Accumulating evidence suggests that endometrium of endometriosis patients exhibits anomalous gene expression profiles that are distinct from healthy populations . To explore such a discrepancy, we selected three gene expression profile datasets. By analysing these datasets, a total of 304 DEGs were identified, including 185 unregulated and 119 downregulated genes. Furthermore, these DEGs provided promising evidence that supported some new hypotheses of the onset of endometriosis.
The most significant symptom of endometriosis is chronic pelvic pain, which is related with the activation of voltage-gated calcium channels. Calcium channels play a critical role in neuropathic pain development through the regulation of the release of excitatory neurotransmitters as part of the second messenger system . In particular, although the endometriosis implants are ectopic, they are highly innervated . A pilot trial showed that the use of gabapentin as a calcium channel blocker could manage pain effectively .
Genes related to uterus development were differentially expressed between healthy populations and endometriosis patients. Crispi et al. proposed the hypothesis that endometriosis may be connected with defects during the development of the female reproductive system. These abnormal genes might be associated with the erroneous localization of the cells that generate the ectopic endometrium during the migration phase . BMP6 belongs to the transforming growth factor-beta super-family that includes proteins involved in cell growth and differentiation . SERPINE1 is a member of the serine protease inhibitor family that contains inhibitors of tissue plasminogen activator and are involved in tissue remodelling. SERPINE1 exhibited significantly higher expression in ovarian cancer patients, indicating a potential role in tumour invasion and metastasis . Up-regulated SERPINE1 expression could also explain some malignant characteristics of ectopic endometrium; however, samples included in this study were obtained from patients with deep infiltrating endometriosis.
KEGG analysis revealed that up-regulated DEGs were related to cytokine-cytokine receptor interaction. In patients with endometriosis, cytokine levels in the retained fluid were increased compared with that in normal subjects, and ectopic lesions typically occurred at the site of retained fluid. This finding suggested that cytokines might play an important role in endometrial cell peritoneal implantation, infiltration, vascular regeneration and local hyperplasia. TNF (tumour necrosis factor) is a cytokine derived from macrophages and monocytes that plays an important role in immune regulation, cell growth and differentiation. Enzyme linked immunosorbent assay results revealed significantly increased TNF-α levels in peritoneal fluid of patients with endometriosis and infertility compared with the control group (P < 0.05). Increased TNF in the circulating blood attracts activated monocytes and inflammatory cells to the peritoneal cavity, and the number of monocytes was also increased in the local immune system, which stimulates the growth of ectopic endothelium . In patients with endometriosis, a high concentration of VEGF (vascular endothelial growth factor) was noted in the peritoneal fluid. Endometrial cells were locally attached and infiltrated the endothelium, and a large number of blood vessels are required to ensure their growth. VEGF is a proliferating factor that plays a major role in neovascularization. Bioinformatic analysis and molecular biology characterization indicated that pro-inflammatory cytokines induced VEGF-C overexpression to enhance lymphangiogenesis in lymphoendothelial cells by inhibiting COUP-TFII levels . IL-8 is an angiogenic factor that promotes the proliferation of new blood vessels, allowing the ectopic endometrium to grow and proliferate, resulting in extensive pelvic adhesions. IL-8 is involved in the pathological process of endometriosis. Ectopic endometrial stromal cells exhibited significantly increased IL-6 and IL-8 mRNA gene expression and secretion compared with orthotopic and control endometrial stromal cells prior to treatment .
On the other hand, KEGG analysis suggested that down-regulated DEGs were related to protein processing in the endoplasmic reticulum. The endoplasmic reticulum played an important role in the interaction between multiple intracellular organelles along with collateral bio-activities, especially including processes associated with the proteasome and attached ribosome, protein synthesis and other processes. Accumulation of unfolded or misfolded proteins during endoplasmic reticulum stress activated a homeostatic coping mechanism called the unfolded protein response. Female reproductive tissues were highly active at cellular, molecular and genetic levels, and this activity requires the endoplasmic reticulum. In certain severe conditions, the unfolded protein response was not sufficient to restore normal endoplasmic reticulum function, which further contributed to the pathogenesis of various diseases, including endometriosis .
GATA6 is a fertility-related gene that is expressed in vertebrate ovaries . GATA6 overexpression, which is induced by aberrant methylation in endometriotic cells, regulated the expression of steroid metabolism and steroid hormone receptors. For example, the transcripts of oestrogen receptor α and progesterone receptor are reduced, whereas oestrogen receptor β transcript levels were increased. MMP11 is significantly reduced by the overexpression of GATA6 as shown in Table 2. This process transformed healthy endometrium away from spontaneous decidualization and toward the disease phenotype by restricting the ability of endometrial stromal cells to decidualize. PRL and IGFBP1 expression expected to be inhibited, but these genes were up-regulated .
A few bioinformatic analyses related to endometriosis have been performed. Tissues in the control groups from datasets were included. Zhang and Wang et al., Yao et al., and Cheng et al. obtained samples from not only endometriosis patients but also healthy women [23–25]. In addition, samples defined as ectopic endometrium were obtained from various regions, which weakened the strength of the conclusions. In this study, we include samples from endometriomas from endometriosis patients and ectopic endometrium from healthy women. However, as this study is only based on analysis, further studies with larger samples and clinical trials are required to confirm the association of identified genes in endometriosis.