BCL10

Gene Summary

Gene:BCL10; B-cell CLL/lymphoma 10
Aliases: CLAP, mE10, CIPER, IMD37, c-E10, CARMEN
Location:1p22
Summary:This gene was identified by its translocation in a case of mucosa-associated lymphoid tissue (MALT) lymphoma. The protein encoded by this gene contains a caspase recruitment domain (CARD), and has been shown to induce apoptosis and to activate NF-kappaB. This protein is reported to interact with other CARD domain containing proteins including CARD9, 10, 11 and 14, which are thought to function as upstream regulators in NF-kappaB signaling. This protein is found to form a complex with MALT1, a protein encoded by another gene known to be translocated in MALT lymphoma. MALT1 and this protein are thought to synergize in the activation of NF-kappaB, and the deregulation of either of them may contribute to the same pathogenetic process that leads to the malignancy. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:B-cell lymphoma/leukemia 10
HPRD
Source:NCBIAccessed: 06 August, 2015

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 06 August 2015 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 06 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: BCL10 (cancer-related)

Majewski IJ, Nuciforo P, Mittempergher L, et al.
PIK3CA mutations are associated with decreased benefit to neoadjuvant human epidermal growth factor receptor 2-targeted therapies in breast cancer.
J Clin Oncol. 2015; 33(12):1334-9 [PubMed] Related Publications
PURPOSE: We investigated whether mutations in the gene encoding the phosphatidylinositol 3-kinase (PI3K) catalytic subunit (PIK3CA) correlates with response to neoadjuvant human epidermal growth factor receptor 2 (HER2) -targeted therapies in patients with breast cancer.
PATIENTS AND METHODS: Baseline tissue biopsies were available from patients with HER2-positive early breast cancer who were enrolled onto the Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial (NeoALTTO). Activating mutations in PIK3CA were identified using mass spectrometry-based genotyping.
RESULTS: PIK3CA mutations were identified in 23% of HER2-positive breast tumors, and these mutations were associated with poorer outcome in all of the treatment arms. Patients treated with a combination of trastuzumab and lapatinib who had wild-type PIK3CA obtained a total pathologic complete response (pCR) rate of 53.1%, which decreased to 28.6% in patients with tumors that carried PIK3CA activating mutations (P = .012).
CONCLUSION: Activating mutations in PIK3CA predicted poor pCR in patients with HER2-positive breast cancer treated with neoadjuvant therapies that target HER2. Consequently, the combination of anti-HER2 agents and PI3K inhibitors is being investigated.

Rauh-Hain JA, Foley OW, Winograd D, et al.
Clinical characteristics and outcomes of patients with stage I epithelial ovarian cancer compared with fallopian tube cancer.
Am J Obstet Gynecol. 2015; 212(5):600.e1-8 [PubMed] Related Publications
OBJECTIVE: The purpose of this study was to compare clinical characteristics and survival between patients with stage I epithelial ovarian cancer and fallopian tube cancer.
STUDY DESIGN: We identified women with stage I epithelial ovarian cancer and fallopian tube cancer who underwent treatment from 2000-2010. Correlation between categoric variables was assessed with χ2 test. The Kaplan-Meier survival analysis was used to generate overall survival data. Factors predictive of outcome were compared with the use of the log-rank test and Cox proportional hazards model.
RESULTS: The study group consisted of 385 women with epithelial ovarian cancer and 43 women with fallopian tube cancer. Patients with fallopian tube cancer had a higher rate of stage IA disease (65% vs 48%; P=.02) and grade 3 tumors (60.4% vs 30.9%; P<.001). Patients with fallopian tube cancer had a significantly higher rate of breast cancer (25.6% vs 5.7%; P<.001) and BRCA 1 mutations (45.8% vs 9.1%; P<.001). There was no difference in the rates of platinum-based and paclitaxel chemotherapy between the groups. Women with fallopian tube cancer were more likely to have received ≥6 cycles of chemotherapy (58.1% vs 44.1%; P=.02). The 5-year disease-free survival rates were 100% in women with fallopian tube cancer and 93% in patients with epithelial ovarian cancer (P=.04). The 5-year overall survival rates were 100% and 95% for fallopian tube cancer and epithelial ovarian cancer, respectively (P=.7).
CONCLUSION: We found a higher rate of stage IA, grade 3, and serous carcinoma in fallopian tube cancer. Women with fallopian tube cancer had a higher rate of breast cancer. There was no difference in overall survival between the groups.

