No abstract

Hereditary colorectal cancer develops through a series of well-defined genetic and histological changes. However, elucidation of the canonical pathway based on hereditary colorectal cancer has not provided a clear explanation of the molecular mechanisms of sporadic colorectal cancer. To identify the alterative pathways involved in sporadic colorectal tumorigenesis, we performed gene expression analysis in patients with sporadic colorectal tumors. A comparison analysis of gene expression profiles revealed a pattern of upregulation of small proline rich repeat protein 3 (SPRR3) in tumor samples. SPRR3 has previously been reported to be downregulated in esophageal cancer. However, in the present study, we observed that SPRR3 was strongly upregulated in 31 of 35 samples of sporadic colorectal tumors (88%). We also determined that overexpression of SPRR3 not only accelerates colorectal cancer cell proliferation but also is associated with lymphovascular invasion in colorectal cancer. Moreover, AKT was activated and p53 levels were decreased in cells that overexpressed SPRR3. In contrast to the pattern seen in esophageal cancer, these results suggest that increased expression of SPRR3 is involved in colorectal tumorigenesis.

Background: BRAF is a downstream effector kinase of Ras. Results: RNF149, a RING finger domain-containing E3 ubiquitin ligase, is one of the several proteins shown to interact with wild-type BRAF by tandem affinity purification. Conclusion: RNF149 induces ubiquitination and subsequent proteasomal degradation of wild-type but not mutant BRAF. Significance: This is the first ubiquitin ligase shown to degrade wild-type BRAF in a proteasome-dependent manner.