miR-375 targets the p53 gene to regulate cellular response to ionizing radiation and etoposide in gastric cancer cells

• Published in: DNA repair Vol. 12; no. 9; pp. 741 - 750
• Main Authors: Liu, Yixuan, Xing, Rui, Zhang, Xiaodong, Dong, Weiwei, Zhang, Jingyu, Yan, Zhi, Li, Wenmei, Cui, Jiantao, Lu, Youyong
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.09.2013
• Subjects: 3' Untranslated Regions; Animals; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis; Base Sequence; Cell Cycle Checkpoints; Cell Proliferation; Cell Transformation, Neoplastic - genetics; Etoposide; Etoposide - pharmacology; Gastric cancer; Gene Expression - drug effects; Gene Expression - radiation effects; HCT116 Cells; Humans; Ionizing radiation; MCF-7 Cells; Mice; Mice, Nude; MicroRNAs - genetics; miR-375; Neoplasm Transplantation; P53; RNA Interference - drug effects; RNA Interference - radiation effects; Stomach Neoplasms - genetics; Stomach Neoplasms - pathology; Tumor Burden; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Etoposide; Ionizing radiation; Gastric cancer; miR-375; P53
• ISSN: 1568-7864; 1568-7856
• DOI: 10.1016/j.dnarep.2013.06.002

•We demonstrate that p53 is a direct target of miR-375.•miR-375 desensitizes cells to ionizing radiation and etoposide.•miR-375 abrogates the cell cycle arrest and apoptosis after DNA damage.•miR-375 regulates cellular response to stress through inactivation of the p53 pathway. MicroRNAs (miRNAs) offer a new approach for molecular classification and individual therapy of human cancer due to their regulation of oncogenic pathways. In a previous report, elevated miR-375 was found in recurring gastric cancer, and it was predicted that miR-375 may be a regulator of p53 gene. However, its biological role and mechanism of actions remain unknown. In this study, we characterized the expression level of miR-375 in gastric cancer cell lines – BGC823, MGC803, SGC7901, AGS, N87, MKN45 – using RT-PCR. We found that exogenous expression of miR-375 promoted the growth of AGS cells in both liquid and soft agar media. In agreement with the previous report, overexpression of miR-375 in AGS cells reduced the p53 protein expression level. A luciferase assay demonstrated that miR-375 down-regulated p53 expression through an interaction with the 3′ UTR region of p53. In addition, the expression of miR-375 desensitizes cells to ionizing radiation and etoposide. Flow cytometry analyses showed that miR-375 abrogated the cell cycle arrest and apoptosis after DNA damage. These results demonstrate that miR-375 targets p53 to regulate the response to ionizing radiation and etoposide treatment.