Identification of novel candidate targets for suppressing ovarian cancer progression through IL-33/ST2 axis components using the system biology approach

Geovanny Genaro Reivan Ortiz; Carmen Iulia Ciongradi; M V N L Chaitanya; Jayasankar Narayanan; Mohamed Mohany; Salim S Al-Rejaie; José Luis Arias-Gonzáles; Ioan Sârbu; Marjan Assefi; Shaik Vaseem Akram; Yusuf Döğüş; Abolfazl Bahrami; Reza Akhavan-Sigari

doi:10.3389/fmolb.2023.1189527

Identification of novel candidate targets for suppressing ovarian cancer progression through IL-33/ST2 axis components using the system biology approach

Front Mol Biosci. 2023 Jun 2:10:1189527. doi: 10.3389/fmolb.2023.1189527. eCollection 2023.

Authors

Affiliations

¹ Laboratory of Basic Psychology, Behavioral Analysis and Programmatic Development (PAD-LAB), Catholic University of Cuenca, Cuenca, Ecuador.
² Department of Surgery-Pediatric Surgery and Orthopedics, "Grigore T. Popa" University of Medicine and Pharmacy, Iași, Romania.
³ School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India.
⁴ Department of Pharmacology, SRM Institute of Science and Technology, SRM College of Pharmacy, Kattankulathu, Tamil Nadu, India.
⁵ Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
⁶ Department of Social Sciences, Faculty of Social Studies, University of British Columbia, Vancouver, BC, Canada.
⁷ University of North Carolina, Greensboro, NC, United States.
⁸ Uttaranchal University, Dehradun, India.
⁹ Department of Medical Biochemistry, Faculty of Medicine, Cukurova University, Adana, Türkiye.
¹⁰ Biomedical Center for Systems Biology Science Munich, Ludwig-Maximilians-University, Munich, Germany.
¹¹ Department of Neurosurgery, University Medical Center Tuebingen, Tuebingen, Germany.
¹² Department of Healthcare Management and Clinical Research, Collegium Humanum Warsaw Management University, Warsaw, Poland.

Abstract

Background: Cancer-associated fibroblasts (CAFs) of ovarian cancer (OvC) are the most prevalent element of the tumor microenvironment (TM). By promoting angiogenesis, immunological suppression, and invasion, CAFs speed up the growth of tumors by changing the extracellular matrix's structure and composition and/or initiating the epithelial cells (EPT). IL-33/ST2 signaling has drawn a lot of attention since it acts as a pro-tumor alarmin and encourages spread by altering TM. Methods: Differentially expressed genes (DEGs) of the OvC tumor microenvironment were found in the GEO database, qRT-PCR, western blotting, and immunohistochemistry, and their presence and changes in healthy and tumor tissue content were examined. Primary cultures of healthy fibroblasts and CAFs obtained from healthy and tumor tissues retrieved from OvC samples were used for in vitro and in vivo investigations. Cultured primary human CAFs were utilized to investigate the regulation and the IL-33/ST2 axis role in the inflammation reactions. Results: Although ST2 and IL-33 expression was detected in both epithelial (EPT) and fibroblast cells of ovarian cancer, they are more abundant in CAFs. Lipopolysaccharides, serum amyloid A1, and IL-1β, the inflammatory mediators, could all induce IL-33 expression through NF-κB activation in human CAFs. In turn, via the ST2 receptor, IL-33 affected the production of IL-6, IL-1β, and PTGS2 in human CAFs via the MAPKs-NF-κB pathway. Conclusion: Our findings suggest that IL-33/ST2 is affected by the interaction of CAFs and epithelial cells inside the tumor microenvironment. Activation of this axis leads to increased expression of inflammatory factors in tumor CAFs and EPT cells. Therefore, targeting the IL-33/ST2 axis could have potential value in the prevention of OvC progression.

Keywords: IL-33; MAPKs-NF-κB; ST2; cancer-associated fibroblasts; gene expression; ovarian cancer; protein expression.