Journal of Experimental & Clinical Cancer Research 2009, 28:89 http://www.jeccr.com/content/28/1/89 ] r o [ g o l 1 0 -1 -2 Begg's funnel plot with pseudo 95% confidence limits 0 .2 .4 .6 s.e. of: log[or] lFFuuingngunceraelnp4cloetr for publication bias in the analysis of IGFBP-3 and Funnel plot for publication bias in the analysis of IGFBP-3 and lung cancer. Each circle indicates the loga- rithm of the odds ratio of lung cancer comparing the subjects in the highest category with the lowest (vertical axis) and the standard error of logarithm of odds ratio in each study. The line in the centre indicates the summary diagnostic odds ratio. to the pooled ORs, and the corresponding pooled ORs were not materially altered (data not shown). Discussion Lung cancer is the leading cause of malignancy-related mortality. The mechanism of carcinogenesis is very com- plex, which involves many factors, such as IGF-I and IGFBP-3. Conventional studies coordinately think that IGF-I and IGFBP-3 may promote and inhibit tumor growth, respectively. In recent years, there are many epide- miological studies have different results. In this meta- analysis, our data suggests that IGF-I low in the lung can- cer population, though we could not demonstrate statisti- cal significance. With regard to the association between IGFBP-3 and lung caner, the data suggests IGFBP-3 acts as a tumor suppressor and has a inverse correlation with the risk of lung cancer, and it does have statistical significance. The IGF family is supposed to play a pivotal role in regu- lating cell proliferation, apoptosis and transformation [24]. Most circulating IGFs are produced by hepatocytes in response to growth hormone stimulation [25-27]. Circu- lating IGFBP-3 is produced by hepatic endothelium and Kupffer cells [26,27]. A number of in vitro and in vivo studies have demonstrated that IGF-I is an effective mitogen in normal epithelial cells and has strong antiap- optotic effects on lung cancer cells [5,10,11]. However, the effect of IGF-I may be modulated by IGFBP-3 in circu- lation because most of the IGF-I is bound to IGFBP-3 and once bound it is not in its active form. The results of this meta-analiysis indicate that there are no statistically sig- nificant association between IGF-I and lung cancer, while the associaton between IGFBP-3 and lung cancer is very significant. High serum levels of IGFBP-3 associated with a reduced lung cancer risk. Lung cancer is a multifactorial disease that results from complex interactions between many genetic and environ- mental factors. This means that there will not be single gene or single environmental factor that has large effects on lung cancer susceptibility. Due to limited studies and published data in original report, we could not make sub- group analysis by sex, smoking status, histological types and other variables. Possible limitations of our meta-anal- ysis includes relatively small number of studies, different heterogeneous matching factors, different countries and ethnicities, possible publication bias, as well as possible interaction with other biologic and environmental fac- tors. It is well documented that ethnic factor contributes to the lung cancer incidence. In our study, we included 2 U.S., 1 Chinese, 1 Japanese, 1 Finnish and 1 British stud- ies. Therefore, heterogeneity by ethnicity needs to be taken into account when interpreting our data. Heteroge- neous matching factors and differential adjustment for confounding factors are other sources of bias. The above limitations might have contributed to the low statistical power of our meta-analysis. Despite some limitations, our results based on nested case-control studies which represent of best study design. In addition, we obtained the results from dichotomous and continuous variable respectively, which made the results more reliable. What's more, heterogeneity and publication bias of the studies were not significant. Thus, the data of our study are reliability. Conclusion In summary, we found that association between circulat- ing levels of IGF-I, IGFBP-3 and the risk of lung cancer are marginally and statistically significant, respectively. So it may be helpful in the diagnosis and treatment of lung cancer. Since circulating IGF-I and IGFBP-3 remain impor- tant factors in lung cancer, more studies need to be con- ducted to discern this association. And uniform adjustment of confounding factors across the studies will help in terms of interpretability and comparability. Competing interests The authors declare that they have no competing interests. Authors' contributions In our study, all authors are in agreement with the content of the manuscript. Each author's contribution to the paper: BC: First author, background literature search, data analysis, development of final manuscript. JQW: Corre- sponding author, research instruction, data analysis, Page 5 of 6 (page number not for citation purposes)