CD147 Promotes The Chemoresistance Of Pancreatic Cancer Stem Cells

Pancreatic cancer is the fourth most deadly digestive system tumor with high degree of malignity and poor prognosis at present.The first-line drug of pancreatic cancer chemotherapy is gemcitabine,but intrinsic and acquired gemcitabine resistance appear in most pancreatic cancer patients and therapeutic efficacy is not ideal.So the study of pancreatic cancer cells' chemoresistance mechanism is very important to improve the current situation of the treatment of pancreatic cancer patients.Pancreatic cancer stem cells possess the unlimited ability of self-renewal and differentiation potential,can form new tumors in vivo and in vitro,and are resistant to radiotherapy and chemotherapy.Therefor,the existence of pancreatic cancer stem cells may lead to the resistance to chemotherapy drugs.Our earlier results show that CD147 can regulate the gemcitabine and CDDP sensitivity of pancreatic cancer cells,the ratio of pancreatic cancer stem cells,and the tumorigenic ability in vivo and in vitro.So CD147 may promote the chemoresistance of pancreatic cancer cells by influencing pancreatic cancer stem cells.In the first part,our results indicated that the ratio of ALDH+ pancreatic cancer stem cells,CD44+CD133+ pancreatic cancer stem cells,CD44+CD24+ cells and CD44+ESA+ cells were significantly increased after gemcitabine treatment.Using high-concentration of gemcitabine to treat pancreatic cancer cells continuously,we screened out intrinsic chemoresistant cells from pancreatic cancer cells.The ratio of CD44+CD133+ pancreatic cancer stem cells was significantly increased in intrinsic chemoresistant cells,indicating that pancreatic cancer stem cells played an important role in the chemoresistance of pancreatic cancer cells.Moreover,the content of mitochondria and ROS in pancreatic cancer cells were both significantly increased after gemcitabine treatment.Compared with ROS+ pancreatic cancer cells,ROS-pancreatic cancer cells were less sensitive to gemcitabine.For this reason,whether pancreatic cancer cells were able to eliminate the excess ROS in cells was the key to the chemoresistance of pancreatic cancer cells.The subset of ROS-pancreatic cancer stem cells may lead to the chemoresistance of pancreatic cancer cells.In the second part,our results indicated that the expression of CD147 was significantly increased after gemcitabine treatment.The expression of CD147 was significantly increased in intrinsic chemoresistant cells as well.Compared with CD147 low pancreatic cancer cells,CD147 high pancreatic cancer cells were less sensitive to gemcitabine,demonstrating that CD147 promoted the gemcitabine chemoresistance of pancreatic cancer cells.Moreover,the expression of CD147 on the cell surface showed positive correlations with the ratio of pancreatic cancer stem cells,indicating that CD147 played an important role in the chemoresistance mediated by pancreatic cancer stem cells.The above results showed that CD147 played an important role in intrinsic chemoresistant of pancreatic cancer cells.In CD147 stably interfered pancreatic cancer cells and CD147 inducibly interfered pancreatic cancer cells,down-regulating the expression of CD147 significantly inhibited the tumorigenic ability of pancreatic cancer cells and the growth of pancreatic cancer cells in vivo.Further results shown that CD147 can be expressed in mitochondria of pancreatic cancer cells.After interfering the expression of CD147,the expression of CD147 in mitochondria of pancreatic cancer cells was decreased and the mitochondria content of pancreatic cancer cells in vivo was decreased.These results demonstrated that CD147 may regulate the gemcitabine sensitivity of pancreatic cancer stem cells by up-regulating the mitochondrial quantity and function of pancreatic cancer cells.In summary,the results of this study show that pancreatic cancer stem cells may lead to the chemoresistance of pancreatic cancer cells by eliminating the excess ROS in cells,and CD147 may regulate the gemcitabine sensitivity of pancreatic cancer stem cells by affecting the mitochondrial function of pancreatic cancer cells.