The EPH/Ephrin System in Gynecological Cancers: Focusing on the Roots of Carcinogenesis for Better Patient Management

Abstract

Gynecological cancers represent some of the most common types of malignancy worldwide. Erythropoietin-producing hepatocellular receptors (EPHs) comprise the largest subfamily of receptor tyrosine kinases, binding membrane-bound proteins called ephrins. EPHs/ephrins exhibit widespread expression in different cell types, playing an important role in carcinogenesis. The aim of the current review was to examine the dysregulation of the EPH/ephrin system in gynecological cancer, clarifying its role in ovarian, endometrial, and cervical carcinogenesis. In order to identify relevant studies, a literature review was conducted using the MEDLINE and LIVIVO databases. The search terms ephrin, ephrin receptor, ovarian cancer, endometrial cancer, and cervical cancer were employed and we were able to identify 57 studies focused on gynecological cancer and published between 2001 and 2021. All researched ephrins seemed to be upregulated in gynecological cancer, whereas EPHs showed either significant overexpression or extensive loss of expression in gynecological tumors, depending on the particular receptor. EPHA2, the most extensively studied EPH in ovarian cancer, exhibited overexpression both in ovarian carcinoma cell lines and patient tissue samples, while EPHB4 was found to be upregulated in endometrial cancer in a series of studies. EPHs/ephrins were shown to exert their role in different stages of gynecological cancer and to influence various clinicopathological parameters. The analysis of patients’ gynecological cancer tissue samples, most importantly, revealed the significant role of the EPH/ephrin system in the development and progression of gynecological cancer, as well as overall patient survival. In conclusion, the EPH/ephrin system represents a large family of biomolecules with promising applications in the fields of diagnosis, prognosis, disease monitoring, and treatment of gynecological cancer, with an established important clinical impact.

PPP1R14B is a diagnostic prognostic marker in patients with uterine corpus endometrial carcinoma

“…53 Abnormal tyrosine metabolism also plays a very important role in the occurrence and development of tumours. 54 GSEA results showed that PPP1R14B was closely related to H3K27me3, PRC2, and other epigenetic genes, which are closely related to the stem cell characteristics of tumour cells. In many poorly differentiated tumours, the stem cell phenotype is often very obvious.…”

“…In addition, the enrichment of retinol metabolism and tyrosine metabolism has been observed, and retinol and its derivatives can effectively delay or prevent precancerous lesions and induce tumour cell differentiation and apoptosis 53 . Abnormal tyrosine metabolism also plays a very important role in the occurrence and development of tumours 54 . GSEA results showed that PPP1R14B was closely related to H3K27me3, PRC2, and other epigenetic genes, which are closely related to the stem cell characteristics of tumour cells.…”

Hunting for Novel Routes in Anticancer Drug Discovery: Peptides against Sam-Sam Interactions

“…The biggest subfamily of RTKs is represented by the Eph (Erythropoietin-producing hepatocellular) receptors that interact with membrane-bound ligands called ephrins [ 97 , 98 ]. EphA1 was the first discovered Eph receptor tyrosine kinase and was cloned in 1987 from a hepatocellular carcinoma (HCC) cell line; next, in 1990 the screening of a cDNA library of HeLa cells brought the identification of EphA2 [ 99 , 100 , 101 , 102 ]. Currently, 14 Eph receptors and 8 ephrin ligands are known, there are nine Eph receptors of type-A (EphA1-8, and EphA10) and 5 Eph receptors of type-B (EphB1-4,6).…”

The Role of Urothelial Cancer-Associated 1 in Gynecological Cancers

“…OC is the seventh most common gynecological malignancy, with 140,000 deaths per year reported [ 9 , 10 ]. In 2021, 13,770 deaths from OC were documented according to the American Cancer Society [ 11 ]. The vast majority of ovarian tumors are epithelial, which present with vague persistent gastrointestinal and urologic symptoms, such as excessive bloating and discomfort [ 12 ].…”