As a common serious complication of thoracic radiotherapy, radiation-induced pulmonary fibrosis (RIPF) severely limits radiation therapy approaches. Epithelial–mesenchymal transition (EMT) is a direct contributor to the fibroblast pool during fibrogenesis, and prevention of EMT is considered an effective strategy to inhibit tissue fibrosis. Our previous study revealed that TANK-binding kinase 1 (TBK1) regulates EMT in lung cancer cells. In the present study, we aimed to investigate the therapeutic potential of targeting TBK1 to prevent RIPF and EMT progression. We found radiation-induced EMT and pulmonary fibrosis in normal alveolar epithelial cells and lung tissues. TBK1 knockdown or inhibition significantly reversed EMT in vivo and in vitro and attenuated pulmonary fibrosis and collagen deposition. Moreover, we observed that TBK1 was elevated in a time- and dose-dependent manner by radiation. Meanwhile, radiation also induced time- and dose-dependent activation of AKT and ERK, each of whose inhibitors suppressed radiation-induced EMT. Intriguingly, silencing of TBK1 with shRNA also blocked the radiation-induced activation of AKT and ERK signaling. The ERK inhibitor did not obviously affect the expression of TBK1 or phosphorylated AKT, while AKT inhibition suppressed activation of ERK without changing the expression of TBK1. Finally, we found that a TBK1 inhibitor inhibited inflammatory cytokine expression in a RIPF model and Amlexanox protected normal cells and mice from ionizing radiation. In conclusion, our results indicate that the TBK1–AKT–ERK signaling pathway regulates radiation-induced EMT in normal alveolar epithelial cells, suggesting that TBK1 is a potential target for pulmonary fibrosis prevention during cancer radiotherapy.
Radiation‐induced intestinal injury (RIII) is a common complication after radiation therapy in patients with pelvic, abdominal, or retroperitoneal tumours. Recently, in the model of DSS (Dextran Sulfate Sodium Salt) ‐induced intestinal inflammatory injury, it has been found in the study that transgenic mice expressing hVDR in IEC (Intestinal Epithelial Cell) manifest highly anti‐injury properties in colitis, suggesting that activated VDR in the epithelial cells of intestine may inhibit colitis by protecting the mucosal epithelial barrier. In this study, we investigated the effect of the expression and regulation of VDR on the protection of RIII, and the radiosensitivity in vitro experiments, and explored the initial mechanism of VDR in regulating radiosensitivity of IEC. As a result, we found that the expression of VDR in intestinal tissues and cells in mice can be induced by ionizing radiation. VDR agonists are able to prolong the average survival time of mice after radiation and reduce the radiation‐induced intestinal injury. For lack of vitamin D, the radiosensitivity of intestinal epithelial cells in mice increased, which can be reduced by VDR activation. Ensuing VDR activation, the radiation‐induced intestinal stem cells damage is decreased, and the regeneration and differentiation of intestinal stem cells is promoted as well. Finally, on the basis of sequencing analysis, we validated and found that VDR may target the HIF/PDK1 pathway to mitigate RIII. We concluded that agonism or upregulation of VDR expression attenuates radiation‐induced intestinal damage in mice and promotes the repair of epithelial damage in intestinal stem cells.
Background: Hematopoiesis and the differentiation of HSCs have been proved to not only play important roles in cancer progression but also be changed or reprogrammed by the tumor microenvironment itself. In this study, we investigated the changes of HSCs differentiation in advanced tumor-bearing mice.
Methods:The tumor-bearing mice model was established by subcutaneously inoculating with xenografts of B16-F10 mouse melanoma cells into the right back of male wild-type C57BL/6 mice. Hematopoietic stem cells and multilineage differentiation were evaluated using blood routine, HE-staining, flow cytometry assay and HSCs culture techniques. Results: The multilineage differentiation of hematopoietic stem cells was reprogrammed in vivo. Especially, the differentiations of megakaryocyte and erythrocyte were blocked, while myeloid cell and lymphoid cell differentiation was encouraged in advanced tumor-bearing mice. Conclusion: In this study we showed the potential mechanism of hematopoietic disorder in tumor condition from a respective of hematopoietic stem cell and multilineage differentiation, which provided new knowledge regarding cachexia.
AbstractBackground: Radiation induced-intestinal injury (RIII) is a common complication after radiation therapy in patients with pelvic, abdominal or retroperitoneal tumors. The mechanism of RIII includes radiation-induced death of intestinal epithelial cells (IECs) and damage of intestinal stem cells (ISCs), among which damage of ISCs is main cause. Most recently, hypoxia Inducible factor (HIF) has been found to have effect on maintaining stemness and promoting proliferation of ISCs, which suggests a protective role of HIF in the RIII. In this study, we investigated the effect of FG4592, a novel up-regulator of HIF, on the protection of RIII, and further researched its function on ISCs.Methods: With/without FG4592 treatment, the abdomen of mice was radiated at dose of 25Gy, and then the degree of intestinal injury was assessed by H&E staining and Brdu label. By intestinal organoid culture, the multiplication capacity and differentiation features of ISCs were detected. Besides, the effects of FG4592 on the radiated IECs were also evaluated by detecting cell viability, apoptosis, and proliferation potential.Results: FG4592 could effectively up-regulate the expression of HIF-1α and HIF-2α in vivo. An abdominal radiation of 25Gy established the RIII model of mice, by which FG4592 was verified to have protective effect on the intestine from radiation. Morphology and Brdu test of intestinal organoid showed that FG4592 could promote regeneration and differentiation in ISCs after radiation, which were mediated by up-regulating HIF-2 rather than HIF-1.Conclusion: FG4592, a novel up-regulator of HIF could remit RIII and promote regeneration and differentiation of ISCs after radiation, which were depend on HIF-2 rather than HIF-1.
Ionizing radiation is one of the common environmental carcinogens. miRNAs play critical roles in the processes of tumor occurrence, development, metastasis. However, the relationship between radiation-induced carcinogenesis and miRNA rarely reported. This study is aimed to investigate the effect of miRNAs on radiation-induced carcinogenesis. In this study we established the radiation-induced thymic lymphoma mice model. By using miRNA array of RTL tissue and predicting for miRNAs target genes, a miRNA-mRNA crosstalk network was established. Based on this network, we identified a critical miRNA, miR-486, which was the most down-regulated in the radiation-induced carcinogenesis. Then the function of miR-486 was confirmed by using knockout mice and cellular experiments. As a result, miR-486 could inhibit proliferation of mouse lymphoma cells by targeting IGF2BP3 mRNA. The adenovirus over-expression miR-486 vector reduced tumorigenesis in vivo. MiR-486 knockout mice have a strong tendency of radiation-induced carcinogenesis. In conclusion, miR-486 inhibits the proliferation of lymphoma cells and tumorigenesis induced by radiation through targeting IGF2BP3.
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