MicroRNA-21 is involved in ionizing radiation-promoted liver carcinogenesis

• Authors: Yun Zhu, Emory University; Xiaoyan Yu, Emory University; Hanjiang Fu, Beijing Institute of Radiation Medicine; Hongyan Wang, Emory University; Ping Wang, Emory University; Xiaofei Zheng, Beijing Institute of Radiation Medicine; Ya Wang, Emory University
• Journal Title: International Journal of Clinical and Experimental Medicine
• Volume: Volume 3, Number 3
• Publisher: e-Century Publishing | 2010-07-31, Pages 211-222
• Type of Work: Article | Post-print: After Peer Review
• Subjects: Health Sciences, Radiology; Health Sciences, Oncology
• Keywords: microRNA; miR-21; ionizing radiation; carcinogenesis

Abstract

It has been known for decades that ionizing radiation (IR) promotes carcinogenesis and high-linear energy transfer (LET) IR has a higher risk than low-LET IR for carcinogenesis; however, the mechanism remains unclear. MicroRNAs (miRNAs) have a critical effect on carcinogenesis through post-transcriptional modification. In this study, our purpose is to explore whether miRNAs are involved in IR-(especially high-LET IR) promoted liver carcinogenesis. We showed here that among several hundred miRNAs, miR-21 was the only one that increased 6 folds in high-LET IR-promoted mouse liver tumors when compared with that in the non-irradiated liver tissues. We also showed that miR-21 was up-regulated in human or mouse hepatocytes after exposure to IR, as well as in liver tissues derived from whole body irradiated mice. The increased level of miR-21 was more significant in high-LET irradiated cells or liver tissues. After the non-irradiated, low-LET or high-LET irradiated human hepatocytes were over-expressed with miR-21, these cells became tumorigenesis in nude mice. The tumors derived from high-LET-irradiated-cells were largest, and accompanied by more significant changes in the miR-21-targets: PTEN and RECK. In addition, we showed that IR-induced up-regulation of miR-21 depended on the up-regulation/activation of AP-1 (at an earlier time, within 2 h) and the ErbB/Stat3 pathway (at a later time, more than 2 h), which was also IR dose dependent. Taken together, we conclude that IR-induced up-regulation of miR-21 plays an important role in IR (especially high-LET IR)-promoted liver carcinogenesis.