Role Of ACSS2 In Ovarian Cancer Development And Cisplatin Resistance

Background:Ovarian cancer is one of the most fatal malignant tumors in the world and is often diagnosed at a late stage because of its lack of obvious early symptoms.At present,the main treatment methods are surgery and adjuvant chemotherapy.Despite the continuous development and progress of surgical treatment methods and techniques as well as chemotherapeutic drugs,the recurrence rate of ovarian cancer is still very high.In addition,platinum is one of the most commonly used chemotherapeutic drugs for ovarian cancer.Although most patients have a good response to platinum in the initial stage of chemotherapy,due to the resistance of tumor cells to anticancer drugs,patients’ sensitivity to platinum is reduced,which will eventually lead to tumor recurrence and patient death.Acetyl-CoA synthase 2(ACSS2),an important member of the acetyl-CoA synthase family,can catalyze the conversion of acetate to acetyl-CoA.At present,acetyl-CoA is considered to be an important intermediate metabolite in energy substrate metabolism.In addition,acetyl-CoA can assemble nutrients into a common metabolic pathway,that is,tricarboxylic acid cycle and oxidative phosphorylation.ACSS2 not only plays an important role in material and energy metabolism,but also participates in the regulation of a variety of acetylation processes,such as histone acetylation and transcription factor acetylation,and ACSS2-mediated acetylation regulation is related to substance metabolism and tumorigenesis.In addition,studies in the tumor field have shown that under metabolic stress,tumor cells can adapt to the growth conditions of tumor microenvironment(TME)by activating ACSS2 or increasing the expression level of ACSS2.At present,many studies have confirmed that ACSS2 is highly expressed in a variety of malignant tumors,including breast cancer,myeloma,hepatocellular carcinoma,esophageal cancer and so on,and the expression of ACSS2 can affect the prognosis of tumor patients.However,there are few studies on ACSS2 in ovarian cancer.Therefore,in this study,we will detect the expression of ACSS2 in ovarian cancer and explore the effect of ACSS2 expression on the occurrence and development of ovarian cancer and cisplatin resistance.Objective:1.Based on bioinformatics analysis,the expression of ACSS2 in ovarian cancer and the effect of its expression on the prognosis of patients were analyzed.2.To detect the expression of ACSS2 in ovarian cancer tissues and paracancerous tissues,and to detect the expression of ACSS2 in normal ovarian cell lines and ovarian cancer cell lines.3.To investigate the influence of ACSS2 expression on cell proliferation,migration and invasion,and recognizing its subsequent route.4.To detect the effect of ACSS2 expression on cisplatin-induced apoptosis of ovarian cancer cells.Materials and methods:1.The expression of ACSS2 in ovarian cancer and its impact on the prognosis of those afflicted were studied through the utilization of UCSC Xena and Kaplan-Meier Plotter websites.2.Using Western Blot,qPCR and cellular immunohistochemical staining,researchers sought to uncover the expression of ACSS2 in both ovarian cancer and paracancerous tissues,as well as to explore the correlation between ACSS2 and pathological stage,BRCA mutation and other clinical characteristics.Moreover,Western Blot and qPCR were employed to detect ACSS2 expression in both normal ovarian cell lines and distinct ovarian cancer celllines.3.Knock-down ACSS2 stable cell line and over-expressed ACSS2 stable cell line were constructed.Verification of ACSS2’s knock-down and overexpression via Western Blot was followed by cell proliferation count,Transwell migration,and Transwell invasion tests to assess the effect of ACSS2 expression on ovarian cancer cell proliferation,migration,and invasion.Subsequently,Western Blot was employed to identify AKT expression and phosphorylated AKT protein.4.Cisplatin was used to stimulate over-expressed ACSS2 cell line and knock-down ACSS2 cell line,and the expression of apoptotic protein cleaved-PARP was detected by Western Blot.Results:1.The expression of ACSS2 in ovarian cancer was higher than that in normal ovary.2.The expression of ACSS2 in patients with ovarian cancer is related to pathological stage.3.Patients with high expression of ACSS2 in ovarian cancer had a shorter survival time than those with low expression.4.Inhibition of ACSS2 expression can significantly inhibit the proliferation,migration and invasion of human ovarian cancer cells.5.Enhancing the expression of ACSS2 can significantly promote the proliferation,migration and invasion of human ovarian cancer cells.6.ACSS2 promotes tumor by activating PI3K/AKT pathway.7.The high expression of ACSS2 can inhibit the effect of cisplatin on apoptosis of ovarian cancer cells.Conclusion:1.ACSS2 is highly expressed in ovarian cancer,and its increased expression may promote the occurrence and development of ovarian cancer through the PI3K/AKT signaling pathway.2.The expression of ACSS2 in ovarian cancer sufferers being high is linked to a poor prognosis,and the expression of ACSS2 may have a varying impact on the prognosis of ovarian cancer patients with different pathological stages,potentially due to alterations in tumor metabolism in the tumorigenesis and development stage.3.The high expression of ACSS2 may increase the cisplatin resistance of ovarian cancer cells,and ACSS2 can be used as a target to reduce the cisplatin resistance of ovarian cancer.