| Background: The incidence and mortality of colorectal cancer(CRC)are increasing year by year worldwide,and it has become the second largest cancer in China after lung cancer.Although the diagnosis and treatment of colorectal cancer continue to evolve,about 70% of patients still develop metastases,and the occurrence of metastases is still the main cause of high mortality and poor prognosis.Oxaliplatin is the drug of choice for colorectal cancer treatment,but about 70% of patients are unresponsive or resistant to oxaliplatin alone.Previous studies have mostly explained the causes of drug resistance from traditional perspectives such as drug transport,metabolism and epigenetics,but the problem of drug resistance has not been effectively solved.Abnormal lipid metabolism is an important feature of tumor cells,which can enhance the adaptability of tumor cells to various complex environments.Targeting lipid metabolism has been regarded as an important direction for cancer therapy.Studies have found that inhibiting key enzymes in lipid metabolism can inhibit tumor growth and improve chemotherapy sensitivity,but the currently developed inhibitors have not been used in clinical due to the excessive side effects.Studies have found that supplementing specific fatty acids can also affect lipid metabolism and increase chemosensitivity.Based on lipidomics and transcriptomics,the causes and molecular mechanisms of CRC occurrence,development and oxaliplatin resistance were described from lipid metabolism.It is of great significance for the clinical treatment of colorectal cancer by supplementing specific exogenous fatty acids to affect the lipid metabolism process and increase the sensitivity of chemotherapy.Objective: This study aims to explore the effects of lipid metabolism on the occurrence,development,and prognosis of CRC;and then to analyze the effects and mechanisms of lipid metabolism changes induced by exogenous fatty acids on Oxa sensitivity.Methods: 1)UHPLC-MS/MS-based lipidomics technology was used to detect differences in lipid metabolism in CRC and normal tissues,and TCGA datasets were used to analyze the mRNA expression differences of the FADS gene family.2)UHPLC-MS/MS-based lipidomics technology detects TAG metabolism in CRC cells,flow cytometry detects lipid droplet(LD)amount in cells;MTS,flow cytometry,fluorescence imaging,lipidomics technology detects the changes of IC50,apoptosis rate,LD amount and lipid metabolism of CRC cells to Oxa under the action of palmitoleic acid(POA)and palmitic acid(PA).3)RNA-seq was performed on HT-29 cells treated with PA and Oxa,Lipid ROS was detected by flow cytometry,and GPX4 expression was detected by Western Blot.Results 1)Compared with normal tissue,glycerophospholipid(GPL)in CRC tissue increased and polyunsaturated TAG decreased;compared with early CRC tissue,polyunsaturated TAG increased in advanced CRC tissue;GPL decreased in CRC tissue after radiochemotherapy;FADS1 and SCD affect the occurrence,development and prognosis of CRC.2)The amount of LD,saturated and monounsaturated TAG in CRC cells was positively correlated with IC50 value;POA promoted the production of LD and decreased the sensitivity of Lo Vo cells to Oxa;PA promoted the production of saturated TAG and increased the sensitivity of HT-29 cells to Oxa.3)PA combines with Oxa increased Lipid ROS level,decreased GPX4 protein expression,and induced ferroptosis in HT-29 cells.Conclusion The polyunsaturated TAG content in CRC tumor is lower than that in paracancer,which may contribute to the occurrence of CRC;the polyunsaturated TAG content in advanced tumor is higher than that in early tumor tissue,which may promote colorectal progression;POA increases the amounts of LDs in Lo Vo cells and reduces their sensitivity to oxaliplatin;PA increases the amount of saturated TAG in HT-29 cells and induces ferroptosis increases its sensitivity to oxaliplatin. |
