Inhibition of c-MET is a potential therapeutic strategy for treatment of diffuse large B-cell lymphoma.

Abstract

Hepatocyte growth factor/c-MET has emerged as a potential therapeutic target for several cancers; however, its role in diffuse large B-cell lymphoma (DLBCL) has not been fully elucidated. In this study, we first investigated the role of c-Met in a large series of DLBCL tissues in a tissue microarray format. We then followed this with in vitro studies on DLBCL cell lines using either pharmacological inhibitors of c-Met or siRNA knockdown strategy. c-Met was found to be overexpressed in 73.2% of patients (186/254) and was significantly associated with overexpression of p-AKT (P=0.0274), p-GSK3 (P=0.0047) and Ki-67 (P=0.0012). Interestingly, c-Met overexpression was significantly more common in the germinal center subtype of DLBCL, as compared with activated B cell subtype (P=0.0002). Overexpression of c-Met in DLBCL was significantly associated with better survival (P=0.0028) and remained significant in multivariate analysis with international prognostic index, thereby confirming c-Met as independent prognostic marker for better outcome in DLBCL. In vitro pharmacological c-Met inhibition and siRNA targeted against c-Met triggered caspase-dependent apoptosis. These findings provide evidence that c-Met is an independent prognostic marker for better outcome in Middle Eastern DLBCL. This data also enlightens the fact that c-Met through AKT kinase has a critical role in carcinogenesis of DLBCL, and strongly suggest that targeting c-Met may have therapeutic value in treatment of DLBCL.

• Authors: Shahab Uddin, Azhar R Hussain, Maqbool Ahmed, Fouad Al-Dayel, Rong Bu, Prashant Bavi, Khawla S Al-Kuraya
• Journal: Laboratory investigation; a journal of technical methods and pathology (Lab Invest) Vol. 90 Issue 9 Pg. 1346-56 (Sep 2010) ISSN: 1530-0307 [Electronic] United States
• PMID: 20531293 (Publication Type: Journal Article)

Chemical References

• RNA, Small Interfering
• Hepatocyte Growth Factor
• Proto-Oncogene Proteins c-akt

Topics

• B-Lymphocytes (metabolism, pathology)
• Female
• Germinal Center (metabolism, pathology)
• Hepatocyte Growth Factor (metabolism, therapeutic use)
• Humans
• Lymphoma, B-Cell (pathology)
• Lymphoma, Large B-Cell, Diffuse (drug therapy, metabolism, pathology)
• Male
• Middle Aged
• Proto-Oncogene Proteins c-akt (metabolism)
• RNA, Small Interfering (pharmacology, therapeutic use)