Molecular Insights Into KISS1 in Endometriosis

KISS1 Signaling May Contribute to the Molecular Pathogenesis of Endometriosis

Key Points

Highlights: 

• The KISS1/KISS1R signaling axis may contribute to the development of endometriosis through activation of the PI3K/AKT pathway and downstream regulation of CREB5.
• Transcriptomic analysis suggests that progressively altered gene expression patterns accompany the transition from normal endometrium to ectopic endometriotic lesions.

Importance: 

• Understanding the molecular signaling pathways involved in lesion establishment and progression is critical for identifying biological mechanisms that drive endometriosis.
• The identification of signaling pathways such as KISS1–PI3K/AKT–CREB5 may provide insight into novel molecular targets for future research and potential therapeutic strategies.

What’s done here:

• Ectopic endometriotic lesions, eutopic endometrium from women with endometriosis (n=5), and endometrial samples from women without the disease (n=3) were analyzed.
• Transcriptomic analyses were performed to identify differentially expressed genes associated with the development of endometriosis.
• Bioinformatic pathway enrichment analyses were used to identify signaling pathways involved in disease progression, followed by experimental analyses exploring the interaction between KISS1/KISS1R signaling and CREB5 through the PI3K/AKT pathway.

Key results:

• The investigators identified 20 progressively altered genes during the transition from normal endometrium to ectopic endometriotic lesions.
• Among these genes, KISS1R emerged as a key candidate associated with disease progression.• Pathway enrichment analysis showed that progressively altered genes were significantly associated with the PI3K/AKT signaling pathway.
• Experimental findings suggested that KISS1/KISS1R signaling may promote CREB5 activation through PI3K/AKT signaling, implicating this pathway in endometriosis-related cellular processes.

Strengths and Limitations:

• Strengths are the combined use of comparative transcriptomics and experimental models to explore signaling pathways potentially involved in endometriosis.
• Limitations are the small sample size, limited control selection, and the preliminary nature of the mechanistic findings.

From the Editor-in-Chief – EndoNews

"The molecular mechanisms that enable endometrial cells to adhere, invade surrounding tissues, and establish vascularized lesions remain an important area of investigation in endometriosis research. Although retrograde menstruation provides a plausible explanation for the origin of ectopic tissue, additional biological factors are likely required for successful implantation and persistence of endometriotic lesions.

In this context, the present study explores signaling pathways potentially involved in the regulation of cellular invasion and angiogenesis in endometriosis. Through transcriptomic comparisons of eutopic and ectopic endometrium, the authors identified a group of genes demonstrating progressive expression changes during disease development, including KISS1R, and linked these alterations to the PI3K/AKT signaling pathway, a pathway previously implicated in cell proliferation, survival, and vascular regulation. 

Experimental analyses in cellular systems and animal models further examined interactions between kisspeptin signaling and downstream regulators of PI3K/AKT activity. Such studies contribute to the growing body of work investigating molecular pathways that may influence the invasive and angiogenic characteristics of endometriotic tissue.

Nevertheless, the findings should be interpreted within the context of the study design. The transcriptomic analysis was based on a limited number of clinical samples, and mechanistic conclusions derived from experimental models require further validation in larger patient cohorts. Endometriosis is a multifactorial condition involving hormonal, inflammatory, immune, and neurovascular components, and individual signaling pathways are unlikely to account for the full complexity of the disease.

Overall, studies exploring candidate signaling networks remain important for advancing the mechanistic understanding of endometriosis and may help guide future investigations aimed at clarifying the biological processes underlying lesion establishment and progression."

Lay Summary

The KISS1 signaling pathway may play a role in the molecular mechanisms underlying endometriosis, according to a study published in the International Journal of Medical Sciences. In the study, Yuan and Li groups investigated how kisspeptin 1 (KISS1) and its receptor (KISS1R) may interact with cellular signaling pathways involved in lesion development.

To explore genes potentially involved in the pathogenesis of endometriosis, the researchers conducted a comparative transcriptomic analysis of ectopic endometriotic lesions, eutopic endometrium from women with endometriosis, and endometrial tissue from women without the disease. The analysis included samples from five patients with endometriosis and three control subjects.

By comparing gene expression patterns across these tissues, the investigators identified 20 genes whose expression changed progressively during the development of endometriosis, suggesting a possible role in disease progression. One of the genes identified was KISS1R, which encodes the receptor for kisspeptin.

Further pathway analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database showed that these progressively altered genes were primarily associated with the PI3K/AKT signaling pathway, a pathway known to regulate cell proliferation, invasion, and angiogenesis.

Additional experimental analyses in cell culture and animal models suggested that KISS1 and KISS1R may influence the activity of cyclic AMP-responsive element-binding protein 5 (CREB5) and downstream PI3K/AKT signaling, potentially affecting biological processes involved in endometriosis lesion development.

The authors note that these findings provide preliminary mechanistic insights into molecular signaling pathways associated with endometriosis, although further studies will be required to clarify the functional role of the KISS1 signaling axis in the disease.

Research Source: https://pubmed.ncbi.nlm.nih.gov/41399389/