| Lung cancer has a high incidence and mortality,especially higher in Yunnan province,which is a serious threat to human health.Lung cancer of Yunnan population has its particularity in China and even in the world,and has the unique clinical research value.Lung cancer results from multiple factors,among which environmental factors,heredity and living habits are especially important.Human geographical environment of Yunnan province has unique characteristics.The residents of Yunnan province are exposed to strong UV living in this plateau area,accustomed to stir-fry cooking,so bituminous coal combustion is more common and daily living environment pollution exposure is an important pollution.Yunnan ranks in the number of days with good air quality among the top,but the average life expectancy is shorter than the national average.The study of the relationship among characteristics of Yunnan human geography environment,longevity related genes and lung cancer has great significance to reveal the characteristics of lung cancer of Yunnan.MicroRNA is a class of small non-coding RNA molecule that are often amplified or deleted in human cancers.It is a double-edged sword as either a tumor suppressor or a tumor promoter.Dysregulation of miR-34 a has been reported in a variety of cancers,and its transcription is mainly regulated by the key tumor suppressor p53.As an important tumor suppressor,the anticancer effect of miR-34 a has been reported and identified in the studies of liver cancer,prostate cancer and breast cancer cells.MiR-186 acts as a tumor suppressor gene in a variety of human tumors such as gastric cancer,pituitary tumor,breast cancer,melanoma,and it is an oncogene in cutaneum carcinoma.Studies revealed that chronic PM2.5 exposure could significantly down-regulate the miR-34 a expression level and UV exposure had the same effect on miR-186 in the skin of melanoma patients,so miR-34 a and miR-186 may be connecting air pollution and UV exposure.As a member of the NAD+ dependent histone deacetylase family,SIRT6 regulates downstream genes by deacetylation.SIRT6 is an important longevity gene and has conflicting roles in tumors.Therefore,it is of great significance to study the expressions of miR-186,miR-34 a,SIRT6 in lung cancer of Yunnan population and the relationship among their expression and Characteristics of environmental factors,cancer progression and clinical prognosis great significance.The same gene can be regulated by different microRNA,one microRNA can regulate multiple genes at the same time.Studying the different regulatory networks of miRNA is of great significance for understanding the role of miRNA and drug development.It is predicted that hsa-mir-34 a and hsa-mir-186 can jointly target SIRT6,hsa-miR-186 can target HOXB8,and hsa-mir-34 a can target ALDOA.by miRNA prediction software.ALDOA is a member of the aldolase family involved in glycolysis.It may be an important gene in NSCLC for identifying 710 genes positively correlated with ALDOA in NSCLC tissues.HOXB8 is a member of the HOX family and has abnormal expression in a variety of tumors,but has not been studied in NSCLC.Knocking-down HOXB5 which is homologous to HOXB8,significantly inhibits proliferation,invasion,metastasis,and EMT of NSCLC cells by party the Wnt/beta-catenin signaling pathway.We expected to clarify the expressions of miR-34 a,miR-186 and SIRT6 in lung cancer of Yunnan inhabitant,and explore the relationship among their expressions and environmental pollution,UV exposure,disease progression and clinical prognosis.It will be comprehensively revealed that the effects of miR-34 a and miR-186 on proliferation,invasion,migration,apoptosis,epithelial-mesenchymal transformation,tumor formation in vivo and their regulatory pathways in NSCLC cells by cell and animal tumor formation models studies.The results as follows:(1)The expression levels of miR-34 a and miR-186 in non-metastatic cancer tissues were down regulated by 54.60% and 52.31%,by 66.67% and 76.16% in metastatic cancer tissues.In the cancer tissues,mRNA and protein expression of SIRT6 were significantly increased and the expression levels of SIRT6 in the metastatic group were higher.Decreasing expression of miR-34 a was correlated with TP53 gene mutation and air pollution exposure.The results of correlation analysis showed that the decreasing expression of miR-34 a and miR-186 were correlated with clinical stages,moreover increasing expression of SIRT6 was significantly correlated with clinical stages,T stages.The expressions of miR-34 a and miR-186 were negatively correlated with SIRT6 expressions by Spearman correlation analysis.The progression-free survival periods of miR-34 a down-regulated group,miR-186 down-regulated group and SIRT6 up-regulated group were significantly shortened.(2)Over-expression of miR-34 a and miR-186 significantly reduced the malignant biological behavior(including proliferation,invasion,migration,EMT and anti-apoptosis)of A549 cells.Knocking down miR-34 a and miR-186 had opposite effects.(3)MiR-34 a and miR-186 targeted SIRT6 to reduce the malignant biological behavior of A549 cell.SIRT6 might affect EMT of lung cancer cells by regulating Snail and Twist(at least partially),thereby affecting the progress of lung cancer.(4)The experimental results of subcutaneous xenotransplantation ability of nude mice showed that SIRT6 overexpression significantly increased the tumorigenic ability and tumor growth ability of A549 cells in nude mice.The intratumoral injection intervention of miR-34a-agomir and mir-186-agomir significantly reduced the volume and weight of subcutaneous xenografts of the over-expressed SIRT6-A549 cells in nude mice.(5)MiR-34 a regulated the malignant biological behavior of lung cancer cell by ALDOA/ERK signaling pathway.(6)MiR-186 regulated the malignant biological behavior of lung cancer cell by HOXB8-Wnt/β-catenin signaling pathway.Conclusion: MiR-34 a might be a bridge between air pollution exposure and tumorigenesis,and UV exposure was not a risk factor for decreased miR-186 in NSCLC of Yunnan resident.MiR-34 a and miR-186 had the function of tumor suppressor.They regulated the malignant biological behavior of lung cancer cells through respectively ALDOA/ERK signaling pathway and HOXB8-Wnt/β-catenin signaling pathway.SIRT6 was their common target gene,as well as had the function of oncogene in NSCLC of Yunnan resident.They may be used for the diagnosis and treatment in NSCLC of Yunnan resident. |
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