Sphingosine 1-phosphate receptors are dysregulated in endometriosis: possible implication in transforming growth factor β-induced fibrosis.

Caterina Bernacchioni, Tommaso Capezzuoli, Valentina Vannuzzi, Francesca Malentacchi, Francesca Castiglione, Francesca Cencetti, Marcello Ceccaroni, Chiara Donati, Paola Bruni, Felice Petraglia

Journal: Fertility and sterility 2021;115(2):501-511

PMID: 32907751

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Abstract

OBJECTIVE

To study the molecular mechanisms involved in the appearance of the fibrotic trait in endometriosis by investigating whether the signaling pathway of the bioactive sphingolipid sphingosine 1-phosphate (S1P) was altered in endometriotic lesions.

DESIGN

Case-control laboratory study.

SETTING

University research institute and university hospital.

PATIENT(S)

A total of 75 women, with and without endometriosis, were included in the study.

INTERVENTIONS(S)

Endometrial samples were obtained from women affected (n = 15 endometrioma [OMA]; n = 30 deep infiltrating endometriosis [DIE]) and not (n = 30) by endometriosis by means of laparoscopic surgery, followed by clinical and imaging investigation and checking for the expression of fibrosis markers and genes implicated in S1P metabolism and signaling by means of real-time polymerase chain reaction.

MAIN OUTCOME MEASURE(S)

The role of the S1P signaling axis in endometriosis-associated fibrosis was studied in vitro, where RNA interference approaches were used to investigate if S1P synthesis by sphingosine kinases (SKs) and specific S1P receptors (S1PRs) are implicated in the profibrotic effect of the cytokine transforming growth factor (TGF) β1.

RESULT(S)

mRNA expression analysis of S1PR demonstrated a deep dysregulation of S1P signaling in endometriosis, characterized by increased expression of fibrosis markers: S1P was transcriptionally more expressed in OMA, and S1P and S1P mRNA levels were significantly augmented in both OMA and DIE. SK1 and its activating protein calcium- and integrin-binding protein 1 (CIB1) were significantly up-regulated in OMA and DIE. A crucial role for the SK/S1PR axis in the profibrotic effect elicited by TGFβ1 was highlighted in vitro.

CONCLUSION(S)

The S1P signaling axis may represent a useful biomarker or innovative pharmacologic target for endometriosis.

Address: Department of Experimental and Clinical Biomedical Sciences "M. Serio," University of Florence, Florence, Italy.; Histopathology and Molecular Diagnostics, Careggi University Hospital, Florence, Italy.; Department of Obstetrics and Gynaecology, Gynaecologic Oncology, and Minimally Invasive Pelvic Surgery, International School of Surgical Anatomy, Sacred Heart Hospital, Negrar, Verona, Italy.; Department of Experimental and Clinical Biomedical Sciences "M. Serio," University of Florence, Florence, Italy. Electronic address: [email protected].

DOI: 10.1016/j.fertnstert.2020.08.012