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ORIGINAL ARTICLE
Year : 2016  |  Volume : 12  |  Issue : 1  |  Page : 277-282

Increased osteopontin protein expression may be correlated with poor prognosis in non-small-cell lung cancer: A meta analysis


1 Department of Respiratory Medicine, China-Japan Union Hospital of JiLin University, Changchun 130031, Jilin Province, P.R.China
2 Department of Anesthesiology, China-Japan Union Hospital of Jilin University, Changchun 130031, Jilin Province, P.R.China
3 Department of Respiratory Medicine, Jinhua Central Hospital, Jinhua, P.R.China

Date of Web Publication13-Apr-2016

Correspondence Address:
Jing Wang
Department of Respiratory Medicine, China-Japan Union Hospital of JiLin, Xiantai Street 126, Changchun 130031, Jilin Province
P.R.China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.150362

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 > Abstract 

Aim: The present meta-nalysis investigates the prognostic value of osteopontin. (OPN) expression in patients with non-small-cell lung cancer. (NSCLC). Materials and Methods: The Web of Science (1945 ~ 2013), the Cochrane Library Database (Issue 12, 2013), PubMed (1966 ~ 2013), EMBASE (1980 ~ 2013), CINAHL (1982 ~ 2013), and the Chinese Biomedical Database (CBM) (1982 ~ 2013) were searched, without language restrictions, to retrieve studies related to OPN and NSCLC. We compiled carefully selected data and a meta-analysis was conducted using STATA software (Version 12.0, Stata Corporation, and College Station, Texas USA). Hazard ratios (HR) with corresponding 95% confidence interval (95%CI) were calculated. Results: Ten clinical cohort studies were selected for statistical analysis, representing a total of 1,133 NSCLC patients. The main findings of our meta-analysis are that patients who were OPN-positive had significantly shorter overall survival than OPN-negative patients. (HR = 1.47, 95%CI = 1.15. ~ 1.79,P< 0.001). Ethnicity.stratified analysis revealed a significant correlation between expression levels of OPN and poor prognosis of NSCLC patients among both Caucasians and Asians. (Asians: HR = 1.53, 95%CI = 0.95. ~ 2.11, P < 0.001; Caucasians: HR = 1.56, 95%CI = 1.08. ~ 2.03, P < 0.001; respectively). Conclusions: The present meta-analysis is consistent with the hypothesis that increased expression of OPN protein may be significantly associated with poor prognosis in patients with NSCLC.

Keywords: Meta-analysis, non-small cell lung cancer, osteopontin, prognosis


How to cite this article:
Shi SM, Su ZB, Zhao JJ, Yu DJ, Tu JW, Zhu JQ, Zhao JP, Sheng L, Wang SB, Sheng YJ, Chen HJ, Tian JH, Zhang Y, Wang J. Increased osteopontin protein expression may be correlated with poor prognosis in non-small-cell lung cancer: A meta analysis. J Can Res Ther 2016;12:277-82

How to cite this URL:
Shi SM, Su ZB, Zhao JJ, Yu DJ, Tu JW, Zhu JQ, Zhao JP, Sheng L, Wang SB, Sheng YJ, Chen HJ, Tian JH, Zhang Y, Wang J. Increased osteopontin protein expression may be correlated with poor prognosis in non-small-cell lung cancer: A meta analysis. J Can Res Ther [serial online] 2016 [cited 2019 Nov 22];12:277-82. Available from: http://www.cancerjournal.net/text.asp?2016/12/1/277/150362




 > Introduction Top


Non small cell lung cancer (NSCLC) refers to all types of epithelial lung cancer, with the exception of the small cell lung cancer. Lung cancer is the most common cause of cancer deaths in both men and women worldwide.[1] An estimated 226,200 new cases (116,500 in men and 109,700 in women) of lung and bronchial cancer were diagnosed in 2012, with 160,300 deaths (87,700 in men and 72,600 in women) occuring from these diseases.[2] Recently, lung cancer is predominantly observed among former smokers rather than current smokers, in United States and around the world.[3] Developing countries such as China, which has experienced a dramatic increase in cigarette smoking rates over the past 2 decades, has yet to see the expected peak in lung cancer incidence.[4] Generally, genetic and non-genetic risk factors may combine to contribute to the risk of NSCLC.[5],[6] The primary non-genetic risk factors for NSCLC include smoking tobacco, drinking alcohol, insufficient exercise, air pollution, and occupational exposure.[7],[8] Recent studies have indicated that overexpression of osteopontin (OPN), by transfection of exogenous OPN, increased malignant phenotype, while on the other hand, OPN knock-down decreases the malignant potential, suggesting that increased expression of OPN is closely related to NSCLC pathogenesis.[9],[10]

