New Biomarker for Esophageal Cancer Reported in the Journal “Cancer Research”
Reporter: Aviva Lev-Ari, PhD, RN
New biomarker for esophageal squamous cell carcinoma
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.
SOURCE
Adenosine-to-Inosine RNA Editing Mediated by ADARs in Esophageal Squamous Cell Carcinoma
- Yan-Ru Qin1,
- Jun-Jing Qiao1,6,
- Tim Hon Man Chan6,
- Ying-Hui Zhu2,
- Fang-Fang Li4,
- Haibo Liu3,
- Jing Fei6,
- Yan Li2,
- Xin-Yuan Guan2,5, and
- Leilei Chen6
+Author Affiliations
Authors’ Affiliations: 1Department of Clinical Oncology, the First Affiliated Hospital, Zhengzhou University, Zhengzhou; 2State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Centre; 3Key Laboratory for Major Obstetric Disease of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou; 4Department of Clinical Oncology, Nanyang city first people’s hospital, Henan; 5Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China; and 6Cancer Science Institute of Singapore, National University of Singpaore, Singapore
- Corresponding Authors:
Yan-Ru Qin, Department of Clinical Oncology, the First Affiliated Hospital, Zhengzhou University, Zhengzhou, China. Phone: 86-371-66295542; E-mail: yanruqin@zzu.edu.cn; Xin-Yuan Guan, State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Centre, Room 605, 651 East Dongfeng Road, Guangzhou 510050, China. Phone: 86-20-87343166; Fax: 86-852-28169126; E-mail: xyguan@hku.hk; and Leilei Chen, Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore 117599. Phone: 65-6516-8435; Fax: 65-6516-1873; E-mail:csicl@nus.edu.sg
-
Y.-R. Qin and J.-J. Qiao contributed equally to this work.
Abstract
Esophageal squamous cell carcinoma (ESCC), the major histologic form of esophageal cancer, is a heterogeneous tumor displaying a complex variety of genetic and epigenetic changes. Aberrant RNA editing of adenosine-to-inosine (A-to-I), as it is catalyzed by adenosine deaminases acting on RNA (ADAR), represents a common posttranscriptional modification in certain human diseases. In this study, we investigated the status and role of ADARs and altered A-to-I RNA editing in ESCC tumorigenesis. Among the three ADAR enzymes expressed in human cells, only ADAR1 was overexpressed in primary ESCC tumors. ADAR1 overexpression was due to gene amplification. Patients with ESCC with tumoral overexpression of ADAR1 displayed a poor prognosis. In vitro and in vivofunctional assays established that ADAR1 functions as an oncogene during ESCC progression. Differential expression of ADAR1 resulted in altered gene-specific editing activities, as reflected by hyperediting of FLNB and AZIN1 messages in primary ESCC. Notably, the edited form of AZIN1 conferred a gain-of-function phenotype associated with aggressive tumor behavior. Our findings reveal that altered gene-specific A-to-I editing events mediated by ADAR1 drive the development of ESCC, with potential implications in diagnosis, prognosis, and treatment of this disease. Cancer Res; 1–12. ©2013 AACR.
- Received September 4, 2013.
- Revision received October 18, 2013.
- Accepted November 6, 2013.
©2013 American Association for Cancer Research.
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