Researchers at Ludwig Maximilian University of Munich’s (LMU) Institute of Pathology have discovered a gene called 14-3-3sigma that functions as a tumour suppressor in gastrointestinal cancers. Using the mouse as an experimental model, the team demonstrated that inactivation of the 14-3-3sigma gene enhance progression of gastrointestinal cancers and consequently shortens the lifespan of mice. The findings were featured in the study, '4-3-3σ Functions as an Intestinal Tumor Suppressor', published in Cancer Research.
In earlier work with colon carcinoma cell lines, Professor Heiko Hermeking and his colleagues had shown that a protein known as p53, which plays a central role in the suppression of many types of tumours, activates the 14-3-3sigma gene, and that its protein product inhibits passage through the cell cycle. This brake on cell division gives cells more time to repair adventitious or environmentally caused DNA damage, and therefore reduces the risk of uncontrolled cell proliferation. Mutations that inactivate p53 are found in more than half of all tumours.
"But it was not clear whether the 14-3-3sigma gene itself plays an important role in the suppression of tumorigenesis in the intestine," explained Hermeking.
In a project funded by the German Cancer Research Fund (Deutsche Krebshilfe), his team set out to clarify this issue by analysing patterns of gene expression in several thousands of tumour samples isolated from patients with colorectal cancer. The data revealed that the expression of 14-3-3sigma is indeed significantly downregulated in these tumours.
In addition, this effect was particularly pronounced in metastatic tumours, and the level of expression of the gene showed a negative correlation with the degree of cancer progression. Furthermore, patients with lower levels of expression of the 14-3-3sigma gene were found to have a worse prognosis than those with higher expression - and this finding was independent of whether or not the tumours also contained an inactivating mutation in the p53 gene.
To further explore the significance of 14-3-3sigma in intestinal carcinogenesis, the LMU researchers specifically inactivated the gene in a preclinical mouse model of intestinal cancer. Loss of the gene's function was found to stimulate the formation and growth of tumours in the gastrointestinal tract, and ultimately reduced survival times. Subsequent studies showed that, in the absence of the 14-3-3sigma gene, signalling pathways which are regulated by transcription factors that have been implicated in the formation of metastases are selectively induced. Interestingly, the 14-3-3sigma protein is known to bind and negatively regulate these transcription factors.
"Taken together, our results demonstrate that 14-3-3sigma is not only one of the many target genes that are controlled by p53 and mediate its tumour-suppressing function, but also has tumour-suppressive functions on its own in the gastrointestinal tract," he added. "Moreover, the signalling pathways that are triggered upon its inactivation are potential targets for therapeutic interventions.”
The authors of the study suggested that detection of decreased expression of the 14-3-3sigma gene in resected primary colon carcinomas could serve as a prognostic indicator in patient populations.