that inhibits uPA-mediated activities (10).

Numerous studies have indicated that the expression levels of uPA, uPAR, PAI-1 and PAI-2 significantly correlate with poor prognoses (11–13). In the present study, recent and relevant literature regarding associations between the uPA system and NSCLC were analyzed, and inconsistencies in the conclusions were revealed. Certain articles reported that high uPAR expression levels correlate with poor overall survival (OS), while other articles revealed no such association. Thus, a meta-analysis on the current and available research was conducted, in order to evaluate the associations between protein expression in the uPA system and the prognosis of patients with NSCLC.

The present meta-analysis investigated the associations between OS and uPA, uPAR, PAI-1 and PAI-2 expression in patients with NSCLC using English language peer-reviewed scientific articles. Following reading of the full journal articles selected from the databases, certain discrepancies were identified in the conclusions. Thus, to more accurately evaluate the associations between the expression of proteins in the uPA system and the prognosis of patients with NSCLC, a total of 11 articles were selected to conduct a meta-analysis of the included 937 patients. Results of the meta-analysis indicated that the expression levels of uPA, PAI-1 and PAI-2 had no significant association with poor OS in patients with NSCLC. Conversely, high expression of uPAR did significantly correlate with poor OS for patients with NSCLC.

uPAR is a 55–60 kDa glycoprotein that belongs to the Ly-6 family (28). The gene encoding for this receptor is located on chromosome 19q13.2, and is composed of seven exons separated by six introns (29). The binding of uPA to uPAR orchestrates various signaling molecules that mediate a number of biological responses, including proliferation, migration, invasion, angiogenesis and metastasis (30). Cancer cells can produce uPA and uPAR; uPA binds to uPAR on the surface of these cells, activating the proteolytic domain of uPA, as well as stimulating intracellular signals leading to the upregulation of uPAR and uPA itself. The uPA-uPAR complex can subsequently facilitate the transformation of plasminogen to plasmin, which can then cause extracellular matrix degradation (31). These events confer tumor cells with the ability to degrade the components of the surrounding extracellular matrix, thus contributing to tumor cell invasion and metastasis, resulting in poor OS.

The interaction between uPA and uPAR also results in the release of signaling molecules that stimulate cell proliferation/survival and the expression of tumor-promoting genes (32). Consequently, the binding of uPAR by uPA assists in the process of tumor development. Indeed, an inhibitory peptide that prevents uPA-uPAR interaction has demonstrated promise in prolonging patient survival during the early stages of a clinical trial (33). Furthermore, recent studies have identified significant differences in the expression of uPAR between cancer tissues and normal tissues (34). In general, the importance of the uPAR co-receptor in facilitating the tumor-promoting effects of uPAR suggests that disruption of the interactions between uPAR and its functional partners may be a potentially crucial strategy for the development of anticancer therapeutic agents.

Some limitations need to be acknowledged for the current meta-analysis. First, the sample size included was relatively small (937 patients with NSCLC). Second, the various histological types of NSCLC, including squamous cell carcinoma and adenocarcinoma, exhibit stereotypical biological characteristics, which create a certain level of bias. Third, the uPA expression profiles pertaining to numerous rare types of NSCLC, including squamous carcinoma, sarcomatoid carcinoma, carcinoid, and unclassified cancer types, are currently unknown. Thus, further clinical trials are required before these forms of cancer can be optimally evaluated. Fourth, the potential confounding variables in each individual study were unable to be assessed. For example, certain studies may have evaluated a combination of various histological types of NSCLC; alternatively, the methods used for the evaluation of uPAR expression and differences pertaining to the cutoff (detailed data are not listed) may have differed between studies. Fifth, certain studies could not be included in the meta-analysis owing to the lack of detailed data; sixth, the varied locations and ethnicities may have also contributed to hidden bias.

In conclusion, the present meta-analysis demonstrated that uPAR is associated with the poor prognosis of NSCLC. Thus, uPAR can be used as a biomarker for determining the prognosis of NSCLC, and may assist clinicians in selecting and applying more effective strategies for the treatment of patients with NSCLC.