Inhibition of c-MET is a potential therapeutic strategy for treatment of diffuse large B-cell lymphoma.
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.
Uddin
Shahab
S
Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Hussain
Azhar R
AR
Ahmed
Maqbool
M
Al-Dayel
Fouad
F
Bu
Rong
R
Bavi
Prashant
P
Al-Kuraya
Khawla S
KS
D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D005260:Female; D018858:Germinal Center / Q000378:metabolism / Q000473:pathology; D017228:Hepatocyte Growth Factor / Q000378:metabolism / Q000627:therapeutic use; D006801:Humans; D016393:Lymphoma, B-Cell / Q000473:pathology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology / Q000627:therapeutic use
D034741:RNA, Small Interfering; D017228:Hepatocyte Growth Factor; D051057:Proto-Oncogene Proteins c-akt