The Role Of Cellular Senescence In Radioresiatance In Lung Cancer And The Late Effects Of Small Intestine Caused By Radiation

Radiotherapy inhibits tumors growth by using different rays of radioactive energy,which has now become one of the common therapy for cancer patients.Cellular senescence is one of common irradiation effects.Compared with normal cells,senescent cells undergo morphological changes,gene expression changes,and metabolism changes.Futhermore,senescent cells secrete a series of cytokines,which constitute senescence associated secretory phenotype(SASP)that could induce inflammation,and eventually affects radiotherapy efficacy and prognosis.Lung cancer is one of the most common malignancies in the world,and most of them belong to non-small cell lung cancer(NSCLC).Promoting apoptosis is an effective strategy to increase radiosensitivity of tumor.However,it is still unclear how the tumor undergoes apoptosis or senescence,and what is the relationship between senescence and acquired radioresistance of the tumor cells.To clarify the role of cellular senescence in the radioresistance of NSCLC,the radioresistant cell line was established by multiple low dose radiation exposure in the first part of this project.We compared the differences between the parental cells and the radioresistant cells.Our results showed that signal transducer and activator of transcription 5(STAT5)was an improtant protein affecting the radiosensitivity of NSCLC.With multiple irradiation,the number of senescent cells increased,the expression of STAT5 up-regulated,and NSCLC cells got radioresistance.STAT5 inhibitor or FOX04-DRI(a kind of senolytics)promoted apoptosis and increased the radiosensitivity of NSCLC cells in combination with irradiation.Total body irradiation(TBI)is the necessary strategy to clear the recipient bone marrow cells before hematopoietic stem cell transplantation(HSCT)for various hematologic system malignant diseases.However,TBI causes several side effects.The late effects of TBI on intestinal injury are rarely reported.To elucidate the role of cellular senescence in radiation-induced late effects of mouse small intestine,we performed a panel of experiments using a HSCT mouse model.A few alterations of phenotypes were observed 10 months following exposure to y-rays,for example,the whole-body hair of HSCT mice turned to grey,the body weight decreased,the proportion of senescent cells in the small intestine crypt increased.Furthermore,these phenomena may be closely related with intestinal flora changes and dysfunction of digestion and absorption of nutrients such as protein and carbohydrates in the small intestine.In conclusion,we identified STAT5 is the key protein related to apoptosis and senescence of tumor cells,and found a new signal pathway affecting the radiosensitivity of lung cancer,which provided new ideas and experimental basis for further research on improving radiotherapy efficacy of lung cancer.In the second part,the results of radiation-induced long-term intestinal senescence are of great significance for improving bone marrow transplant patients’life quality.