Non-Genetic Factors and Radiation Responses: the Emerging Role of miRNAs.

Accumulating evidence suggests that non-genetic factors, such as environmental, hormonal or lifestyle-related factors, may influence radiation responses and resulting cancer risks through epigenetic mechanisms, such as miRNA regulations, DNA methylation or histone acetylation. Because they are tightly integrated in cellular regulatory circuits, miRNAs are emerging as playing a fundamental role in cancer. There is a crucial need in better understanding the interactions between ionizing radiation effects (especially at low doses) and non-genetic factors. We have studied the effects of diet-induced obesity, restraint-stress and alcohol consumption in irradiated C57BL/6J and C3H mice, using miRNA arrays. Lifestyle-related factors influenced radiation-induced and cancer-associated miRNA regulations in the liver. For example, radiation-triggered miRNA modulations observed in normal mice (such as the upregulation of miR-466e) were not observed in obese mice. In order to mimic in vitro the effects of obesity and alcohol consumption on radiation responses in the mouse liver, we then treated AML12 murine liver cells with free fatty acids or alcohol and evaluated the role of target miRNAs, such as miR-466e or miR-34, on radiation responses in the liver. In order to study the interplay between hormonal effects and radiation in the human breast, we also measured the combined effects of progesterone treatment and X-rays in PR-negative basal-like MCF10A cells. Progesterone and irradiation generated radiation-resistant tumor-initiating cancer stem cells through a new membrane progesterone receptor (mPR)-triggered PI3K/Akt signaling pathway, resulting in the repression of miR-29. A better understanding of the role of miRNAs and non-genetic factors in radiation responses may ultimately allow an individualization of radiation cancer risk assessment. In addition, the discovery of new radiation-related miRNA regulation pathways may be of great interest for basic and clinical radiation research.ICRR2015/日本放射線影響学会第58回大