Oxidative stress due to lack of tumor suppressor gene promotes cancer progression, study shows

Researchers from the Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore have identified that RUNX3, a tumour suppressor gene absent in many cancer types, acts as a barrier against oxidative stress in cancer cells. Consequently, cancer cells that do not possess this gene are more susceptible to oxidative stress, resulting in genetic alterations and development of a carcinogenic character.

The study, which was published in scientific journal Cancer Research, was led by Professor Yoshikai Ito, Senior Principal Investigator at CSI Singapore and a widely recognised scientist for his research on the RUNX genes, and Dr Vaidehi Krishnan, a Senior Research Scientist in his group.

In the team's experiments on lung cancer cells, the researchers observed that cancer cells without RUNX3 were unable to put a halt on cancer progression due to exposure to oxidative stress from outside of the cells, and drew a possible link to the involvement of a protein TGFβ in this observation. TGFβ is a protein abundantly secreted by cancer cells and circulates within the tumour environment to carry out its effects. Although TGFβ is known to interact with RUNX3, its roles in cells are extremely varied, and how it regulates cell behaviour is largely dependent on its surroundings and the molecules it interacts with. Following further investigation, the researchers discovered that TGFβ induces damage to the cell DNA through oxidative activity in the absence RUNX3, causing the cells to become carcinogenic.

In addition, the researchers also found that a middle partner protein called HMOX1 mediates this interaction. HMOX1 is an anti-oxidant gene that regulates oxidative levels in the cell. The team found that cells that lack RUNX3 were also likely to lack HMOX1, and this concurrent loss completely removes the barriers against damage by TGFβ.

Earlier studies on RUNX3 in cancer mostly uncovered the multiple pathways in which RUNX3 suppresses cancer development and progression within the cancer cell. The latest study by CSI Singapore, on the other hand, made inroads into understanding how RUNX3 affects cancer development and progression within and outside of the cancer cell. This study is an unusual indication that damage to cell DNA, which is usually attributed to factors within the cell itself, can also be influenced by messages from the surroundings such as TGFβ that circulate in the tumour environment.

Prof Ito, said, "Many types of cancers have shown to lack RUNX3 hence a deeper understanding of this gene means a better know-how on how we can develop novel cancer therapies that target this gene. Our study lends support to other recently described strategies to target cancer by modulating the amount or action of RUNX3 in cancer cells. An example of this would be to reactivate or restore RUNX3 function, which may contribute to curtailing the progression of TGFβ-dependent cancers."

Moving forward, the research team will work towards restoring RUNX3 function with drugs, and testing HMOX1 inhibitors in a panel of lung cancer cell lines.