A scientific group of researchers has found that RUNX3, which is tumor suppressor gene, increase the oxidative stress that leads to the restraining of the cancer cells. This gene is absent in different types of cancer, operates as a barrier against oxidative stress in cancer cells. Researchers mentioned that this development will provide the ability to create cancer therapies that target RUNX3 gene by stimulating its amount in cancer cells.
The novel discovery was developed by the scientific group from, led by Professor Yoshikai Ito and Dr. Vaidehi Krishnan, from the National University of Singapore.
The team researching cells of lung cancer determined that cancer cells without RUNX3 were incapable to stop cancer progression due to exposure to oxidative stress from outside of the cells. It is connected with tumor microenvironment (TME). TGFβ is the most abundantly secreted cytokine by both tumors and their surrounding stromal cells. TGFβ provides the drug resistance of cancer cells and the invasive migration. Furthermore, scientists managed to found that TGFβ can be involved in another process of genomic instability, specifically by the producing of oxidative DNA damage in cells deficient in RUNX3.
The RUNX family of proteins is comprised of three heterodimeric transcription factors (TF), RUNX1, RUNX2, and RUNX3. RUNX1 and RUNX3 are inactivated in cells by mutation or epigenetic deregulation, manifesting their position as bonafide tumor suppressors. Therefore, TGFβ provides genomic instability in RUNX3-deficient cells by promoting oxidative stress, which is connected with DNA damage by the decreasing the regulation of the redox regulator, HMOX1. Loss of RUNX3 resulted in transcriptional downregulation of the redox regulator heme oxygenase-1 (HO-1 or HMOX1). Consequently, elevated oxidative DNA damage disrupted genomic integrity and triggered cellular senescence, which was accompanied by tumor-promoting inflammatory cytokine expression and acquisition of the senescence-associated secretory phenotype (SASP).
This discovery determines that damage to cell DNA that is typically linked to factors within the cell itself can also be influenced by operations from the surroundings of the cell such as TGFβ. The tumors harboring a TGFβ gene expression signature and RUNX3 loss exhibited higher levels of genomic instability. Protecting against TGFβ-dependent cancer progression, the study results open unique aspects of RUNX3-dependent tumor suppression. Professor Yoshikai Ito mentioned that this innovational founding will allow researchers to create new therapeutic technologies, which are targeting this type of gene.