title: Gene methylation and silencing of SOCS3 in mantle cell lymphoma.
abstract: The significance of loss of SOCS3, a negative regulator of signalling pathways including those of STAT3 and NF-κB, was examined in mantle cell lymphoma (MCL). The protein expression and gene methylation status of SOCS3 were detected using immunohistochemistry/Western blots and methylation-specific polymerase chain reaction, respectively. To evaluate its functional importance, SOCS3 was restored in two SOCS3-negative MCL cell lines using a lentiviral vector. Loss of SOCS3 protein expression was found in 3/4 MCL cell lines and 18/33 (54.5%) tumours. SOCS3 was found consistently methylated in cell lines (3/4) and tumours (7/7) negative for SOCS3, and was unmethylated in all SOCS3-positive cell line (1/1) and tumours (5/5) examined. Treatment of all three SOCS3-negative cell lines with 2'-deoxy-5-azacytidine restored SOCS3 expression. SOCS3 is biologically important in MCL, as lentiviral transfer of SOCS3 in SOCS3-negative cell lines increased their apoptotic activity, downregulated nuclear factor (NF)-κB-p65, cyclin D1 (CCND1), BCL2 and BCL-XL (BCL2L1), and substantially dampened interleukin 10-induced STAT3 activation. In 19 patients aged ≤ 69 years at time of diagnosis, we found that those that carried SOCS3-negative tumours showed a trend toward a worse outcome (P = 0.1, log-rank).
authors: Department of Laboratory Medicine and Pathology, Edmonton, AB, Canada.
authors: Ommoleila
authors: O
authors: Molavi
authors: Peng
authors: P
authors: Wang
authors: Zoulika
authors: Z
authors: Zak
authors: Pascal
authors: P
authors: Gelebart
authors: Andrew
authors: A
authors: Belch
authors: Raymond
authors: R
authors: Lai
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor / Q000187:drug effects; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D005822:Genetic Vectors; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D011379:Prognosis; D011993:Recombinant Fusion Proteins / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics* / Q000502:physiology; D051996:Transcription Factor RelA / Q000096:biosynthesis / Q000235:genetics; D014161:Transduction, Genetic; D016896:Treatment Outcome
chemical_list: D051017:Apoptosis Regulatory Proteins; C530104:CCND1 protein, human; D009363:Neoplasm Proteins; C498143:RELA protein, human; D011993:Recombinant Fusion Proteins; C106644:SOCS3 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D051996:Transcription Factor RelA; D019938:Cyclin D1; D000077209:Decitabine; D001374:Azacitidine