The Study On Induction Of The Epithelial-mesenchymal Transition Of The Human Lung Cancer Cell By Lactate Acid Through TAZ/JNK/STAT3 Signaling Pathway

Background and objective Lung cancer has become the world's biggest threat to human health and life of malignant tumor.Air pollution is more serious,due to the incidence of lung cancer increased year by year,such as not take effective control measures timely,lung cancer patients will reach 1 million by 2025 in our country,to become the world's first lung cancer country.Because of lung cancer easy to invasion and metastasis,the 5-year survival rate is only 12-16%.Therefore,if you can more clearly understand its concrete mechanisms of invasion and metastasis,and take corresponding prevention and treatment measures,for inhibiting tumor metastasis and improving the effect of the treatment of lung cancer has great clinical significance and social significance.Invasion and metastasis of lung cancer is a complex and continuous dynamic,progressive,multi-step process of multiple genes.According to the recent studies,the tumor microenvironment has great influence on the tumor metastasis,the main features of the tumor microenvironment is oxygen deficit and acid environment,acidic environment is mainly caused by tumor metabolic remodeling and lactic acid in the extracellular accumulation,the steady accumulation of lactic acid and tumor metastasis is closely related,and the transformation of epithelial mesenchymal as an early event of the tumor metastasis may be affected by the accumulation of lactic acid,the transcription factor Snail is known to regulate epithelial cell marks as a key factor.The study indicate that the co-transcription activator TAZ in the Hippo signaling pathways can activate the expression of multiple proto-oncogenes,It plays an important role in the process of invasion and metastasis of tumor,provides a new target for anti-cancer drugs and furthermore turn into the new hot spot of cancer research.c-Jun N-terminal kinase(JNK)family is a member of mitogen-activated protein kinase(MAPK)superfamily,JNK activation plays an important role in the occurrence and development of various human diseases,the study found that JNK is associated with tumor metastasis.Signal transduction and transcriptional activation factor-3(STAT3)is a member of the family of transcription factors,STAT3 continuously activation is associated with a wide variety of tumor,can promote the tumor metastasis happen.This article aims to how the lactate influences the expression of transcription factor Snail that regulate tumor cell epithelial mesenchymal transformation and the role of TAZ,JNK,STAT3 in depth studies and then research the effect of lactic acid on the tumor metastasis.To further elucidate the molecular mechanism of tumor metastasis,tumor therapy to provide new targets and ideas.Materials and methods Selection the human lung adenocarcinoma cell line A549?H1299 as research subject.?After transfection of TAZ c DNA in A549?H1299,transfection efficiency and changes of Snail? p-STAT3?p-JNK was tested by Western blot.?After transfection of TAZ si RNA in A549?H1299,transfection efficiency and changes of Snail ? p-STAT3 ? p-JNK was detected by Western blot.? After transfection of TAZ c DNA,TAZ si RNA,TAZS89 A c DNA,pc DNA 3.1,Snail Promoter and CMV in A549?H1299,changes of Snail Promoter was tested by luciferase assay.? After co-transfection of TAZ c DNA? TAZS89 A c DNA and Dominant Negative STAT3 c DNA(STAT3 DN c DNA)in A549?H1299,transfection efficiency and changes of Snail was tested by Western blot.?After co-transfection of TAZ c DNA?TAZS89A c DNA and Dominant Negative STAT3 c DNA(STAT3 DN c DNA),Snail Promoter and CMV in A549?H1299,changes of Snail Promoter was tested by luciferase assay.?After transfection of TAZ c DNA,treated by different signaling inhibitors,transfection efficiency and changes of p-STAT3 and Snail was detected by Western blot.Results 1?After transfection of TAZ c DNA,the protein level of TAZ increased and CTGF?p-JNK?p-STAT3 and the EMT biomarker Snail was up regulated.2?After transfection of TAZ si RNA,the protein level of TAZ decreased and CTGF?p-JNK?p-STAT3 and the EMT biomarker Snail was down regulated.3?The expression level of Snail Promoter increased after transfection of TAZ c DNA,TAZS89 A c DNA,yet after transfection of TAZ si RNA it is down.4?After co-transfection of TAZ c DNA?TAZS89A c DNA and Dominant Negative STAT3 c DNA(STAT3 DN c DNA),we found that STAT3 DN c DNA can markedly decrease TAZ promotes the expression of Snail.5?The expression level of Snail Promoter increased after transfection of TAZ c DNA,TAZS89 A c DNA,yet after co-transfection of pc DNA 3.1+STAT3 DN c DNA,TAZ c DNA+STAT3 DN c DNA,TAZS89 A c DNA+STAT3 DN c DNA it is down.6?After transfection of TAZ c DNA,treated with JNK signaling inhibitor SP600125,the protein level of p-TAZ and CTGF has no change,and the expression of p-STAT3 and Snail was down regulated.Yet others treatment are different from this.Conclusions 1?STAT3 can promote TAZ increases the expression of Snail.2?JNK signaling pathways involved in the TAZ induced STAT3 and activated the expression of Snail.3?Lactate can induce the epithelial-mesenchymal transition of the human lung adenocarcinoma through TAZ/JNK/STAT3 Signaling Pathway.