Scientists at KBFU have identified the molecular mechanism that makes brain tumors such as gliomas and neuroblastomas extremely aggressive and resistant to treatment. It turns out to be an increased activity of the urokinase receptor gene PLAUR, which regulates the “remodeling” of the extracellular matrix in tissues, promotes metastasis and the migration of tumor cells throughout the body. The findings suggest that PLAUR may serve as a promising target for new anticancer drugs. The results of the study have been published in Advances in Molecular Oncology.
Many tumors can metastasize—create new growth sites in the body by spreading cancer cells. This is especially true for such aggressive brain and nerve tissue cancers as gliomas and neuroblastomas. Treating metastases and recurrences of these tumors is notoriously difficult—surgery, chemotherapy, and radiation therapy often prove ineffective. To develop new targeted therapies that specifically attack tumor cells, researchers need to identify the molecular targets that distinguish cancer cells from healthy ones and enable their proliferation and spread. One such potential target is the urokinase receptor (uPAR), encoded by the PLAUR gene. Previous studies have shown , that high PLAUR activity is associated with tumor cell metastasis and poor patient prognosis, but the precise molecular mechanisms behind this relationship have remained unclear.
Researchers from Immanuel Kant Baltic Federal University and Lomonosov Moscow State University (Moscow) investigated human glioma and neuroblastoma cell lines to determine how the PLAUR gene influences the aggressiveness of these tumors.
The authors significantly increased PLAUR activity in the studied cells (by 3- and 20-fold in glioma cell lines U251 and U87, respectively, and by 234-fold in neuroblastoma cells SH-SY5Y). This activation triggered epithelial–mesenchymal transition (EMT)—a process in which cells lose their “anchored” state and become mobile. Under conditions of high PLAUR expression, the researchers observed a sharp rise in the activity of ZEB1, ZEB2, and SNAI2 genes, which regulate EMT. As a result, glioma and neuroblastoma cells gained enhanced motility, a hallmark of highly aggressive tumor subtypes prone to forming multiple metastases.
| Our research has shown that artificially increasing PLAUR expression not only boosts cancer cell motility but comprehensively reprograms them, activating genes responsible for metastasis. This explains why patients whose tumors exhibit high levels of uPAR protein—and consequently elevated PLAUR activity—often experience relapse. Therefore, uPAR can be considered a promising target for the development of new anticancer drugs. In the future, we plan to study the effects of PLAUR knockout to obtain a clearer and more complete picture of it’s role in the aggressiveness of glioma and neuroblastoma tumors, |
| says Dr. Ekaterina Semina. |
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