MicroRNA-96 expression induced by low-dose cisplatin or doxorubicin regulates chemosensitivity cell death and proliferation in gastric cancer SGC7901 cells by targeting FOXO1

摘要

MicroRNA-96 (miR-96) is transcriptionally associated with the induction of chemoresistance following chemotherapy by targeting to FOXO1 mRNA at one of two predicted binding sites in its 3′-untranslated region sequence. The upregulation of miR-96 is associated with a high risk of chemoresistance. Nevertheless, the mechanism by which miR-96 is upregulated remains largely undefined. In the present study, the gastric cancer SGC7901 cell line was treated with different doses of the chemotherapeutic agents cisplatin and doxorubicin. miR-96 expression was analyzed by reverse transcription-quantitative polymerase chain reaction at different time points. Western blot and chromatin immunoprecipitation were performed to analyze the expression levels of the target gene. The effects of miR-96 on chemosensitivity were assessed by a carboxyfluorescein succinimidyl ester/propidium iodide labeling assay, and its effects on proliferation were assessed by Cell Counting Kit-8 or EdU staining assays. The results demonstrated that treatment with a low dose of either chemotherapeutic agent induced miR-96 expression. Upregulation of miR-96 caused the post-transcriptional repression of FOXO1 expression. Decreases in FOXO1 protein levels led to a decrease in the transcriptional activity of the cyclin-dependent kinase inhibitor 1A (CDKN1A, also known as p21) promoter region, and thus the expression of p21 was downregulated in a tumor protein p53-independent manner. As a result, induction of miR-96 expression caused chemoresistance and promoted proliferation in SGC7901 cells. Taken together, the results of the present study revealed that treatment with cisplatin or doxorubicin could induce expression of miR-96 at certain doses. Upregulation of miR-96 is partially associated with chemoresistance and miR-96 can also promote cell proliferation by repressing p21.