The aim of this study was to investigate the clinical feature of mucosa-associated lymphoid tissue lymphoma and clarify the relationship between the pathological, clinical features, the expression of API2-MALT1 and the prognosis. A number of factors including pathological characters, grade, stage, prognosis and treatment of 49 cases of MALT lymphoma were analyzed, and the API2-MALT1 rearrangement was detected by RT-PCR. The results showed that 49 patients were diagnosed as MALT lymphoma, in which median age was 52.4 years. The percentage of patients older than 50 years was 67.3%. The majority of tumors were found in stomach (22 cases), intestine (13 cases), thyroid (6 cases) and so on. Among 49 patients, stage I, II was 77. 6%, stage III, IV was 22.4%. API2-MALT1 rearrangement were found 38.1% in low grade, and 12.5% in transform type. Among 18 patients with gastric MALT lymphoma, 9 cases (50.0%) were helicobacter pylori (HP) positive and received antibiotic treatment. The 3 years overall survival was 93.8%. It is concluded that MALT lymphoma is often seen in older patients, most of them were in low grade with slow progression. The site, grade, stage and molecular genetic changes are important prognostic factors, which can contribute to choosing suitable treatment for patients with MALT lymphoma. The antibiotic treatment is effective for patients with positive HP.
Adult ; Aged ; Caspases ; genetics ; metabolism ; Female ; Gene Rearrangement ; Humans ; Lymphoma, B-Cell, Marginal Zone ; diagnosis ; genetics ; Male ; Middle Aged ; Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein ; Neoplasm Proteins ; genetics ; metabolism ; Neoplasm Staging ; Oncogene Proteins, Fusion ; genetics ; Prognosis ; Young Adult

OBJECTIVETo study the expression of API2-MALT1 mRNA in mucosa-associated lymphoid tissue (MALT) lymphoma, extranodal diffuse large B-cell lymphoma (DLBCL) and Hashimoto's thyroiditis, to investigate the expression pattern of API2-MALT1 variants, and to correlate the findings with the clinicopathologic features and prognosis.

METHODSSixty-two cases of MALT lymphoma (10 from lung, 31 from stomach, 9 from intestine and 12 from thyroid), 32 cases of extranodal DLBCL (16 from stomach, 13 from intestine and 3 from thyroid), 8 cases of Hashimoto's thyroiditis and 5 cases of reactive lymph nodes hyperplasia as negative controls were collected. The expression of API2-MALT1 mRNA was studied in all cases by reverse transcriptase (RT)-polymerase chain reaction (PCR) and nested PCR. The 94 cases of lymphoma were subdivided into API2-MALT1-positive and API2-MALT1-negative groups. Among the patients, 78 were followed up for 6 to 120 months. The differences in clinicopathologic features and prognosis between the two groups were analyzed.

RESULTSAPI2-MALT1 transcripts were detected in 39 of the 94 lymphoma cases (with 28 cases being MALT lymphoma and 11 cases being extranodal DLBCL). mRNA expression was not detected in all cases of Hashimoto's thyroiditis and the negative controls. Two fusion gene variants, A1446-M1123 and A1446-M814 were found, and A1446-M1123 expression was more common. As for MALT lymphoma cases, the frequency of the fusion gene expression was lower in thyroid, when compared with that in lung, stomach and intestine. API2-MALT1-positive cases had tumors in an earlier stage with milder infiltration of cancer cells, lower relapse rate, and higher five-year survival rate.

CONCLUSIONSThe expression of API2-MALT1 mRNA can be detected in both MALT lymphoma and extranodal DLBCL, but not in Hashimoto's thyroiditis. These cases tend to show a more indolent clinical course and better survival. The frequency of t (11; 18) (q21; q21) correlates with the primary sites of MALT lymphoma. The higher incidence of breakpoint at 1123 bp of MALT1 gene in Chinese people may be due to geographical variation.