Xi Y, Garshott DM, Brownell AL, et al.
Cantharidins induce ER stress and a terminal unfolded protein response in OSCC.
J Dent Res. 2015; 94(2):320-9 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Mortality and morbidity associated with oral squamous cell carcinoma (OSCC) remain unacceptably high with disfiguring treatment options and a death rate of 1 per hour in the United States. The approval of cituximab for advanced OSCC has been the only new treatment for these patients since the 1970s, although it has not significantly increased overall survival. To address the paucity of effective new therapies, we undertook a high-throughput screen to discover small molecules and natural products that could induce endoplasmic reticulum (ER) stress and enforce a terminal unfolded protein response (UPR) in OSCC. The terpenoid cantharidin (CNT), previously used to treat various malignancies in culture-specific medical practices for over 2,000 y, emerged as a hit. CNT and its analog, cantharidic acid, potently induced protein and gene expression profiles consistent with the activation of ER stress, the UPR, and apoptosis in OSCC cells. Murine embryonic fibroblasts null for the UPR-associated transcription factors Atf4 or Chop were significantly protected from CNT, implicating a key role for the UPR in the death response. These data validate that our high-throughput screen can identify novel modulators of UPR signaling and that such compounds might provide a new therapeutic approach to treating patients with OSCC.

Ma Y, Liao Z, Xu Y, et al.
Characteristics of CARMA1-BCL10-MALT1-A20-NF-κB expression in T cell-acute lymphocytic leukemia.
Eur J Med Res. 2014; 19:62 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
BACKGROUND: Knowledge of the oncogenic signaling pathways of T-cell acute lymphoblastic leukemia (T-ALL) remains limited. Constitutive aberrant activation of the nuclear factor kappa B (NF-κB) signaling pathway has been detected in various lymphoid malignancies and plays a key role in the development of these carcinomas. The zinc finger-containing protein, A20, is a central regulator of multiple NF-κB-activating signaling cascades. A20 is frequently inactivated by deletions and/or mutations in several B-and T-cell lymphoma subtypes. However, few A20 mutations and polymorphisms have been reported in T-ALL. Thus, it is of interest to analyze the expression characteristics of A20 and its regulating factors, including upstream regulators and the CBM complex, which includes CARMA1, BCL10, and MALT1.
METHODS: The expression levels of CARMA1, BCL10, MALT1, A20, and NF-κB were detected in peripheral blood mononuclear cells (PBMCs) from 21 patients with newly diagnosed T-ALL using real-time PCR, and correlations between the aberrant expression of these genes in T-ALL was analyzed. Sixteen healthy individuals, including 10 males and 6 females, served as controls.
RESULTS: Significantly lower A20 expression was found in T-ALL patients (median: 4.853) compared with healthy individuals (median: 8.748; P = 0.017), and significantly increased expression levels of CARMA1 (median: 2.916; P = 0.034), BCL10 (median: 0.285; P = 0.033), and MALT1 (median: 1.201; P = 0.010) were found in T-ALL compared with the healthy individuals (median: 1.379, 0.169, and 0.677, respectively). In contrast, overexpression of NF-κB (median: 0.714) was found in T-ALL compared with healthy individuals (median: 0.335; P = 0.001). A negative correlation between the MALT1 and A20 expression levels and a positive correlation between CARMA1 and BCL10 were found in T-ALL and healthy individuals. However, no negative correlation was found between A20 and NF-κB and the MALT1 and NF-κB expression level in the T-ALL group.
CONCLUSIONS: We characterized the expression of the CARMA-BCL10-MALT1-A20-NF-κB pathway genes in T-ALL. Overexpression of CARMA-BCL10-MALT in T-ALL may contribute to the constitutive cleavage and inactivation of A20, which enhances NF-κB signaling and may be related to T-ALL pathogenesis.

