406892

MIR100

Evidence in literature has demonstrated that some microRNAs (miRNAs) play a pivotal role in most solid tumor metastasis. Previous studies have showed that miR-100 is downregulated in human prostate cancer tissue compared to normal prostate and also significantly decreased in bone metastatic prostate cancer samples compared with primary prostate cancer. Argonaute 2 (AGO2) is the core effector protein of the miRNA-induced silencing complex and overexpression of AGO2 might enhance tumor metastasis. However, it is unknown whether and how miR-100 and AGO2 regulates metastasis of prostate cancer. Here, we report that miR-100 negatively regulated migration, invasion, epithelial-mesenchymal transition (EMT), colony formation, spheroid formation and expression of the stemness factors c-Myc, Oct4 and Klf4 in PC-3 and DU145 cells. Furthermore, miR-100 expression was negatively correlated with bone metastasis of prostate cancer patients. Notably, luciferase assay showed that AGO2 was a direct target of miR-100. Downregulation of AGO2 repressed migration, invasion, EMT and stemness of prostate cancer cells, and reversed the effects seen with miR-100 downregulation. Downregulation of AGO2 enhanced expression of miR-34a and miR-125b which can suppress migration, invasion, EMT and stemness of cancer cells. Taken together, our findings indicate that loss of miR-100 promotes the metastatic ability of prostate cancer cells at least partially by upregulating AGO2 expression through modulating migration, invasion, EMT and stemness of cancer cells, and suggest that miR-100/AGO2 may play an important role in regulating the metastasis of prostate cancer and is a potential target of prevention and therapy.

Chronic arsenic treatment induces epithelial-mesenchymal transition (EMT) and promotes tumorigenicity, but the mechanism is unclear. MiR-100 has been shown to be involved in this biologic process. In this study, we hypothesize that inactivation of miR-100 combined with low concentration of arsenic exposure could promote the malignant transformation of human bronchial epithelial cells (BEAS-2B cell) by promoting EMT. To test this hypothesis, BEAS-2B cells were treated with low-dose of As2O3 chronically, and lentiviral vectors were used to mediate the inhibition of miR-100 expression. Flow cytometry, cloning formation, and transwell assays were used to examine cell cycle progression, cell proliferation, and cell migration, respectively. The mouse xenograft model was used to investigate the cell malignant growth in vivo, and western blot was used to detect EMT related marker expressions. Our results showed that, the inactivation of miR-100 combined with arsenic treatment significantly promoted the proliferation, viability, and migration of BEAS-2B cells in vitro, and tumorigenesis in vivo. Consistently, the EMT related marker expressions were also significantly increased in corresponding groups. Our data indicate that inactivation of miR-100 combined with chronic arsenic treatment promotes tumorigenicity of BEAS-2B cells via activation of EMT. This novel insight may help us to better understand the pathogenesis of arsenic carcinogenesis.