OPN, also known as bone sialoprotein I (BSP-1 or BNSP), is a multifunctional glycophosphoprotein and an important member of the secreted acidic proteins family, originally identified as a protein secreted from malignant epithelial cells.[9] Along with its function in biomineralization, wound healing, and tissue remodeling, OPN also serves an important adhesive bone matrix protein, playing a critical role in immune cell recruitment, cell activation, and apoptosis.[11],[12],[13] In fact, OPN may interact with multiple cell surface receptors that are ubiquitously expressed and may contribute to its activation in many physiological and pathological processes, including bone turnover, tumorogenesis, inflammation, ischemia, and immune responses.[14],[15] For these reasons, it is hypothesized that regulating the plasma levels of OPN may be useful in treating autoimmune diseases, cancer metastasis, bone mineralization diseases, and some forms of stress.[16],[17],[18] Indeed, previous evidence has shown that increased levels of OPN were detected in various diseases, including development of allergic airway disease, breast cancer, ovarian cancer, Duchenne muscular dystrophy.[19],[20],[21],[22] More importantly, overexpression of OPN was also frequently observed in human NSCLC, and is associated with shortened survival in patients with early-stage or late-stage disease.[23] A potential reason for this association was suggested that OPN promotes invasion and metastasis of lung cancer cells is by interacting with integrins and participating in the cell proliferation, extracellular matrix remodeling, and decreases cell adhesion, all of which eventually contribute to tumor progression.[4],[24] Therefore, we hypothesize that increased expression of OPN may be a critical in predicting the clinical outcome of NSCLC. In this context, several studies have observed that elevated OPN levels may be an indicator of the aggressiveness of NSCLC, based on its critical role in mediating angiogenesis and stimulating growth, metastasis, and survival of malignant cells.[25],[26] However, other studies failed to observe such a correlation and discussed inconsistent and sometimes contradictory results.[27],[28] Given the conflicting evidence on this topic, we conducted a meta-analysis of all available cohort studies to investigate the correlation between OPN expression and NSCLC prognosis.


 > Materials and Methods Top


Literature search and selection criteria

The Web of Science (1945 ~ December 30, 2013), the Cochrane Library Database (Issue 12, 2013), PubMed (1966 ~ December 30, 2013), EMBASE (1980 ~ December 30, 2013), CINAHL (1982 ~ December 30, 2013), and the Chinese Biomedical Database (CBM) (1982 ~ December 30, 2013) were searched without language restrictions. We used the following keywords and MeSH terms in conjunction with a highly sensitive search strategy: (”osteopontin”, “sialoprotein 1”, “secreted phosphoprotein 1”, “bone sialoprotein 1”, “uropontin”, “OPG”, “Eta-1”, “2ar”) and (”non-small cell lung carcinomas” or “non-small-cell lung cancer” or “non-small cell lung cancer” or “NSCLC” or “NSCLC carcinogenesis” or “non-small cell lung carcinogenesis”). A manual search on the basis of references identified in the included articles was also carried out to acquire additional potential articles.

Eligible studies conformed to the following criteria: (1) must concern the correlation between increased OPN expression and prognosis in NSCLC; (2) all patients diagnosed with NSCLC must be confirmed via pathological examination, including bronchoscopic biopsy, percutaneous lung biopsy, pleural biopsy, pleural fluid cytology, and metastatic lymph node biopsy; (3) the survival curves for the OPN-positive and -negative groups must be provided in those included studies; (4) Sufficient information and integrity of data with regard to expression levels of OPN should be provided. If the authors published several similar studies with the same subjects, either the most recent publication or the publication with the largest sample size was included. Articles that did not meet the inclusion criteria were excluded. Exclusion criteria were: (1) animal studies or NSCLC cell line studies; (2) uncertain diagnosis; (3) duplicate publications; (4) lack of data integrity.

