Hypoxia inducible factor-alpha activation in lymphoma and relationship to the thioredoxin family.
Hypoxia inducible factors (HIFs) activate oncogenic pathways, while thioredoxins (Trx), including Trx1 and Trx reductases-1 and -2 (TrxR1 and TrxR2), promote HIF-alpha stabilization. In immunoblotting studies in lymphoma cell lines we found that Raji and SUDHL4 cells exhibited normoxic HIF-2alpha protein stabilization. Five cell lines showed increased TrxR1 expression, while only Namalwa, HF1 and SUDHL4 had Trx1 and TrxR2 activation. Tissue microarrays in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) identified different HIF expression among histological subgroups (e.g. 44% DLBCL vs. 11% of FL cases with moderate-to-high expression of HIF-1alpha and HIF-2alpha, P = 0.0017). These data demonstrate that HIF and the thioredoxin family are abnormally activated in lymphoma.
Evens
Andrew M
AM
Lymphoma Program, Division of Hematology-Oncology, and Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL 60611, USA. a-evens@northwestern.edu
Schumacker
Paul T
PT
Helenowski
Irene B
IB
Singh
Amareshwar T K
AT
Dokic
Danijela
D
Keswani
Anjeni
A
Kordeluk
Elizabeth
E
Raji
Adekunle
A
Winter
Jane N
JN
Jovanovic
Borko D
BD
Holmgren
Arne
A
Nelson
Beverly P
BP
Gordon
Leo I
LI
D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008223:Lymphoma / Q000378:metabolism*; D008224:Lymphoma, Follicular / Q000378:metabolism; D016403:Lymphoma, Large B-Cell, Diffuse / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D013879:Thioredoxins / Q000502:physiology*; D014407:Tumor Cells, Cultured; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009363:Neoplasm Proteins; D013879:Thioredoxins; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human