Lung cancer is the second leading illness that contributes to years of life lost due to premature mortality (19). The prognosis of MPM is even much worse. Therefore, search of additional biomarkers for the development of novel strategies for its early detection is mandatory.
Although the incidence of adenocarcinoma (50.60%) during the period 1998–2007 was about twice that of squamous cell carcinoma (25.24%), the former did not attract as much attention as the latter, which is associated with cigarette smoking, according to data from the National Cancer Registry (20). In the current study, adenocarcinoma was present in 57.1% and squamous cell carcinoma was present in 42.9% of the included patients with non-small cell lung carcinoma (NSCLC). Recently, there is an increased incidence of MPM, associated with a poor prognosis. It is classified pathologically into epithelioid, sarcomatoid, or biphasic types, 55, 15, and 30% of cases of MPM, respectively (21,22). In the current study, 66.7% of the included MPM patients had epithelial mesthothelioma, while the remaining 33.3% had sarcomatoid type.
Survivin over expression in different malignant tumors pretends to be a causal association between survivin up-regulation, higher malignant grades and decreased survival rates (23). In this study, the expression levels of survivin and fibulin-3 were evaluated in oncologic and non-oncologic diseases of the lung and the pleura. Our findings revealed a significantly higher circulating and local expression levels of survivin in bronchogenic carcinoma patients compared to those with benign lung diseases; with a non-significant difference in its serum levels as regards the histological types and a non-significant correlation with the tumor stage. Many investigators were in line with our findings (24–26).
Although a meta-analysis performed by Duan et al.(27) indicates survivin expression was correlated with tumor stage, but not pathological type and tumor size. They also reported higher survivin expression in patients with NSCLC compared with normal controls. In addition, Naumnik et al.(28) reported no correlation between serum survivin concentrations and the histological type or staging of lung cancer, in contrary, they reported that survivin concentrations were the same in patients with NSCLC as in healthy people. The discrepancy may be attributable to differences in the tumor entities, different experimental settings such as patients' selection criteria and study design. In these sense, putative survivin antagonists under study are showing promising antitumoral potential (29).
Notably, our results showed significantly higher serum survivin levels in patients with benign lung diseases when compared with the healthy controls. This confirms similar findings reported by Terasaki et al,(30) who described its high expression as a key mediator of cytoprotection in acute lung injury that is partly dependent on apoptosis inhibition.
The findings of the present study revealed significantly lower circulating and local fibulin-3 expression levels in patients with lung cancer when compared with those having benign lung lesions with non-significant differences in its serum levels in term of histological types and no significant correlation with the stage of lung cancer. Additionally, there was a non-significant difference in fibulin-3 serum levels between patients with benign lung lesions compared to the healthy controls. Our results were consistent with other studies documenting downregulation of fibulin-3 in lung cancer due promoter hypermethylation (10,31,32). Participation of fibulin-3 in cancer may depend on the pathways, protein-protein interactions and tumor microenvironment involved (33). In lung cancer, downregulation of fibulin-3 is needed to enhance invasion and metastasis through Wnt/β-catenin activation and matrix metalloproteinase-7 (MMP-7) expression (11).
Regarding the included patients with pleural diseases, there were significant higher circulating and local expression levels of both survivin and fibulin-3 in patients with MPM when compared with both those had benign pleural lesions and the healthy controls with lack of association of survivin and fibulin-3 with the MPM stage or histological types. Additionally, there were no significant differences in the circulating fibulin-3 between benign pleural diseases group and the healthy controls. Many researchers were in consistent with our findings (13,34,35,36).
To the best of our knowledge, this is the first study to report absence of significant correlations between survivin and fibulin-3 in various benign or malignant respiratory diseases.
Area under curve (AUC) of summary receiver operating characteristics (sROC) is an index that specifies the overall diagnostic value of a test [37]. The literature researches lack the validity of survivin and fibulin-3 in diagnosing lung cancer and MPM. We reported non-significant difference in the diagnostic validities of survivin and fibulin-3 in diagnosing lung cancer or predicting MPM. Although no published data regarding the utility of survivin in diagnosing lung cancer, humoral fibulin-3 test data published revealed high variability among studies and still remains a contentious issue (38). A meta-analysis study reported that blood fibulin-3 is useful for MPM diagnosis and its validity was higher than soluble mesothelin-related peptides (SMRP) and osteopontin (38). Few studies could be traced in literature and reported similar findings (37, 39).
To the best of our knowledge, this is the first report comparing the validity of serum survivin vs fibulin-3 in discriminating lung cancer from MPM and revealed that sensitivity, specificity and AUC for survivin at cut-off point > 632 pg/ml were 52.38%, 86.67%, and 0.603, respectively, while for fibulin-3 at cut-off point ≤ 9.16 pg/ml were 100.0%, 93.3%, and 0.994, revealed that fibulin-3 a more valid biomarker in differentiating MPM from lung cancer.
In conclusion, the current research showed that serum survivin and fibulin-3 could be used for lung cancer and MPM as effective diagnostic markers. No significant differences in the diagnostic validity of serum survivin and fibulin-3 were found in predicting lung cancer or MPM from corresponding benign lesions, while serum fibulin-3 was more helpful in differentiating lung cancer from MPM. Furthermore, the present study confirms the lack of associations between survivin and fibulin-3 expression levels with both the histological types and tumor stage.