Role And Mechanism Of MiR-222 In Regulating Tumor Growth And Angiogenesis Of Arsenic-induced Lung Cancer

Lung cancer is one of the most common respiratory system tumors.It is the first leading cancer-related deaths in the world.With the intensification of the human environment pollution and aging trend,the incidence of lung cancer also showed a rising trend year by year.Insidious onset and no obvious symptoms in early stage of lung cancer render it very difficult to diagnose at early stage.The principle therapeutic method is surgery.But the deficiency of the surgical technique may leave residual and easily cause cancer recurrence and metastasis.In the non-surgical therapy,the traditional radiotherapy and chemotherapy are lack of sensitivity,there are still lesions metastasis,recurrence and other issues,and has a more serious side effects.Therefore,it is urgent and important to investigate molecular mechanisms of lung cancer,and to look for a more effective treatment for lung cancer.Arsenic(As)is a class of environmental pollutants,long-term exposure to arsenic in the environment likely to induce lung cancer,bladder cancer,skin cancer.Some studies have shown that exposure to environmental arsenic risk of lung cancer in men is the 17 times of the world average,women 8.34 times.Arsenic-induced lung cancer has been among one of the most active research fields.MicroRNAs(miRNAs),approximately 17-22 nucleotides in length,are a class of small non-coding RNAs discovered recently that regulate gene expression at the transcriptional level by binding to the 3’-untranslated region(UTR)of target mRNAs.The abnormal expression levels of miRNAs are associated with tumors to function as oncogenes or tumor suppressors.The formation of new blood vessels is crucial in the onset of tumor.Vascular endothelial growth factor(VEGF)plays a central role in tumor angiogenesis.Angiogenesis inhibitors prevent the tumors from growth and metastasis.In order to investigate roles of miR-222 in arsenic-induced lung cancer,we continuously treated human lung epithelial BEAS-2B(B2B)cells with arsenite for six months and gained arsenic-induced cells(As-T).Through cell proliferation assay,cloning formation assay and tumorigenicity in nude mice experiment,we found that the proliferation capacity and tumorigenic ability of As-T cells were significantly improved.We also found that the expression levels of miR-222 were higher in As-T cells when compared with B2B cells by RT-PCR,suggesting that miR-222 may play an important role in lung cancer.To further determine the biological functions of miR-222 in arsenic-induced lung cancer,we found that inhibited expression of miR-222 in As-T cells significantly inhibited both growth rate and colony formation in vitro,and tumor growth and angiogenesis in vivo.We also found that miR-222 directly inhibited expression of ARID1A and suppressed their protein expression levels,suggesting that both miR-222 and ARID 1A may play an important role in lung cancer.In summary,we identified that the expression of miR-222 by arsenic-induced in As-T cells,miR-222 promoted tumor growth and angiogenesis by targeting ARID 1A and regulating the downstream signaling pathways of PI3K/AKT.These results provide useful information for miR-222 and its target genes used as molecular markers and therapeutic targets in lung cancer in the future.