April 17, 2009

Potential Therapeutic Target For Gastric Cancer

Gastric cancer (GC) is the fourth most common malignancy and the second most frequent cause of cancer-related death in the world. The carcinogenesis of GC involved numerous genetic and epigenetic alterations, as well as many environmental risk factors. Environmental pollutants such as polycyclic aromatic hydrocarbons (PAHs) and halogenated hydrocarbons (HAHs) are well-known carcinogens that play important roles in GC development. The toxic effects of PAHs and HAHs are mediated by a conserved signaling pathway that binds and activates the aryl hydrocarbon receptor (AhR). AhR is a ligand-activated transcription factor and can mediate the carcinogenic and other toxic effects of a variety of environmental pollutants. Many studies in recent years have demonstrated a close relationship between AhR and tumorigenesis. However, the role of AhR in gastric tumorigenesis is still unclear.

A research team led by Dr Min-Hu Chen from China addressed this question. Their study will be published on April 14, 2009 in the World Journal of Gastroenterology.

In this study, RT-PCR, real-time PCR, and Western blotting were performed to detect AhR expression in 39 GC tissues and five GC cell lines. AhR protein was detected by immunohistochemistry (IHC) in 190 samples: 30 chronic superficial gastritis (CSG), 30 chronic atrophic gastritis (CAG), 30 intestinal metaplasia (IM), 30 atypical hyperplasia (AH), and 70 GC. The AhR agonist tetrachlorodibenzo-para-dioxin (TCDD) was used to treat AGS cells. MTT assay and flow cytometric analysis were performed to measure the viability, cell cycle and apoptosis of AGS cells.

They found that AhR expression was significantly increased in GC tissues and GC cell lines. IHC results indicated that the levels of AhR expression gradually increased, with the lowest levels in CSG, followed by CAG, IM, AH and GC. AhR expression and nuclear translocation were significantly higher in GC than in precancerous tissues. TCDD inhibited proliferation of AGS cells via induction of growth arrest at the G1-S phase.

This is the first report suggesting an inhibitory role of AhR agonists on human GC cell growth. Furthermore, the present findings suggest that AhR may be a potential therapeutic target for GC.

Peng TL, Chen J, Mao W, Liu X, Tao Y, Chen LZ, Chen MH. Potential therapeutic significance of increased expression of aryl hydrocarbon receptor in human gastric cancer. World J Gastroenterol 2009; 15(14): 1719-1729 http://www.wjgnet.com/1007-9327/15/1719.asp