Gallot YS, Durieux AC, Castells J, et al.
Myostatin gene inactivation prevents skeletal muscle wasting in cancer.
Cancer Res. 2014; 74(24):7344-56 [PubMed] Related Publications
Cachexia is a muscle-wasting syndrome that contributes significantly to morbidity and mortality of many patients with advanced cancers. However, little is understood about how the severe loss of skeletal muscle characterizing this condition occurs. In the current study, we tested the hypothesis that the muscle protein myostatin is involved in mediating the pathogenesis of cachexia-induced muscle wasting in tumor-bearing mice. Myostatin gene inactivation prevented the severe loss of skeletal muscle mass induced in mice engrafted with Lewis lung carcinoma (LLC) cells or in Apc(Min) (/+) mice, an established model of colorectal cancer and cachexia. Mechanistically, myostatin loss attenuated the activation of muscle fiber proteolytic pathways by inhibiting the expression of atrophy-related genes, MuRF1 and MAFbx/Atrogin-1, along with autophagy-related genes. Notably, myostatin loss also impeded the growth of LLC tumors, the number and the size of intestinal polyps in Apc(Min) (/+) mice, thus strongly increasing survival in both models. Gene expression analysis in the LLC model showed this phenotype to be associated with reduced expression of genes involved in tumor metabolism, activin signaling, and apoptosis. Taken together, our results reveal an essential role for myostatin in the pathogenesis of cancer cachexia and link this condition to tumor growth, with implications for furthering understanding of cancer as a systemic disease.

Steinhardt JJ, Peroutka RJ, Mazan-Mamczarz K, et al.
Inhibiting CARD11 translation during BCR activation by targeting the eIF4A RNA helicase.
Blood. 2014; 124(25):3758-67 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Human diffuse large B-cell lymphomas (DLBCLs) often aberrantly express oncogenes that generally contain complex secondary structures in their 5' untranslated region (UTR). Oncogenes with complex 5'UTRs require enhanced eIF4A RNA helicase activity for translation. PDCD4 inhibits eIF4A, and PDCD4 knockout mice have a high penetrance for B-cell lymphomas. Here, we show that on B-cell receptor (BCR)-mediated p70s6K activation, PDCD4 is degraded, and eIF4A activity is greatly enhanced. We identified a subset of genes involved in BCR signaling, including CARD11, BCL10, and MALT1, that have complex 5'UTRs and encode proteins with short half-lives. Expression of these known oncogenic proteins is enhanced on BCR activation and is attenuated by the eIF4A inhibitor Silvestrol. Antigen-experienced immunoglobulin (Ig)G(+) splenic B cells, from which most DLBCLs are derived, have higher levels of eIF4A cap-binding activity and protein translation than IgM(+) B cells. Our results suggest that eIF4A-mediated enhancement of oncogene translation may be a critical component for lymphoma progression, and specific targeting of eIF4A may be an attractive therapeutic approach in the management of human B-cell lymphomas.

