Ovarian cancer comprises one of the three major malignant tumor types in the female reproductive system. The mortality rate of this cancer is the highest among all gynecological tumors, with ovarian cancer metastasis constituting an important cause of death. Therefore, markers for disease prediction and prognosis are highly desirable for early diagnosis as well as for helping optimize and personalize treatment. Recently, microRNAs (miRNAs), which consist of short-sequence RNAs that do not encode a protein, have emerged as new biomarkers in the clinical diagnosis and treatment of ovarian cancer. By pairing with bases specific to the target messenger RNA (mRNA), miRNAs cause degradation of the target mRNA or inhibit its translation, thereby regulating various cellular processes including cell proliferation and adhesion. Increasing numbers of studies have shown that miRNA expression abnormality plays an important role in the development of ovarian cancer. In this review, we discuss the mechanisms of miRNA action, current research regarding their role in the suppression or promotion of ovarian cancer, and their use as markers for diagnosis of prognosis or as therapeutic targets for this disease. Finally, we present future perspectives regarding the clinical management of ovarian cancer and the role for miRNAs therein.

Decline in ovarian reserve with aging is associated with reduced fertility and the development of metabolic abnormalities. Once mitochondrial homeostasis is imbalanced, it may lead to poor reproductive cell quality and aging. However, Phosphoglycerate translocase 5 (PGAM5), located in the mitochondrial membrane, is associated with necroptosis, apoptosis, and mitophagy, although the underlying mechanisms associated with ovarian aging remain unknown. Therefore, we attempted to uncover whether the high phosphoglycerate mutant enzyme family member 5 (PGAM5) expression is associated with female infertility in cumulus cells, and aims to find out the underlying mechanism of action of PGAM5. We found that PGAM5 is highly expressed and positively associated with aging, and has the potential to help maintain and regulate mitochondrial dynamics and metabolic reprogramming in aging granulosa cells, ovaries of aged female mice, and elderly patients. PGAM5 undergoes activation in the aging group and translocated to the outer membrane of mitochondria, co‐regulating DRP1; thereby increasing mitochondrial fission. A significant reduction in the quality of mitochondria in the aging group, a serious imbalance, and a significant reduction in energy, causing metabolism shift toward glycolysis, were also reported. Since PGAM5 is eliminated, the mitochondrial function and metabolism of aging cells are partially reversed. A total of 70 patients undergoing in vitro fertilization (IVF) treatment were recruited in this clinical study. The high expression of PGAM5 in the cumulus cells is negatively correlated with the pregnancy rate of infertile patients. Hence, PGAM5 has immense potential to be used as a diagnostic marker.

Dehydroepiandrosterone (DHEA) is now widely used as an adjuvant for in vitro fertilization (IVF) cycles in poor ovarian responders (PORs). Several studies showed that DHEA supplementation could improve IVF outcomes of PORs. However, most of the PORs do not respond to DHEA clinically. Therefore, the aim of this study is to confirm the beneficial effects of DHEA on IVF outcomes of PORs and to investigate which subgroups of PORs can best benefit from DHEA supplementation. This retrospective cohort study was performed between January 2015 and December 2017. A total of 151 PORs who fulfilled the Bologna criteria and underwent IVF cycles with the gonadotropin-releasing hormone antagonist protocol were identified. The study group (n = 67) received 90 mg of DHEA daily for an average of 3 months before the IVF cycles. The control group (n = 84) underwent the IVF cycles without DHEA pretreatment. The basic and cycle characteristics and IVF outcomes between the two groups were compared using independent t-tests, Chi-Square tests and binary logistic regression. The study and control groups did not show significant differences in terms of basic characteristics. The study group demonstrated a significantly greater number of retrieved oocytes, metaphase II oocytes, fertilized oocytes, day 3 embryos and top-quality embryos at day 3 and a higher clinical pregnancy rate, ongoing pregnancy rate and live birth rate than those measures in the control group. The multivariate analysis revealed that DHEA supplementation was positively associated with clinical pregnancy rate (OR = 4.93, 95% CI 1.68–14.43, p = 0.004). Additionally, in the study group, the multivariate analysis showed that serum dehydroepiandrosterone-sulfate (DHEA-S) levels < 180 μg/dl were significantly associated with a rate of retrieved oocytes > 3 (OR = 5.92, 95% CI 1.48–23.26, p = 0.012). DHEA supplementation improves IVF outcomes of PORs. In PORs with DHEA pretreatment, women with lower DHEA-S level may have greater possibility of attaining more than 3 oocytes.

Aging of functional ovaries occurs many years before aging of other organs in the female body. In recent years, a greater number of women continue to postpone their pregnancies to later stages in their lives, raising concerns of the effect of ovarian aging. Mitochondria play an important role in the connection between the aging granulosa cells and oocytes. However, the underlying mechanisms of mitochondrial dysfunction in these cells remain poorly understood. Therefore, we evaluated the molecular mechanism of the aging granulosa cells, including aspects such as accumulation of mitochondrial reactive oxygen species, reduction of mtDNA, imbalance of mitochondrial dynamics, and diminished cell proliferation. Here, we applied bioinformatics approaches, and integrated publicly available resources, to investigate the role of CREB1 gene expression in reproduction. Senescence hallmark enrichment and pathway analysis suggested that the downregulation of bioenergetic-related genes in CREB1. Gene expression analyses showed alterations in genes related to energy metabolism and ROS production in ovary tissue. We also demonstrate that the biogenesis of aging granulosa cells is subject to CREB1 binding to the PRKAA1 and PRKAA2 upstream promoters. In addition, cofactors that regulate biogenesis significantly increase the levels of SIRT1 and PPARGC1A mRNA in the aging granulosa cells. These findings demonstrate that CREB1 elevates an oxidative stress-induced senescence in granulosa cells by reducing the mitochondrial function.

This paper investigates the expression of the CREB1 gene in ovarian cancer (OV) by deeply excavating the gene information in the multiple databases and the mechanism thereof. In short, we found that the expression of the CREB1 gene in ovarian cancer tissue was significantly higher than that of normal ovarian tissue. Kaplan–Meier survival analysis showed that the overall survival was significantly shorter in patients with high expression of the CREB1 gene than those in patients with low expression of the CREB1 gene, and the prognosis of patients with low expression of the CREB1 gene was better. The CREB1 gene may play a role in the occurrence and development of ovarian cancer by regulating the process of protein. Based on differentially expressed genes, 20 small-molecule drugs that potentially target CREB1 with abnormal expression in OV were obtained from the CMap database. Among these compounds, we found that naloxone has the greatest therapeutic value for OV. The high expression of the CREB1 gene may be an indicator of poor prognosis in ovarian cancer patients. Targeting CREB1 may be a potential tool for the diagnosis and treatment of OV.