title: Overexpression of heme oxygenase-1 induced by constitutively activated NF-κB as a potential therapeutic target for activated B-cell-like diffuse large B-cell lymphoma.
abstract: There is an urgent requirement for a new therapeutic target for activated B-cell-like lymphoma (ABC-DLBCL), which is known to have dismal outcome and constitutive activation of NF-κB. Heme oxygenase-1 (HO-1) can inhibit apoptosis and promote proliferation in many cancers. To our knowledge, no studies have been performed on the correlation between HO-1 and DLBCL. In this study, immunohistochemical analysis of 31 tumor tissues from DLBCL patients [20 of ABC subtype and 11 of germinal center B-cell-like (GCB) subtype] and 11 normal lymph nodes revealed that HO-1 overexpression was characteristic of ABC-DLBCL. In addition, HO-1 mRNA expression levels were consistent with the immunohistochemistry results. High levels of HO-1 expression were significantly correlated with the involvement of more than 1 extranodal site (p=0.025), with a high positivity rate of Ki-67 (p<0.01). Similar to its anti-apoptotic role in other malignancies, HO-1 upregulation suppressed apoptosis of the ABC-DLBCL cell line OCI-ly10, whereas its downregulation sensitized the tumor cells to chemotherapeutic drugs. Further study demonstrated that the HO-1 overexpression was mediated by constitutively activated NF-κB which together played an anti-apoptotic role in ABC-DLBCL. Combination of the NF-κB inhibitor Bay11‑7082 and the lentivirus vector Lenti-siHO-1 significantly decreased HO-1 protein expression and increased apoptosis in OCI-ly10 cells. However, in GCB-DLBCL cells with low levels of NF-κB expression, the TNF-α-mediated activation of NF-κB leading to HO-1 upregulation rescued the cells from apoptosis caused by HO-1 silencing. These results indicated that HO-1 can be a potential target for the treatment of ABC-DLBCL.
authors.affiliation: Guizhou Medical University, Guiyang 550004, P.R. China.
authors.forename: Jun
authors.initials: J
authors.lastname: Huang
authors.affiliation: People's Hospital of Guizhou Province, Guiyang 550004, P.R. China.
authors.forename: Pengxiang
authors.initials: P
authors.lastname: Guo
authors.affiliation: Guizhou Medical University, Guiyang 550004, P.R. China.
authors.forename: Dan
authors.initials: D
authors.lastname: Ma
authors.affiliation: Guizhou Medical University, Guiyang 550004, P.R. China.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Lin
authors.affiliation: Department of Pharmacy, The Affiliated Baiyun Hospital of Guizhou Medical University, Guiyang 550004, P.R. China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Fang
authors.affiliation: Guizhou Medical University, Guiyang 550004, P.R. China.
authors.forename: Jishi
authors.initials: J
authors.lastname: Wang
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D051547:Heme Oxygenase-1 / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D058990:Molecular Targeted Therapy; D016328:NF-kappa B / Q000096:biosynthesis* / Q000235:genetics; D009570:Nitriles / Q000008:administration & dosage; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013450:Sulfones / Q000008:administration & dosage; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics*
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D016328:NF-kappa B; D009570:Nitriles; D012333:RNA, Messenger; D013450:Sulfones; D014409:Tumor Necrosis Factor-alpha; D051547:Heme Oxygenase-1