Role of microRNAs in glycolysis in gynecological tumors (Review)

Abstract

Gynecological malignancies are a leading cause of mortality among females worldwide, and difficulties in early diagnosis and acquired drug resistance constitute obstacles to effective therapies. Ovarian cancer causes more deaths than any other cancer of the female reproductive system. Specifically, in females aged 20 to 39 years, cervical cancer is the third leading cause of cancer‑related mortality, and the incidence rates of cervical adenocarcinoma are increasing. Endometrial carcinoma is the most common gynecological cancer in developed countries, such as the United States. Vulvar cancer and uterine sarcomas are considered rare, and therefore require further investigation. Notably, the development of novel treatment options is critical. Previous research has revealed metabolic reprogramming as a distinct feature of tumor cells, which includes aerobic glycolysis. In this instance, cells produce adenosine triphosphate and various precursor molecules through glycolysis, despite oxygen levels being sufficient. This is to meet the energy required for rapid DNA replication. This phenomenon is also known as the Warburg effect. The Warburg effect results in an increased glucose uptake, lactate production and reduced pH values in tumor cells. The results of previous studies have demonstrated that microRNAs (miRNAs/miRs) regulate glycolysis, and participate in tumorigenesis and tumor progression via interactions with glucose transporters, essential enzymes, tumor suppressor genes, transcription factors and multiple cellular signaling pathways that play critical roles in glycolysis. Notably, miRNAs affect the levels of glycolysis in ovarian, cervical and endometrial cancers. The present review article provides a comprehensive overview of the literature surrounding miRNAs in the glycolysis of gynecological malignant cells. The present review also aimed to determine the role of miRNAs as potential therapeutic options rather than diagnostic markers.

Keywords: Warburg effect; cervical cancer; endometrial carcinoma; glycolysis; microRNA; ovarian cancer.

Figure 1

Schematic diagram of the generation of miRNAs. miRNAs, microRNAs; pre-miRNAs, precursor miRNAs; AGO, Argonaute; RISC, RNA-induced silencing complex.

Figure 2

Glucose is transported into the cell by GLUT, and HK catalyzes the production of G-6-P. Phosphohexose isomerase catalyzes the production of F-6-P. PFK1 is further phosphorylated to form F-1, 6-BP, which is catalyzed by aldolase into DHAP and glyceraldehyde 3-phosphate. PEP is subsequently generated through multiple reversible reactions, and PEP is converted to pyruvate with PK catalysis. The + symbol indicates promotion, and the-symbol indicates inhibition. miR, miRNA; GLUT, glucose transporter; HK, hexokinase; G-6-P, glucose 6 phosphate; F-6-P, fructose 6-phosphate; PFK1, phosphofructokinase L; F-1, 6-BP, fructose 1,6-diphosphate; DHAP, dihydroxyacetone phosphate; PEP, phosphoenolpyruvate; PK, pyruvate kinase; LDH, lactate dehydrogenase; PDK, pyruvate dehydrogenase.

Figure 3

Downstream targets of miRNAs. miRNAs/miRs, microRNAs; GLUT, glucose transporter; HK2, hexokinase 2; PFKFB3, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3; PDK, pyruvate dehydrogenase; AMPK, AMP kinase.