The dilemma of autophagy and its role in endometriosis

Two autophagy-related markers Beclin-1 and LC3 are downregulated in endometriosis, study finds

Key Points

Highlight

• The proliferation and development of endometriotic lesions may be linked to the downregulation of specific genes in the autophagic pathways.

Importance

• Autophagy which is the process of degradation and phagocytosis of tissues is a highly controlled survival mechanism for cells under stress.
• The link between autophagy and certain disorders such as some cancers or endometriosis may be important in providing new diagnostic and treatment methods if proven.

What’s done here

• The study aimed to evaluate the expression of two autophagy-related genes, Beclin-1 and Microtubule-associated protein light chain 3 (LC3) in the tissues obtained from endometriotic lesions.
• It included 84 patients with endometriosis and 32 controls.
• The expression of both genes in both ectopic and endometriotic tissues was immunohistochemically evaluated and scored by two pathologists.
• The positivity rates were compared with the clinical disease stage.

Key results

• Positive expression of the markers was seen in both ectopic and eutopic endometrium.
• The positivity rate of Beclin-1 and LC3 was significantly reduced in ectopic endometriotic tissue compared to eutopic endometrium.
• The higher the clinical stage was, the lower the positivity rate for Beclin-1 and LC3 expression was.
• The correlation analysis for the co-positivity of Beclin-1 and LC3 revealed a statistically significant correlation in ectopic endometrial tissue.

Lay Summary

Autophagy is a mechanism for cell survival under metabolic stress that involves the degradation and recycling of intracellular components. Multiple genes actively control this process. Among these, the initiation stage of autophagosome formation is regulated by the gene Beclin-1 and Microtubule-associated protein light chain 3 (LC3) which is located on the membrane surface of autophagosomes has roles such as cell ingestion and antigen presentation and is used widely as a marker to detect autophagosomes. The autophagy pathway plays several functions in the immune system, and defects in autophagy have been linked to inflammatory diseases.

The relationship between endometriosis and autophagy has not been extensively studied and the present ones show conflicting results. With the aim of clarifying this inconsistency, Dr.s Kong and Yao from China have performed a study in which they evaluated Beclin-1 and LC3 genes immunohistochemically in ectopic and normal endometrial tissue. The article was published in the June 2022 issue of the journal BMC Women’s Health. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9245300/)

The patient group included 84 women who underwent laparoscopic ovarian endometriosis cystectomy and the control group had 32 patients who had gynecologic surgery for reasons other than endometriosis. The tissue samples were embedded into paraffin blocks which were then used for immunohistochemical evaluation. Two pathologists double-blindly assessed the slides that were stained with Beclin-1 and LC3 antibodies. In each case, 100 cells were counted by observing five 400x high power fields and the cell ratio and depth of staining were decided. A total score was obtained by multiplying the positive staining cell ratio score and the staining intensity score.

Both of the genes were positively expressed in ectopic and eutopic endometrial tissue, although the endometriosis group showed significantly less positive staining than the control group for both Beclin-1 and LC3. This was interpreted by the authors as an increased ability of ectopic endometrial cells to escape from autophagy, invade tissues, and survive with the inactivation of apoptotic pathways. What is more, local and systemic inflammation is thought to be triggered by the insufficient digestion of the ectopic endometrial tissue and the elimination of tissue debris.

Regarding the clinical stage of endometriosis and the expression of these genes, it was found that the positivity rate for both genes was statistically significantly reduced in higher stages. When co-positivity was assessed, the statistical analysis showed these two markers to be significantly correlated in the ectopic endometrium. The authors discuss that these findings indicate a reduced autophagic activity that may induce endometriosis because the autophagic mechanism of digesting these ectopic endometrial cells is clearly altered allowing the proliferation and development of endometriotic lesions.

The authors conclude by saying that to further analyze the effects of autophagy on endometriosis, new studies should be performed combining human epididymis protein 4 and cancer antigen 125.

Research Source: https://pubmed.ncbi.nlm.nih.gov/35768796/