Integrated Bioinformatics Investigation of Novel Biomarkers of Uterine Leiomyosarcoma Diagnosis and Outcome

Uterine leiomyosarcomas (uLMS) have a poor prognosis and a high percentage of recurrent disease. Bioinformatics has become an integral element in rare cancer studies by overcoming the inability to collect a large enough study population. This study aimed to investigate and highlight crucial genes, pathways, miRNAs, and transcriptional factors (TF) on uLMS samples from five Gene Expression Omnibus datasets and The Cancer Genome Atlas Sarcoma study. Forty-one common differentially expressed genes (DEGs) were enriched and annotated by the DAVID software. With protein–protein interaction (PPI) network analysis, we selected ten hub genes that were validated with the TNMplotter web tool. We used the USCS Xena browser for survival analysis. We also predicted TF-gene and miRNA-gene regulatory networks along with potential drug molecules. TYMS and TK1 correlated with overall survival in uLMS patients. Finally, our results propose further validation of hub genes (TYMS and TK1), miR-26b-5p, and Sp1 as biomarkers of pathogenesis, prognosis, and differentiation of uLMS. Regarding the aggressive behavior and poor prognosis of uLMS, with the lack of standard therapeutic regimens, in our opinion, the results of our study provide enough evidence for further investigation of the molecular basis of uLMS occurrence and its implication in the diagnosis and therapy of this rare gynecological malignancy

Glutathione Transferase P1: Potential Therapeutic Target in Ovarian Cancer

Chemotherapy resistance of ovarian cancer, regarded as the most lethal malignant gynecological disease, can be explained by several mechanisms, including increased activity of efflux transporters leading to decreased intracellular drug accumulation, increased efflux of the therapeutic agents from the cell by multidrug-resistance-associated protein (MRP1), enhanced DNA repair, altered apoptotic pathways, silencing of a number of genes, as well as drug inactivation, especially by glutathione transferase P1 (GSTP1). Indeed, GSTP1 has been recognized as the major enzyme responsible for the conversion of drugs most commonly used to treat metastatic ovarian cancer into less effective forms. Furthermore, GSTP1 may even be responsible for chemoresistance of non-GST substrate drugs by mechanisms such as interaction with efflux transporters or different signaling molecules involved in regulation of apoptosis. Recently, microRNAs (miRNAs) have been identified as important gene regulators in ovarian cancer, which are able to target GST-mediated drug metabolism in order to regulate drug resistance. So far, miR-186 and miR-133b have been associated with reduced ovarian cancer drug resistance by silencing the expression of the drug-resistance-related proteins, GSTP1 and MDR1. Unfortunately, sometimes miRNAs might even enhance the drug resistance in ovarian cancer, as shown for miR-130b. Therefore, chemoresistance in ovarian cancer treatment represents a very complex process, but strategies that influence GSTP1 expression in ovarian cancer as a therapeutic target, as well as miRNAs affecting GSTP1 expression, seem to represent promising predictors of chemotherapeutic response in ovarian cancer, while at the same time represent potential targets to overcome chemoresistance in the future