A recent study demonstrated that the p38 MAPK pathway, including MKK3, is constitutively 501951-42-4 activated in B-CLL cells but not their normal peripheral B-cell counterpart. The constitutive p38 MAPK pathway activation results in up-regulation of matrix metalloproteinase-9, a critical factor in tumour angiogenesis and tumour homing. Elevated serum Dinaciclib supplier levels of MMP-9 are associated with an unfavourable prognosis for patients with CLL. Our study identified significantly lower levels of MKK3 expression in CLL patients with down-regulated MIR-15a/16-1. This is consistent with CLL patients harbouring chromosome 13q14 deletions, and hence MIR-15a/16-1 down-regulation, displaying a more favourable prognosis. LRIG1 is a member of a family of LRIG genes that encode integral membrane proteins with extracellular/lumenal extensions consisting of leucine-rich and immuloglobulin-like domains. LRIG1 interacts with the ErbB receptor tyrosine kinase to negatively regulate EGFR signalling. This regulation is mediated through the recruitment of E3 ubiquitin ligases, resulting in ubiquitinylation, internalisation and lysosomal degradation of the ErbB receptors. LRIG1 is a proposed tumour suppressor gene. It localizes at chromosome band 3p14.3, a chromosomal region that is commonly deleted in human cancers. Additionally, LRIG1 is down-regulated in a variety of different tumour cell lines consistent with it being a tumour suppressor gene. It has been hypothesised that the down-regulation of LRIG1 could unleash EGFR signalling which may contribute to the development of various malignancies. Of note, however, LRIG1 expression is up-regulated in some tumours, suggesting that the gene functions as a tumour promoter under certain circumstances. Further studies are required to unravel the functions of the LRIG proteins and to further understand the contribution of LRIG1 dysregulation to human tumorigenesis. The majority of the computationally-predicted targets investigated in this study were not differentially regulated in CLL patients with varying levels of MIR-15a/16-1 expression. A possible explanation for this may be that the analysis was performed on mRNA rather than on proteins. Through imperfect pairing with their target mRNAs, some miRNAs can reduce the protein levels of a target gene withminimal variation of themRNA levels. Alternatively, the low predictive power of the bioinformatics tools used for miRNA gene target prediction may also have contributed to this findin
