Studying the roles of SOX proteins in promoting malignant cell phenotypes (SOPROMAL)
Serbian Academy of Sciences and Arts, F24, 2020-2022
Principal investigator: Academician Milena Stevanovic, IMGGE
Participants from IMGGE: Dr Danijela Drakulic, dr Isidora Petrovic, dr Marija Svirtlih, dr Marija Mojsin, dr Natasa Kovacevic-Grujicic, dr Andrijana Lazic, dr Milena Milivojevic
SOX proteins represent a family of transcription factors involved in the regulation of various biological processes, from the early stages of development to the maintenance of homeostasis in adult tissues. In the last few years, there is a growing number of literature data linking altered SOX protein functions to the occurrence of malignancies in humans. Depending on the cellular context, certain members of SOX gene family may play the role as oncogene or tumor suppressor. Literature data indicate that SOX proteins contribute to the malignant phenotype of tumor cells through the regulation of different cellular processes, such as maintenance of tumor stem cell populations, proliferation, migration, invasion, survival, apoptosis, senescence and differentiation.
Glioblastoma is the most common malignant brain tumor in adults and one of the most aggressive and deadly types of tumors. Literature data indicate that numerous members of the SOX gene family are expressed in glioblastomas. Previous research reveals that SOX1, SOX2, SOX4 and SOX9 function as oncogenes in glioblastomas, while SOX11 and SOX21 function as tumor suppressors. The results of our previous studies showed that SOX1 and SOX3 genes promote the malignant potential of glioblastoma cells and that high level of their expression correlates with the undifferentiated state of glioblastoma stem cells.
Pancreatic adenocarcinoma is one of the most aggressive malignant tumors with a very poor prognosis and a five-year survival rate below 8%. The results of previous studies have shown that SOX genes may act as both activator and suppressor of pancreatic tumorigenesis. It has been shown that SOX9 gene has a key role in the initiation of this type of tumor, while SOX2, SOX4 and SOX18 genes have an important role in promotion of malignant characteristics of pancreatic adenocarcinoma cells.
Breast cancer is a heterogeneous disease with subtypes that respond differently to therapy and develop different mechanisms of resistance. Elevated SOX2 gene expression is known to be responsible for the development of tamoxifen resistance and is positively correlated with tumor size and lymph node metastases. Increased SOX18 gene expression positively correlates with tumor growth and metastatic potential of invasive ductal breast cancer.
Despite intensive research, the roles of SOX proteins in development of the above-mentioned tumors are not fully understood. Therefore, one of the aims of the Project is to modulate the expression of selected SOX genes in tumor cell lines and to monitor the impacts of these modulations on basic cellular processes such as proliferation, cell cycle, apoptosis, migration, invasion and adhesion of tumor cells.
Having in mind that despite current therapeutic approaches cancer is one of the leading causes of death, nowadays there is a growing interest for alternative therapeutic strategies and identification of new drugs. It has been shown that natural bioactive compounds and their synthetic analogues with improved biological activity represent an important basis, not only for improving the properties of existing drugs, but also for the design of novel drugs. Accordingly, one of the aims of the Project is to examine the effects of bioactive natural and synthetic compounds, plant and fungal extracts and carbon nanomaterials on the proliferative capacity and viability of different types of tumor cells, including glioblastoma, pancreatic and breast cancer cell lines, as well as to analyze the effect of these compounds on the expression of selected SOX genes.