Despite their well-known and essential role in estrogen- and progesterone-mediated cellular processes, the roles of SRCs in the progression of endometriosis have not been well studied. In this paper, we propose a new TNF-α/MMP9/SRC-1 isoform functional axis as a novel pathogenic pathway for endometriosis. The SRC-1 isoform promotes endometriosis progression by causing EMT and invasion of endometrial epithelial cells. An accompanying alteration of proinflammatory signaling is closely associated with inflammatory diseases and cancer progression because proinflammatory signaling changes the molecular properties of target cells32,33
. For example, TNF-α treatment changes steroid hormone responsiveness in uterine smooth muscle cells by suppressing the expression of SRC-1 and SRC-234
. In the present study, we found that TNF-α also changes the molecular properties of SRC-1 by proteolytic processing to a 70kDa form that protects ectopic lesions from immune surveillance. Collectively, these results suggested that TNF-α signaling has an essential role in the initiation of endometriotic cellular processes. In addition to uterus, the TNF-α induced inflammatory response to endometriosis can impact the SRC-1 milieus of other organs of the abdominal cavity, such as intestine and liver, In this way, endometriosis may be accompanied by serious harmful systemic effects secondary to a widespread inflammatory response.
We found that MMP9, induced by TNF-α, is responsible for processing SRC-1 to the 70 kDa isoform. It preciously was suggested that MMPs are secreted and then activated to remodel the mesothelial lining of the peritoneum and to allow tissue invasion during progression of endometriosis35
. However, we found that both pro-MMP9 and processed MMP9 activities were detected in the eutopic endometrium when compared to the sham-treated uterus. These data imply that the intracellular activation of MMP9 can occur within endometriotic tissue. In support of our conclusion, the co-localization of trypsin-2 and MMP-9 has been reported in “intracellular pro-MMP-9 processing” that causes fully or partially activated MMP-9 in the intracellular vesicles of carcinoma cells36
. Therefore, it is likely that intracellular MMP9 activation in endometriosis is performed by a specific TNF-α-induced protease to process SRC-1 for the progression of endometriosis. In addition to the proteolytic activity of MMP9, the non-proteolytic activity of MMP-9 may be involved in the progression of endometriosis because non-proteolytic MMP9 activity is associated with cell migration37
Proinflammatory signaling is frequently associated with tissue-remodeling pathways in other inflammatory diseases and cancer. For example, TNF-α-induced MMP9 activation is associated with the progression of various cancers38
. Therefore, the TNF-α/MMP9 functional axis may play an essential role not only in endometriosis but also in other types of inflammatory diseases and cancer. Consequently, this functional axis should be considered a new molecular therapeutic target for the treatment of these diseases.
What is the pathobiological function of SRC-1 C-terminal isoform-mediated anti-apoptotic processing in human endometrial epithelial cells during the progression of endometriosis? The communication between the epithelial and stromal compartments plays an essential role in endometrial function. Therefore, paracrine factors produced from stromal cells regulate cell survival signaling in epithelial cells in the normal endometrium. In endometriosis, paracrine factors are also released from stromal cells to modulate cell survival signaling in epithelial cells in the endometriotic eutopic endometrium39
. In contrast to the eutopic endometrium, however, ectopic stromal cells lose the ability to regulate cell survival signaling in ectopic epithelial cells39
. Therefore, epithelial cells in ectopic lesions must acquire a new cell survival system. In this context, epithelial cells in ectopic lesions activate the TNF-α/MMP9/SRC-1 isoform pathway in response to TNF-α during the progression of endometriosis. The activation of this pathway processes SRC-1 to the SRC-1 C-terminal isoform, protecting epithelial cells in ectopic lesions from TNF-α-induced cell death and, thus, promoting their survival. In this way, the activation of the TNF-α/MMP9/SRC-1 isoform pathway in ectopic lesions can compensate for the loss of paracrine survival signaling generated from ectopic stromal cells.
Endometriosis has been known as an estrogen-dependent inflammatory disease. What is the role of the SRC-1 C-terminal isoform in the estrogen-dependent nature of endometriosis? Ectopic lesions require estrogen-dependent cellular processes for growth. However, ectopic lesions cannot use SRC-1 for estrogen-dependent gene regulation because full-length SRC-1 increased TNF-α-mediated cell death in IHEECs. For survival, SRC-1 must be processed to the SRC-1 C-terminal isoform in the epithelial cells of ectopic lesions to modulate estrogen-dependent cellular processes during activated proinflammatory signaling. In this way, the endometriosis-induced microenvironment actively changes the molecular properties of SRC-1 by proteolytic processing to prevent apoptosis but can still allow an estrogen-dependent progression of endometriosis.
We propose that this novel TNF-α/MMP9/SRC-1 C-terminal isoform functional axis is a new pathogenic pathway for the progression of endometriosis that has potential as a therapeutic target for endometriosis therapy.