YAP/Aurora A-mediated ciliogenesis regulates ionizing radiation-induced senescence via Hedgehog pathway in tumor cells.

Primary cilia are antenna-like organelles that play critical roles in sensing and responding to various signals. Nevertheless, the function of primary cilia in cellular response to ionizing radiation (IR) in tumor cells remains unclear. Here, we show that primary cilia are frequently expressed in tumor cells and tissues. Notably, IR promotes cilia formation and elongation in time- and dose-dependent manners. Mechanistic study shows that the suppression of YAP/Aurora A pathway contributes to IR-induced ciliogenesis, which is diminished by Aurora A overexpression. The ciliated tumor cells undergo senescence but not apoptosis in response to IR and the abrogation of cilia formation is sufficient to elevate the lethal effect of IR. Furthermore, we show that IR-induced ciliogenesis leads to the activation of Hedgehog signaling pathway to drive senescence and resist apoptosis, and its blockage enhances cellular radiosensitivity by switching senescence to apoptosis. In summary, this work shows evidence of primary cilia in coordinating cellular response to IR in tumor cells, which may help to supply a novel sensitizing target to improve the outcome of radiotherapy.

Identification of the Kupffer cell-derived circulating IGFBP-3 as a universal radiation biomarker for heavy ion, proton, and X-ray exposure.

The minimally invasive biomarkers that can facilitate a rapid dose assessment are valuable for the early medical treatment when accidental or occupational radiation exposure happens. Our previous proteomic research identified one kind of circulating protein, Insulin-like Growth Factor Binding Protein 3 (IGFBP-3), which showed a significant increase after total body exposure of mice to carbon ions and X-rays. However, several critical issues such as the responses to diverse radiation, the origin and underlying mechanism in radiation response obstruct the utilization of circulating IGFBP-3 as a reliable radiation biomarker. In this study, mice were subjected to total or partial body irradiation with carbon ions, protons or X-rays, or treated with chloroform as a comparison. The level of IGFBP-3 in serum and different organs were measured via Enzyme Linked Immunosorbent Assay (ELISA), Western blot (WB) and Immunohistochemistry (IHC). A significant increase of IGFBP-3 was discovered in serum and liver tissue post-irradiation with three kinds of radiation, but absent when challenged with chloroform. Likewise, a similar response was also observed in blood samples from patients receiving radiotherapy. Moreover, the effect of radiation on three main hepatic cells was investigated, the findings indicated that IGFBP-3 could be detected in the culture medium of Kupffer cells (MKC) alone and was elevated in cells and cultured medium of MKC post-irradiation. Additionally, we observed a co-expression effect between P53 and IGFBP-3 in liver tissues and MKC post-irradiation. Along with down-regulation of Trp53 by siRNA, the response of IGFBP-3 to radiation was attenuated. The present study demonstrated that circulating IGFBP-3 could be a promising universal biomarker for complex environmental radiation exposure, and the upregulation of IGFBP-3 is attributed to the MKC in a P53-dependent manner. Circulating IGFBP-3 assays would offer rapid, convenient and effective dose and toxicity assessment methods in occupational exposure or radiation disaster management.

Circulating tRNA-Derived Small RNAs as Novel Radiation Biomarkers of Heavy Ion, Proton and X-ray Exposure.

The effective and minimally invasive radiation biomarkers are valuable for exposure scenarios in nuclear accidents or space missions. Recent studies have opened the new sight of circulating small non-coding RNA (sncRNA) as radiation biomarkers. The tRNA-derived small RNA (tsRNA) is a new class of sncRNA. It is more abundant than other kinds of sncRNAs in extracellular vesicles or blood, presenting great potential as promising biomarkers. However, the circulating tsRNAs in response to ionizing radiation have not been reported. In this research, Kunming mice were total-body exposed to 0.05-2 Gy of carbon ions, protons, or X-rays, and the RNA sequencing was performed to profile the expression of sncRNAs in serum. After conditional screening and validation, we firstly identified 5 tsRNAs including 4 tRNA-related fragments (tRFs) and 1 tRNA half (tiRNA) which showed a significant level decrease after exposure to three kinds of radiations. Moreover, the radiation responses of these 5 serum tsRNAs were reproduced in other mouse strains, and the sequences of them could be detected in serum of humans. Furthermore, we developed multi-factor models based on tsRNA biomarkers to indicate the degree of radiation exposure with high sensitivity and specificity. These findings suggest that the circulating tsRNAs can serve as new minimally invasive biomarkers and can make a triage or dose assessment from blood sample collection within 4 h in exposure scenarios.