Study On The Effect Of Exosome-mediated Oxaliplatin Resistance In Colon Cancer

Background and Objective:Colon cancer is a kind of high incidence cancer in China,and its incidence trend is increasing in recent years.Surgery is the main treatment for colon cancer,however,postoperative metastasis and recurrence are still the key adverse factors restricting the prognosis of colon cancer.As a necessary adjuvant therapy,chemotherapy is widely used in clinical practice.However,patients receiving chemotherapy often develop drug resistance,which greatly affects the effectiveness of chemotherapy.Exosomes are a class of extracellular vesicles ranging in size from 40 to 150 nm that are released by all types of cells and have a lipid bilayer containing DNA,RNA,and proteins.Exosomes act as actual mediators of cell-to-cell communication and are involved in the transfer of biological signals and substances between different cells.Recent studies have shown that exosomes of colon cancer cells can promote the proliferation,migration and invasion of cancer cells,and affect angiogenesis and immune system activity.Exosomes are increasingly becoming participants in the development of resistance to chemotherapeutic and targeted drugs in patients with metastatic colon cancer.At present,the specific mechanism of exosomes’ involvement in colon cancer is still controversial.This study aims to explore the role of exosomes in drug resistance of colon cancer,and to verify the possibility of β-elemene,an effective anticancer component extracted from the Zingiberaceae plant Radix Eulens,as a potential drug for the treatment of colon cancer.Part Ⅰ:Oxaliplatin-resistant colon cancer cell HCT116/L promotes the progression of colon cancer and reduces the efficacy of oxaliplatin by inducing sensitive cell transformation through exosomesObjective:The purpose of this study was to investigate the role of exosomes in drug resistance of colon cancer and to analyze its possible molecular mechanisms.Methods:Build the resistant cells secrete body cell line model,the assessment of oxaliplatin into drug-resistant colon cancer cell HCT116/L,sensitive cell HCT116,HCT116+HCT116/L-exosomes(HCT116-exo)of the three cell proliferation,migration,invasion,and apoptosis resistance and resistance of oxaliplatin into outside and secrete body may affect signaling pathways and mechanisms.Results:In different colon cancer cells,chimeric drug-resistant cells HCT116-exo showed stronger proliferation,migration and invasion ability compared with sensitive cells HCT116(statistically significant difference,P<0.05).After the above cells were treated with oxaliplatin the apoptosis rate of chimeric drug-resistant cells HCT116-exo was significantly decreased(P<0.05),and its IC50 was significantly increased(P<0.05)compared with the sensitive cells HCT116.Western blot results showed that compared with HCT116,the expression of Vimentin,Bcl-2,FGFR4 and SHMT2 in HCT116-exo cells were significantly enhanced,and the expression of Caspase-3 and E-cadherin was significantly down-regulated.In addition,the expression of p-STAT3 in drug-resistant cells HCT116/L was higher than that in sensitive cells HCT116 and chimeric drug-resistant cells HCT116-exo.Conclusion:Exosomes of drug-resistant cells can mediate oxaliplatin resistance in colon cancer,improve its malignant phenotype and promote the process of EMT.This process may be related to the involvement of exosome-related molecules FGFR4 and SHMT2.Part Ⅱ:β-elemene and STAT3 inhibitors can reverse oxaliplatin resistance in colon cancer cellsObjective:To explore whether β-elemene and STAT3 inhibitors affect oxaliplatin resistance in colon cancer,and to explore its possible molecular mechanisms.Methods:STAT3 inhibitor,β-elemene and oxaliplatin were given to oxaliplatin-resistant colon cancer cells HCT116/L,sensitive cells HCT116 and chimeric drug-resistant cells HCT116-exo alone or in combination,and the changes of cell proliferation,invasion,migration and apoptosis were investigated under different treatments.The molecular changes after different treatments were investigated by Western blot.Results:The proliferation,invasion and migration of cells treated with STAT3 inhibitor or β-elemene combined with oxaliplatin were significantly reduced compared with those treated with oxaliplatin or β-elemene alone(P<0.05).STAT3 inhibitor or β-elemene combined with oxaliplatin significantly increased the apoptosis rate compared with oxaliplatin or β-elemene alone(P<0.05).Western blot results showed that β-elemene combined with oxaliplatin significantly enhanced the expression of E-cadherin and Caspase-3,and significantly down-regulated the expression of Vimentin,Bcl-2,STAT3 and p-STAT3,compared with oxaliplatin alone.STAT3 inhibitor combined with oxaliplatin significantly enhanced the expression of E-cadherin and Caspase-3,and significantly down-regulated the expression of Vimentin,Bcl-2,STAT3 and p-STAT3.Conclusion:STAT3 inhibitor or β-elemene combined with oxaliplatin can effectively reduce drug resistance and proliferation and invasion ability,which may be due to the correlation between β-elemene and the STAT3 pathway and EMT pathway in colon cancer.β-elemene is expected to become a new drug to reverse oxaliplatin resistance.Full text conclusion:Oxaliplatin-resistant exosomes can enhance the proliferation,invasion and migration of colon cancer,reduce the efficacy of oxaliplatin,and promote EMT,which may be related to the involvement of exosomal-related molecule FGFR4.The use of STAT3 inhibitors and β-elemene can affect the biological characteristics of colon cancer and reduce its resistance to oxaliplatin.