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Loss of Ron Signaling Linked to Development of Inflammatory Bowel Disease

By BiotechDaily International staff writers
Posted on 14 May 2014
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Image: Micrograph showing inflammation of the large bowel in a case of inflammatory bowel disease (Photo courtesy of Wikimedia Commons).
Image: Micrograph showing inflammation of the large bowel in a case of inflammatory bowel disease (Photo courtesy of Wikimedia Commons).
Cancer researchers have found that decreased molecular signaling by the Ron receptor tyrosine kinase (macrophage-stimulating protein receptor) is linked to the development of inflammatory bowel disease (IBD), a group of chronic inflammatory disorders of the intestine that result in painful and debilitating complications.

The Ron receptor tyrosine kinase, a member of the MET proto-oncogene family, is a pathogenic factor implicated in tumor malignancy. Specifically, aberrations in Ron signaling result in increased cancer cell growth, survival, invasion, angiogenesis, and drug resistance. Biochemical events such as ligand binding, receptor overexpression, generation of structure-defected variants, and point mutations in the kinase domain contribute to Ron signaling activation.

Investigators at the University of Cincinnati (Ohio, USA) have now found that decreased Ron signaling is linked to the development of IBD. This data was obtained from experiments conducted with a line of mice that had been genetically engineered to lack the tyrosine kinase signaling domain of Ron (TK-/- mice). These animals and wild-type controls were utilized as a well-characterized model of chronic colitis induced by cyclic exposure to dextran sulfate sodium.

Results reported in the April 17, 2014, online edition of the American Journal of Physiology-Gastrointestinal and Liver Physiology revealed that TK-/- mice were more susceptible to injury as judged by increased mortality compared to control mice and developed more severe colitis. In addition, loss of Ron led to significantly reduced body weights and more aggressive clinical histopathologies. Ron loss also resulted in a dramatic reduction in colonic epithelial cell proliferation and increased proinflammatory cytokine production, which was associated with alterations in important signaling pathways known to regulate IBD.

"Genome-wide linkage studies have identified the Ron receptor tyrosine kinase and its hepatocyte growth factor-like protein (HGFL) as genes highly associated with IBD,” said senior author Dr. Susan Waltz, professor in of cancer biology at the University of Cincinnati. "However, only scant information exists on the role of Ron or HGFL in IBD. Based on the linkage of Ron to IBD, we examined the biological role of Ron in colitis.”

"We found that genetic loss of Ron led to aggressive inflammation and damage to the colon of models with IBD,” said Dr. Waltz. "In addition, there are a number of small changes called single nucleotide polymorphisms (SNP) in humans which map to both the Ron and HGFL gene and have been identified to strongly associate IBD disease in humans. Our studies suggest that these SNPs may reduce the function of Ron and HGFL leading to chronic intestinal inflammation and damage. With the knowledge that we have gained in studying these proteins in cancer biology, we hope this information may be translated to help patients with Crohn’s disease and ulcerative colitis. Further studies on the Ron signaling pathway are needed and could reveal an important new target for these conditions."

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