BAP1 Deficiency In Lung Adenocarcinoma Leads To Poor Prognosis And Tumor Invasion

Part I Expression of BAP1 and clinicopathological characteristics and prognosis in lung adenocarcinomaObjective:To investigate different expression levels of BAP1 in lung adenocarcinoma and health lung tissue. To explore the expression of BAP1 in LAC and analyse the correlation with clinicopathological parameters and prognosis.Materials and methods:112 cases of LAC and their clinical and pathological data were selected in our study, as well as 101 cases of benign lung diseases. BAP1 expression was detected by immunohistological methods. Analysis was stratified by clinicopathological features. BAP1 was evaluated as a prognostic factor of LAC.Results:BAP1 expression was lower in LAC than that in benign lung tissues and the difference was statistically significant (p< 0.001). There were no significant correlation between BAP1 expression and patients’age, sex, gross type, maximum tumor diameter, histologic differentiation and histologic subtype. BAP1 expression was higher in early LAC (TNM stage I/II) than in late stage (TNM stage III) (p= 0.007), and higher in LAC without pleural invasion than those invased (p= 0.004), with significant differences. Moreover, there were significant difference of BAP1 expression between different T stage, N stage, postoperation recurrence and metastasis. Survival analysis showed relevancy of BAP1 expression and prognosis, yet not independent prognostic factor.Conclusion:BAP1 high expression commonly appeared with the condition of early T/N/TNM stage, as well as those patients without pleural invasion, which suggested that BAP1 as an inhibitor of the abilities of invasion and metastasis of LAC. High expression of BAP1 prompted a better prognosis, yet dependens on other factors, such as pleural invasion, N stage.Part II The underlying mechanism of BAP1 influcing proliferation and deducing invasive ability in lung adenocarcinomaObjective:To study the influencing of BAP1 on cell cycle, apoptosis and necrosis, proliferation, migration, invasion and metastatic potential of LAC cells in vitro.Materials and methods:BAP1 background expression in several common LAC cell lines was detected. Then we transfected BAP1 low-expression cell line NCI-H1299 with BAP1 over-expression plasmid vector transiently, while high-expression cell line NCI-H1650 with siBAPl, in order to intervene the protein level of BAP1. Cell cycle, apoptosis and necrosis were detected by flow cytometry, based on different BAP1 protein level. CCK-8 colorimetry was used to detect cell survival and proliferation. Besides, we detected the ability of cell migration by wound-healing assay and Transwell chamber. The expression changed of cell cycle-associated protein and EMT-associated protein was detected by Western Blot.Results:Plasmid vector and siBAP1 were transmitted into LAC cells efficiently. Over-expression of BAP1 could promote cell cycle, induce apoptosis and necrosis, but no significant effect on cell proliferation has been detected. The trends of BAP1 expression was coincident with CyclinB1 while contrast to P27. Over-expression of BAP1 could downregulate invasive ability and migration of LAC cells, while BAP1 silencing could upregulate it. Over-expression of BAP1 was associated with increasing expression of E-Cadherin and decreasing expression level of Vimentin and MMP-2.Conclusion:BAP1 could promote LAC cell cycle, induce apoptosis and necrosis. It can also inhibit cell invasion and migration through EMT process. From the cell biological level, it is demonstrated that BAP1 is a novel tumor suppressor in LAC. And the related molecular pathway of BAP1 needs further investigation.