MAPK signaling pathway and endometriosis: what is the link?

Abstract

Endometriosis is defined as the presence of endometrial tissue outside the uterus, predominantly on the ovary and pelvic peritoneum [1]. It occurs in approximately 10 % of women of reproductive age and, although it is a benign disease, it causes infertility and pelvic pain, compromising the quality of life [1]. Out of various theories put forward to explain the origin of endometriosis, retrograde menstrual reflux has gained the widest acceptance [1, 2]. Endometriosis has been reported to be characterized by the presence of endometrial cells with capacity to avoid apoptosis beyond the uterine cavity [1, 2]. Apoptosis plays an important role in maintaining tissue homeostasis by striking a balance between proliferation and cell death [1]. Endometriotic cells have been described to show the peculiar biological characteristics of resistance to apoptosis with the inability to transmit apoptotic signal and the ability to avoid cell death [1, 2]. Recently, endometriosis has been correlated with aberrant endometrial expression of telomerase and survivin implying modifications in cell fate [1, 2]. Telomerase is a specialized transcriptase that can prevent telomere shortening [2, 3]. Telomeres are noncoding tandemly repeated DNA sequences that are vital for maintaining chromosomal integrity and cell stability [2]. The critical shortening of telomeres is linked to cell division and their senescence and death [2, 3]. Consequently, telomerase activation allows cells to overcome apoptosis acquiring immortal capacity [2, 3]. Survivin is the smallest member of the inhibitor of apoptosis protein family that acts by suppressing primarily caspases [1, 4]. It is prominently expressed in embryonic and fetal tissues and over-expressed in virtually all tumor types [1]. It is transcriptionally silent in most differentiated adult tissues, but it is expressed in ovary and in the proliferative phase of the cycling human endometrium, suggesting a physiological role in normal endometrial function [1, 4]. Survivin has been shown to be closely linked to escape from apoptosis of endometriotic cells and their viability with a critical role in the pathogenesis and progression of endometriosis together with telomerase [1–4]. It has been found that both the survivin and telomerase are up-regulated by epidermal growth factor (EGF) through MAPK (mitogen activated protein kinase) signaling pathway activation [3, 4]. MAPK has been reported to play an important role in many cellular reactions such as apoptosis, proliferation and inflammation [5]. Many studies have demonstrated that MAPK is involved directly in regulating the pathogenesis of endometriosis [5]. MAPK pathways seem to play a pivotal role as intracellular and extracellular signal transducers in endometriotic cells [6, 7]. It has been reported that enhanced proliferation and survival of eutopic endometrial cells from patients with endometriosis compared with healthy women have correlated with abnormal activation of MAPK signaling pathways [7]. In addition, accumulating evidences, show that MAPK pathways regulate pain hypersensitivity in different injury conditions implying their possible involvement in endometriosisrelated pelvic pain [8]. With respect to the above, we suggest that inhibition of MAPK signaling pathway downregulating both telomerase and survivin expression, may be candidate as a new therapeutic target for endometriosis. Moreover, understanding the possible regulatory role of MAPK in apoptosis and, ultimately, in the signal R. Mormile (&) Division of Pediatrics and Neonatology, Moscati Hospital, Via A. Gramsci, 3, 81031 Aversa, Italy e-mail: raffaellamormile@alice.it; raffaellamormile@libero.it