Caspases ; biosynthesis ; genetics ; Female ; Follow-Up Studies ; Genetic Variation ; Hashimoto Disease ; metabolism ; Humans ; Lymphoma, B-Cell, Marginal Zone ; metabolism ; pathology ; Lymphoma, Large B-Cell, Diffuse ; metabolism ; pathology ; Male ; Middle Aged ; Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein ; Neoplasm Invasiveness ; Neoplasm Proteins ; biosynthesis ; genetics ; Neoplasm Staging ; Oncogene Proteins, Fusion ; biosynthesis ; genetics ; RNA, Messenger ; biosynthesis ; genetics ; Reverse Transcriptase Polymerase Chain Reaction ; methods ; Survival Rate

Animals ; Antineoplastic Agents ; pharmacology ; B-Cell CLL-Lymphoma 10 Protein ; deficiency ; metabolism ; CARD Signaling Adaptor Proteins ; deficiency ; metabolism ; Cell Survival ; drug effects ; DNA Damage ; Doxorubicin ; pharmacology ; HeLa Cells ; Humans ; Mice ; Mice, Knockout ; Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein ; deficiency ; metabolism ; NF-kappa B ; metabolism

The paracaspase MALT1 is essential for the activation of NF-κB in response to T cell receptor (TCR) stimulation. It recruits downstream TRAF6 and activates the E3 ligase activity of TRAF6 to polyubiquitinate several targets, which ultimately leads to NF-κB activation. Here we identified ubiquitin-specific protease 2a (USP2a) as a MALT1-associated protein by biochemical affinity purification. Endogenous USP2a constitutively interacted with TRAF6, but dynamically interacted with MALT1 and CARMA1 in a stimulation-dependent manner. RNA interference (RNAi)-mediated silencing of USP2a attenuated TCR-induced NF-κB activation and production of interleukin-2 (IL-2). In addition, the ubiquitination of MALT1 and TRAF6 were both suppressed by USP2a knockdown. By knockdown and reconstitution assays, we found that USP2a mediated the interaction between MALT1 and TRAF6 in a catalytic activity-dependent manner. Furthermore, USP2a deSUMOylated TRAF6. Our findings implicate that USP2a plays an important role in TCR signaling by deSUMOylating TRAF6 and mediating TRAF6-MALT1 interaction.
Caspases ; metabolism ; Endopeptidases ; deficiency ; genetics ; metabolism ; Gene Knockdown Techniques ; HEK293 Cells ; Humans ; Interleukin-2 ; biosynthesis ; Jurkat Cells ; Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein ; NF-kappa B ; metabolism ; Neoplasm Proteins ; metabolism ; Receptors, Antigen, T-Cell ; metabolism ; Signal Transduction ; Sumoylation ; TNF Receptor-Associated Factor 6 ; metabolism

OBJECTIVETo study the genetic aberrations of ocular extranodal marginal zone B-cell lymphomas of mucosa-associated lymphoid tissue (MALT) type occurring in patients from southern China.

METHODSFifty seven paraffin-embedded ocular MALT lymphoma specimens from patients in southern China were studied by interphase fluorescence-in-situ hybridization (FISH) for genetic aberrations including t(11;18)(q21;q21)/API2-MALT1, t(1;14)(p22;q32)/IgH-bcl-10, t(14;18) (q32;q21)/IgH-MALT1 and bcl-6/FOXP1 gene translocations.

RESULTSAmongst the 57 cases studied, 9 cases (15.8%) showed chromosome translocations, including 4 cases (7.0%) of t(11;18)(q21;q21)/API2-MALT1, 1 case (1.8%) of t(14;18) (q32;q21)/IgH-MALT1, 1 case (1.8%) of bcl-6 gene-related chromosome translocation and 3 cases (5.3%) of IgH-unknown translocation partner. FISH revealed 17 cases (29.8%) with 3 copies of bcl-6 gene, 21 cases (36.8%) with 3 copies of MALT1 gene and 12 cases (21.1%) with 3 copies of both genes.

