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.