A gene linked to skin and colon cancers may offer a new therapeutic target for patients with advanced stomach cancer, report Japanese scientists in PNAS.

Stomach cancer, associated with smoking, salted or smoked foods and Helicobacter pylori infections, continues to have a high mortality despite its declining incidence. Now researchers led by Shin Maeda, from the University of Tokyo, have evidence to suggest that targeting the ASK-1 gene may offer a new approach to treatment.

Apoptosis signal-regulating kinase 1 (ASK1), is a ubiquitously expressed MAPK kinase that is activated by stress stimuli including reactive oxygen species and TNFα. ASK1 has been reported to be involved in the pathogenesis of various human diseases including neurodegenerative, cardiovascular and inflammatory diseases, and has been shown to participate in colon and skin tumourigenesis through the regulation of inflammation and apoptosis.

Maeda and colleagues explored the role of the ASK-1 gene in stomach cancer by comparing tissue samples taken from 66 patients with the disease to those of healthy controls. They demonstrated that the ASK-1 protein was more abundant in the stomach tumour cells of patients than controls.

The team then compared the amount of ASK-1 in colon cancer cells and healthy colon cells and found that the levels were similar and not elevated in either group, indicating that ASK-1 elevation may be a unique characteristic of stomach cancer. Next investigators found that "knock-out" mice that had been specially created to lack the ASK-1 gene displayed a lower risk of stomach cancer than wild type mice.

Further investigations revealed that ASK-1 is likely to stimulate gastric cancer cells to divide more rapidly. "These results indicate an auto regulatory mechanism of ASK1 in the development of gastric cancer. Targeting this positive feedback loop, ASK1 may present a potential therapeutic target for the treatment of advanced gastric cancer," concluded the authors.

Reference

Y Hayakawa, Y Hirata, H Nakagawa et al Apoptosis signal-regulating kinase 1 and cyclin D1 compose a positive feedback loop contributing to tumor growth in gastric cancer PNAS Doi 10.1073/pnas.1011418108