CONCLUSIONSThe MALT lymphoma-associated chromosome translocations t(11;18)(q21;q21)/API2-MALT1 and t(14;18) (q32;q21)/IgH-MALT1 are demonstrated in ocular MALT lymphomas of southern Chinese patients. The prevalence is significantly different from that reported in northern Chinese and northern American patients, indicating a geographic heterogeneity in the MALT lymphoma-associated genetic aberrations. The presence of 3 copies of bcl-6 and MALT1 genes is the commonest genetic abnormalities observed in ocular MALT lymphomas, suggesting a possible role in MALT lymphomagenesis.

Caspases ; genetics ; metabolism ; China ; Chromosome Aberrations ; Chromosomes, Human, Pair 11 ; genetics ; Chromosomes, Human, Pair 14 ; genetics ; Chromosomes, Human, Pair 18 ; genetics ; Chromosomes, Human, Pair 3 ; genetics ; DNA-Binding Proteins ; genetics ; metabolism ; Eye Neoplasms ; genetics ; metabolism ; Humans ; In Situ Hybridization, Fluorescence ; Lymphoma, B-Cell, Marginal Zone ; genetics ; metabolism ; Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein ; Neoplasm Proteins ; genetics ; metabolism ; Proto-Oncogene Proteins c-bcl-6 ; Translocation, Genetic ; Trisomy

AIMTo determine how SDF-1 alpha/CXCR4 activates nuclear factor-kappa B (NF-kappaB) and promotes oral squamous cell carcinoma (OSCC) invasion.

METHODOLOGYA lentivirus-based knockdown approach was utilized to deplete gene expression. NF-kappaB activation was evaluated by Western blot analysis and electrophoretic mobility shift (EMSA).

RESULTSWe show that the activation of NF-kappaB by CXCR4 occurs through the Carma3/Bcl10/Malt1 (CBM) complex in OSCC. We found that loss of components of the CBM complex in HNSCC can inhibit SDF-1 alpha induced phosphorylation and degradation of IkappaBalpha, while TNF alpha induced IKK activation remains unchanged. Further, we identified a role for novel and atypical, but not classical, PKCs in activating IKK through CXCR4. Importantly, inhibition of the CBM complex leads to a significant decrease in SDF-1 alpha mediated invasion of OSCC.

CONCLUSIONThe CBM complex plays a critical role in CXCR4-induced NF-kappaB activation in OSCC. Targeting molecular components of the NF-kappaB signaling pathway may provide an important therapeutic opportunity in controlling the progression and metastasis of OSCC mediated by SDF-1 alpha.

Adaptor Proteins, Signal Transducing ; antagonists & inhibitors ; physiology ; B-Cell CLL-Lymphoma 10 Protein ; CARD Signaling Adaptor Proteins ; antagonists & inhibitors ; physiology ; Carcinoma, Squamous Cell ; pathology ; Caspase Inhibitors ; Caspases ; physiology ; Cell Line, Tumor ; Chemokine CXCL12 ; antagonists & inhibitors ; physiology ; Enzyme Activation ; drug effects ; Gene Silencing ; Genetic Vectors ; genetics ; Humans ; I-kappa B Kinase ; drug effects ; I-kappa B Proteins ; metabolism ; Isoenzymes ; antagonists & inhibitors ; Lentivirus ; genetics ; Membrane Proteins ; antagonists & inhibitors ; physiology ; Mouth Neoplasms ; pathology ; Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein ; NF-KappaB Inhibitor alpha ; NF-kappa B ; antagonists & inhibitors ; physiology ; Neoplasm Invasiveness ; Neoplasm Proteins ; antagonists & inhibitors ; physiology ; Phosphorylation ; Plasmids ; genetics ; Protein Kinase C ; antagonists & inhibitors ; Receptors, CXCR4 ; physiology ; Tumor Necrosis Factor-alpha ; pharmacology