A study carried out by Dr. Ignacio Casal’s group at the Centro de Investigaciones Biológicas Margarita Salas (CIB-CSIC) and published in Nature Cell Death & Disease, uncovered the participation of the transcription factor Schnurri-3 (SNH3) in the interleukin 13 (IL-13)/IL-13 receptor alpha 2 (IL13Rα2) signaling pathway that promotes tumor growth and invasion in glioblastoma and other tumors.
The IL-13/IL13Rα2 signaling pathway is involved in colorectal and ovarian cancers, as well as glioblastoma progression. Currently, IL13Rα2 is being used as a therapeutic target in glioblastoma and other cancers. Previously, the Casal group demonstrated that protein tyrosine phosphatase 1B (PTP1B) is a key mediator of the IL-13/IL13Rα2 signaling pathway that regulates cancer cell invasion. The researchers found that the PTP1B inhibitor claramine blocked IL-13/IL13Rα2-mediated invasion and metastasis development in colorectal cancer and glioblastoma.
In this work published in Cell Death & Disease, the researchers have characterized the mechanisms and molecular mediators of the IL-13/IL13Rα2 pathway that promote glioblastoma and colorectal cancer cell invasion. They discovered that the transcription factor SHN3 connects IL-13 with NF-κB, the Wnt signaling pathway, and matrix metalloprotease 9 (MMP9) expression through the tyrosine phosphatase PTP1B and that this mechanism promotes cancer cell proliferation and invasion. Mouse models have confirmed that specific inhibition of SHN3 promotes a substantial regression of tumor growth and metastasis, associated with negative regulation of the Wnt pathway and extensive inhibition of MMP9 expression.
At the clinical level, researchers have observed a correlation between SHN3 expression and poor prognosis in both glioblastoma and colorectal cancer. In glioblastoma, SHN3 expression correlates significantly with the expression of CHI3L1 and CD44, which are biomarkers of the mesenchymal subtype, and with other markers of the classical subpopulation of this tumor, all of which have a poor prognosis. In colorectal cancer, scientists describe a strong association of SHN3 expression with the mesenchymal subtypes CMS4 and CRIS-B, which correspond to patients with the worst prognosis.
Understanding the mechanistic basis of IL13/IL13Rα2-promoted invasion may have relevant implications for treating glioblastoma and other tumors. Furthermore, these findings support a potential therapeutic value for SHN3.
Reference: Schnurri-3 drives tumor growth and invasion in cancer cells expressing interleukin-13 receptor alpha 2. R. Bartolomé, A. Martín-Regalado, L. Pintado-Berninches, J. Robles, M.A. Ramírez-González, I. Boukich, P. Sanchez-Gómez, I. V. Balyasnikova and J. I. Casal. Cell Death & Disease. https://www.nature.com/articles/s41419-023-06255-4