The Effect Of Atmospheric Fine Particles On Lung Cancer Metastasis Through The ARNT2/PP2A/STAT3 Signaling Pathway

Objective:Accumulating evidence indicates that fine particulate matter(diameter<2.5?m;PM_2.5)exposure is a risk factor for many cardiopulmonary diseases,particularly lung carcinoma.Nevertheless,the underlying biological mechanisms by which PM_2.5 exposure initiates and aggravates lung carcinoma remain elusive.In this study,we advance research into the possible mechanism.Methods:we collected PM_2.5 in Guangzhou Road,Nanjing and the PaHs components were analyzed with high performance liquid chromatography;Interactions between PM_2.5 and LLC?Lewis Lung Carcinoma?cells were observed under flow cytomerty and co-focal microscopy;ARNT2 and B56?in the PM_2.5 treated LLC cells were measures with Western-blotting.To explore the possible binding between Arnt2 and B56?,Co-immunoprecipitation and co-immunofluorescence were applied;Again,associated proteins PP2A and STAT3 and phosphorylation level were measured in the PM_2.5.5 treated LLC cells;And PP2A was silenced with siRNA and inhibitor to clarify the possible roles of PP2A on the STAT3 activation;MMP-2,which were the putative targets contributing to the cancer metastasis,were assessed by q-RT PCR,western blots,zymography and invasion assay.Last,PM_2.5 inoculated mice were injected with LLC cells.The survival of operated mice was recorded daily.And lung tissues were fixed by H&E and India ink staining to observe the primary and metastasis nodules;Finally,a human lung carcinoma tissue was assessed by the transmission electron microscope to find out PM_2.5.Results:Varied PaHs was detected in our PM_2.5 sample,indicating the toxic role of PaHs,PM_2.5 was closely attached with and internalized by lung cancer cells.Moreover,PM_2.5 increased the production of ARNT2 and the inactivation of a tumor-suppressor B56?-PP2A,followed by the activation of the ^pS727STAT3 and enhanced invasion ability by MMP-2.Furthermore,the mouse orthotopic lung carcinoma model illustrated the pro-metastasis effect of PM_2.5 in vivo.Finally,we observed bulk of PM_2.5 deposited in human lung carcinoma.Conclusions:Our findings demonstrated that fine particulate matter PM2.5 interact with LLC cells directly and promoted the invasion of lung cancer via an ARNT2/PP2A/STAT3/MMP-2 pathway,which may be targeted to alleviate the tumorigenesis of PM_2.5 in lung cancer.