Role And Mechanism Of MiR-137 In CrT Cell-induced Tumor Growth And Angiogenesis Of Lung Cancer

Lung cancer is one of the most common caners,leading to the most cancer-related deaths in the world.With the increase of the human environment pollution and the aging,the incidence of lung cancer also showed a rising trend year by year.Chromium is widespread environmental pollutants and potent carcinogen.Occupational exposure is the main mode for human contact with chromium.Hexavalent chromium is the main form of toxicity.Human intakes hexavalent chromium mainly through the respiratory tract and mouth.A small amount of hexavalent chromium can be absorbed through the skin.Through the respiratory tract due to inhalation of chromium,chromium smoke dust is the main contact way,professional workplaces and chromium cause of lung cancer is the most common.The international agency for research on cancer determined the chromium for “human carcinogen” early in 1990.MicroRNAs(miRNAs)are small noncoding double-stranded RNA molecules,21–22 nucleotides in length that regulate 30% of human gene expression at a post-transcriptional level by targeting messenger RNAs(mRNAs).MiR-137 is detected as a tumor suppresser,and is downregulated in many cancers.For example,miR-137 can inhibit the tumor growth and invasion of gastric tumor,lung cancer,colorectal cancer and neuroblastoma.However,the role and mechanism of miR-137 in inhibiting tumorigenesis remain to be elucidated.In order to mimic the pathophysiological impact of long-time exposure to chromium,we established an in vitro model by transforming immortalized and nontumorigenic human lung epithelial BEAS-2B cells via exposure to 1 ?M Cr(VI)for six months.We found that the chromium-transformed cells(CrT)significantly increased cell proliferation,migration and angiogenic response.The qRT-PCR results showed that miR-137 expression was significantly downregulated in the CrT cells.In order to investigate biology function of miR-137,we have established the stable cell lines that expressing miR-NC and miR-137.Overexpression of miR-137 suppressed CrT cell proliferation and migration.MiR-137 can also inhibit the expression of p70S6K1 and its downstream signaling molecules such as HIF-1? and VEGF expression.Furthermore,overexpression of miR-137 decreased tube formation and tumor angiogenesis.Forced expression of p70S6K1 restored miR-137-inhibiting expression of HIF-1? and VEGF,and restored tube formation and to the similar level of the control cells.In summary,we identified that levels of miR-137 expression in Cr-exposed humans subjects are significantly lower than those of the normal subjects,similar results were obtained in CrT cells.While the levels of p70S6K1 protein were significantly upregulated in CrT cells.We also found that miR-137 inhibited CrT cell-induced tumor growth and angiogenesis through targeting p70S6K1 and suppressing expression of p70S6K1 downstream molecules such as HIF-1? and VEGF.This study reveals new mechanism of Cr(VI)induced carcinogenesis,and may provide a potential new marker for Cr(VI)exposure and lung cancer in the future.