Data extraction and methodological assessment

Two independent investigators used a standardized form to extract the following data from included studies: Publication language, year of article publication, the first author's surname, geographical location, study design, total number of cases, sample size, control source, survival curves for the OPN-positive and -negative groups, etc., In case of disagreement on data and analyses, further discussions were continued by including a third expert and the matter resolved by consensus.

Two observers independently assessed the methodological quality using the Newcastle-Ottawa Scale (NOS) criteria.[29] The standard for NOS criteria were: (1) selection of the cohort: Representativeness of the exposed cohort (NOS1); selection of the non-exposed cohort (NOS2); ascertainment of exposure (NOS3); demonstration that outcome of interest was not present at start of study (NOS4); (2) comparability of the cohorts: whether the study was selected and analyzed according to the most important factor (NOS5); Whether the study controlled other confounding factors (NOS6); (3) assessment of outcome: Was follow-up long enough for outcomes to occur (NOR8); adequacy of follow-up of cohorts (NOR9). The NOS criterion comprises three aspects: (1) subject selection: 0 ~ 4; (2) comparability of subject: 0 ~ 2; (3) clinical outcome: 0 ~ 3. NOS scores range from 0 to 9, but a score with good quality should be ≥7.

Statistical analysis

In order to achieve rigorous statistical analysis, STATA statistical software (Version 12.0, Stata Corporation, College Station, TX, USA) was used for data analysis. Hazard ratios (HR) and their corresponding 95% confidence intervals (95%CI) were calculated. The statistical significance of pooled HRs was evaluated with the Z test. Inter-study heterogeneity was assessed with Cochran's Q-statistic and I 2 tests.[30] If I2> 50%, which indicates that these studies were heterogeneous, or P < 0.05, then the random-effect model was employed; otherwise, the fixed-effects model was implemented. We also made use of subgroup analyses to explore sources of heterogeneity. A sensitivity analysis was implemented for the purpose of evaluating the influence of a single study on the overall estimate. Potential publication bias was examined with Funnel plots and Egger's linear regression test.[31]


 > Results Top


Characteristics of included studies

Initially, our highly sensitive search strategy identified 184 articles. After screening the titles and abstracts of all retrieved articles, 95 articles were excluded. Following a review of full texts, another 76 articles were excluded. An additional three studies were also excluded due to a lack of data integrity [Figure 1]. Eventually, 10 clinical cohort studies, which contained a total of 1,133 NSCLC patients, were selected for statistical analysis.[4],[9],[25],[26],[27],[28],[32],[33],[34],[35] Overall, five studies were conducted among Asian populations, and the other 5 studies among Caucasian populations. Plasma OPN levels were reported in seven studies, and OPN expression in lung cancer tissue were only documented in three studies. Enzyme-linked immunosorbent assay (ELISA), and Max Vision methods were utilized in the studies to measure OPN levels. NOS scores of all included studies were ≥5. The main characteristics and methodological quality of eligible studies are recorded in [Table 1] and [Figure 2].
Figure 1: The flow chart shows study selection procedure. Ten cohort studies were included in this meta-analysis

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Table 1: Main characteristics and methodological quality of all eligible studies

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Figure 2: Methodological quality of eligible studies using the Newcastle-Ottawa Scale (NOS) criteria

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Quantitative data analysis

Since no heterogeneity was detected among studies (I2= 0.00%, P = 0.527), the fixed effects model was employed. Our findings suggest that NSCLC patients with positive expression of OPN had worse overall survival than those with negative OPN expression (HR = 1.47, 95% CI = 1.15 ~ 1.79, P < 0.001) [Figure 3]. Ethnicity-stratified analysis indicated that there was a significant correlation between expression levels of OPN and poor prognosis of NSCLC patients among both Caucasians and Asians (Asians: HR = 1.40, 95% CI = 0.97 ~ 1.83, P < 0.001; Caucasians: HR = 1.56, 95% CI = 1.08 ~ 2.03, P < 0.001; respectively) [Figure 4]. We also performed subgroup analyses based on sample size and sample source. The results indicated a significant association between OPN-positive expression and poor prognosis of NSCLC patients in all such subgroups (all P < 0.05). Sensitivity analysis indicated that the removal of any single study did not affect the overall pooled ORs [Figure 5]. There was no significant evidence for asymmetry in the funnel plots [Figure 6]. No evidence of publication bias was detected by Egger's test (t = 0.49, P = 0.636).
Figure 3: Forest plots for the relationships between osteopontin protein expression and prognosis of patients with non-small-cell lung cancer

