Targeted repression of overexpressed CD30 downregulates NF-kappaB and ERK1/2 pathway in Hodgkin lymphoma cell lines.
We previously reported that CD30 is induced during lymphocyte transformation and that overexpressed CD30 can transduce ligand-independent signals in Hodgkin lymphoma (HL) cells. However, its biological consequence is not fully addressed. In this study, we examined the effects of targeted repression of overexpressed CD30 on cell signaling and proliferation using small-interfering RNAs (siRNAs) in HL cell lines. Repression of CD30 inhibited cellular proliferation through reduced activation of IkappaB kinase (IKK) and extracellular signal-regulated kinase (ERK) 1/2 in both B- and T-HL cell lines. These HL cell lines bear one or more defects in negative regulators of nuclear factor (NF)-kappaB signaling, including A20, cylindromatosis tumor suppressor protein (CYLD), and IkappaBalpha, and when CD30 is repressed, they show reduced activation of the canonical NF-kappaB pathway. This suggests that CD30 governs NF-kappaB and ERK1/2 signaling pathways, and is involved in the proliferation of HL cells. Defective mutations in negative regulators of NF-kappaB signaling appear to promote CD30-initiated basal NF-kappaB activation. These results indicate that CD30 is involved in the tumorigenic process of HL, and that it may be useful as a therapeutic target for the treatment of HL.
Department of Hematology, School of Medicine, Kitasato University, Kanagawa, Japan.
Mariko
M
Watanabe
Kazumi
K
Nakano
Tomiteru
T
Togano
Makoto
M
Nakashima
Masaaki
M
Higashihara
Marshall E
ME
Kadin
Toshiki
T
Watanabe
Ryouichi
R
Horie
D053285:CD30 Ligand / Q000502:physiology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D015536:Down-Regulation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006689:Hodgkin Disease / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010766:Phosphorylation; D034622:RNA Interference; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors
D053285:CD30 Ligand; D016328:NF-kappa B; C505774:TNFSF8 protein, human; D018808:Transcription Factor AP-1; D051550:I-kappa B Kinase; D048049:Extracellular Signal-Regulated MAP Kinases