Understanding the Correlation between Metabolic Regulator SIRT1 and Exosomes with CA-125 in Ovarian Cancer: A Clinicopathological Study

Abstract

Background. Ovarian cancer (OvCa), the deadliest gynaecological malignancy, is associated with poor prognosis and high mortality rate. Ovarian cancer has been related with CA-125 and metabolic reprogramming by SIRT1 leading to metastasis with the involvement of exosomes. Methods. Clinicopathological data of OvCa patients were collected to perform the analysis. Patients’ samples were collected during surgery for immunohistochemistry and flow cytometric analysis of SIRT1, HIF-1α, exosomal markers (CD81 and CD63), ki-67, and PAS staining for glycogen deposition. Adjacent normal and tumor tissues were collected as per the CA-125 levels. Results. CA-125, a vital diagnostic marker, has shown significant correlation with body mass index (BMI) ( $P=0.0153$ ), tumor type ( $P=0.0029$ ), ascites level, ascites malignancy, degree of dissemination, tumor differentiation, FIGO stage, TNM stage, laterality, and tumor size at $P<0.0001$ . Since significant correlation was associated with BMI and degree of dissemination, as disclosed by IHC analysis, metabolic marker SIRT1 ( $P=0.0003$ ), HIF-1α ( $P<0.0001$ ), exosomal marker CD81 ( $P<0.0001$ ), ki-67 status ( $P=0.0034$ ), and glycogen deposition (P <0.0001) were expressed more in tumor tissues as compared to the normal ones. ROC analysis of CA-125 had shown 327.7 U/ml has the best cutoff point with 82.4% sensitivity and specificity of 52.3%. In addition, Kaplan-Meier plots of CA-125 ( $P<0.0001$ ), BMI ( $P=0.001$ ), degree of dissemination ( $P<0.0001$ ), and ascites level (P <0.0001) reflected significant correlation with overall survival (OS). Upon multivariate Cox-regression analysis for overall survival (OS), BMI ( $P=0.008$ , HR 1.759, 95% CI 1.156-2.677), ascites malignancy ( $P=0.032$ , HR 0.336, 95% CI 0.124-0.911), and degree of dissemination ( $P=0.004$ , HR 1.994, 95% CI 1.251-3.178) were significant proving to be independent indicators of the disease. Conclusion. Clinicopathological parameters like BMI, degree of dissemination, and ascites level along with CA-125 can be prognostic factors for the disease. Levels of CA-125 can depict the metabolic and metastatic factors. Thus, by targeting SIRT1 and assessing exosomal concentrations to overcome metastasis and glycogen deposition, individualized treatment strategy could be designed. In-depth studies are still required.