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Figure 4: Subgroup analysis by ethnicity, sample type, and sample size for the relationship between osteopontin protein expression and prognosis of patients with non-small-cell lung cancer

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Figure 5: Sensitivity analysis of the summary odds ratio coefficients on the relationships between osteopontin protein expression and prognosis of patients with non-small-cell lung cancer

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Figure 6: Funnel plot of publication biases on the relationship between osteopontin protein expression and prognosis of patients with non-small-cell lung cancer

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 > Discussion Top


Our results show that positive OPN expression is closely correlated with shorter overall survival as compared to negative OPN expression, suggesting that expression levels of OPN may be an important prognostic factor for NSCLC. OPN is a key factor in tumorigenesis, tumor progression, and metastasis in several cancers.[25] The specific impact of OPN expression on the clinical outcome in NSCLC, however, still remains unclear. OPN facilitates cell migration and protects against programmed cell death in cancers, hence, it is reasonable to link the expression of OPN in cancer tissue to tumor growth, tumor staging, and lymph node invasion for patients with NSCLC.[36],[37] OPN modulates vascular endothelial growth factor expression through the activation of various signaling pathways,[24] and secreted OPN interacts with members of the integrin family, to activate downstream processes related to tumor progression and cellular transformation.[4] Furthermore, OPN stimulates the expression of the urokinase-type plasminogen activator and increases the migration and adhesion of tumor cells, which further induces cellular transformation and metastasis.[26] Therefore, through activation of multiple pathways, OPN promotes angiogenesis, leading to a more aggressive tumor phenotype and exacerbating cancer severity.[38] Interestingly OPN levels are elevated under hypoxic conditions and hypoxia is linked to chemotherapy and radiotherapy resistance. We hypothesized that high OPN expression impacts the overall survival in chemotherapy-treated NSCLC patients and may be correlated with NSCLC poor prognosis. Ostheimer et al., conducted a study on 55 patients with advanced NSCLC, and found a statistically significant association between high expression levels of OPN and shorter overall survival of NSCLC patients.[28] Rud et al., also provided further evidence of the importance of OPN in the etiology of NSCLC, and demonstrated that high expression levels of OPN in NSCLC tumors is connected to poor clinical outcome, stressing that OPN is a promising and independent prognostic determinant of outcome in NSCLC patients.[34] Ethnicity-stratified analysis indicated that increased expression levels of OPN might be significantly associated with poor prognosis of NSCLC patients among both Caucasians and Asians. The results indicate that ethnicity is not the predominant source of heterogeneity and did not have a crucial impact on the statistical outcomes. Our results support those previous studies that showed a correlation between high expression of OPN and poor clinical outcome of NSCLC. We further confirm that OPN levels could be used as a standard diagnostic method to identify NSCLC patients with an unfavorable prognosis.

Our study had several potential limitations. First, due to the small number of studies, our results failed include all of the data from all trials to evaluate the relationship of OPN expression with NSCLC prognosis. A second potential limitation to our meta-analysis is the fact that the results from might lack reliability due to its retrospective nature, which may induce publication bias. Another potential limitation is that our meta-analysis was unable to acquire the original data from the included studies. Even though our meta-analysis faced the above limitations, this is the first meta-analysis focusing on the association of OPN expression with NSCLC prognosis.

In summary, this meta-analysis provides evidence that increased expression of the OPN protein is significantly associated with poor prognosis in patients with NSCLC. Thus, increased OPN expression may serve as a potential prognostic factor for NSCLC. However, given that several limitations existed in our meta-analysis, further studies with better data integrity and larger sample-sizes are needed confirm our finding and test its general applicability.


 > Acknowledgments Top


We would like to acknowledge the helpful comments on this paper received from our reviewers.

 
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