The leading cause of cancer death worldwide is esophageal squamous cell carcinoma (ESCC), the major histological form of esophageal cancer. A biomarker, adenosine deaminase acting on RNA-1 (ADAR1), has been discovered, and it has the potential to improve the diagnosis, prognosis, and treatment of this disease.
Led by Polly Chen, MD, PhD, of the Cancer Science Institute of the National University of Singapore, the research team also demonstrated that the editing of protein-making sequences promotes the development of ESCC. Their study was published in Cancer Research (2013; doi:10.1158/0008-5472.CAN-13-2545).
Currently, patients with ESCC have a poor prognosis, as overall survival ranges from 20% to 30%. These dismal numbers indicate the urgent need for biomarkers that can diagnose this disease as early as possible, estimate reactions to chemotherapy or radiotherapy in patients, and predict the overall survival rate of patients undergoing treatment.
In normal human cells, deoxyribonucleic acid (DNA), which comprises the genetic code, serves as a template for the precise production of ribonucleic acid (RNA) such that the DNA code and RNA code are identical. Editing is a process in which RNA is changed after it is made from DNA, resulting in an altered gene product. This RNA editing is likely to play a role in the formation of tumors by either inactivating a tumor suppressor or activating genes that promote tumor progression.
In this study, the researchers discovered that the RNA-editing enzyme ADAR1, which catalyzes the editing process, is significantly overexpressed in ESCC tumors. They observed that ADAR1 changes the product of the AZIN1 protein to a form which promotes the development of the disease. Clinically, the tumoral overexpression of ADAR1 was correlated with the shorter survival time of ESCC patients.
The findings suggest that ADAR1 can serve as a useful biomarker to detect disorders leading to ESCC and as a potential therapeutic target. The study may also provide the key to a biological process for drug development in the treatment of ESCC.
“Investigating the connection between ADAR1-mediated RNA editing and cancer progression is only the initial step in this research. The tumoral overexpression of ADAR1 can be used as an early warning sign of ESCC and halting or reversing the process may block the cells’ conversion from normal to malignant,” said Chen.
Moving forward, the researchers will further investigate the key RNA-editing events regulated by ADAR1 during ESCC development. They plan to develop a method to correct the RNA-editing process through restoring ADAR balance by silencing ADAR1 and reinstating a specific hyper-edited or hypo-edited transcript.