Laafi J, Homedan C, Jacques C, et al.
Pro-oxidant effect of ALA is implicated in mitochondrial dysfunction of HepG2 cells.
Biochimie. 2014; 106:157-66 [PubMed] Related Publications
Heme biosynthesis begins in the mitochondrion with the formation of delta-aminolevulinic acid (ALA). In acute intermittent porphyria, hereditary tyrosinemia type I and lead poisoning patients, ALA is accumulated in plasma and in organs, especially the liver. These diseases are also associated with neuromuscular dysfunction and increased incidence of hepatocellular carcinoma. Many studies suggest that this damage may originate from ALA-induced oxidative stress following its accumulation. Using the MnSOD as an oxidative stress marker, we showed here that ALA treatment of cultured cells induced ROS production, increasing with ALA concentration. The mitochondrial energetic function of ALA-treated HepG2 cells was further explored. Mitochondrial respiration and ATP content were reduced compared to control cells. For the 300 μM treatment, ALA induced a mitochondrial mass decrease and a mitochondrial network imbalance although neither necrosis nor apoptosis were observed. The up regulation of PGC-1, Tfam and ND5 genes was also found; these genes encode mitochondrial proteins involved in mitochondrial biogenesis activation and OXPHOS function. We propose that ALA may constitute an internal bioenergetic signal, which initiates a coordinated upregulation of respiratory genes, which ultimately drives mitochondrial metabolic adaptation within cells. The addition of an antioxidant, Manganese(III) tetrakis(1-methyl-4-pyridyl)porphyrin (MnTMPyP), resulted in improvement of maximal respiratory chain capacity with 300 μM ALA. Our results suggest that mitochondria, an ALA-production site, are more sensitive to pro-oxidant effect of ALA, and may be directly involved in pathophysiology of patients with inherited or acquired porphyria.

Wu TS, Tan CT, Chang CC, et al.
B-cell lymphoma/leukemia 10 promotes oral cancer progression through STAT1/ATF4/S100P signaling pathway.
Oncogene. 2015; 34(10):1207-19 [PubMed] Related Publications
B-cell lymphoma/leukemia 10 (BCL10) is an apoptotic regulatory protein related to advanced TNM stage and disease recurrence in oral squamous cell carcinoma (OSCC). However, the regulatory mechanism of BCL10 in OSCC progression is still unknown. Here, we showed that knockdown of endogenous BCL10 could significantly reduce cell migration and invasion abilities, retard cell proliferation by G0/G1 phase accumulation and inhibit tumorigenicity in vivo. In molecular level, we identified S100P as a crucial downstream effector of BCL10-inhibited OSCC progression by high-throughput microarray analysis. S100P messenger RNA and protein expression levels were significantly diminished in silenced-BCL10 clones, and transfected S100P expression plasmids restored migration, invasion, proliferation abilities and tumorigenicity in shBCL10 transfectants. Furthermore, we provided evidence that BCL10 regulated S100P expression through signal transducers and activators of transcription 1 (STAT1) and activating transcription factor 4 (ATF4). Knockdown of BCL10 decreased S100P promoter activity, but showed no effect in truncated STAT1/ATF4 S100P promoter.  In addition, we also found that the P50/P65 signaling pathway was involved in BCL10-enhanced OSCC progression. Restored S100P in silenced-BCL10 clones could markedly reverse P65 activation via outside-in signaling. Taken together, we discovered a novel axis of BCL10-regulated OSCC progression via STAT1/ATF4/S100P/P65 signaling, which could predict the prognosis of OSCC and will be beneficial for developing therapeutic strategy against advanced OSCC.

Du S, Jia L, Zhang Y, et al.
CARMA3 is upregulated in human pancreatic carcinoma, and its depletion inhibits tumor proliferation, migration, and invasion.
Tumour Biol. 2014; 35(6):5965-70 [PubMed] Related Publications
Elevated CARMA3 expression has been reported to be involved in tumor progression of several cancer types. In the present study, we examined the expression pattern of CARMA3 protein and its biological roles in human pancreatic carcinoma. Using immunohistochemistry, we checked CARMA3 protein expression in 95 pancreatic ductal carcinoma specimens. We found that CARMA3 was overexpressed in 34 of 95 (35.8 %) specimens. A significant association was observed between CARMA3 overexpression with histological grade (p=0.0099) and nodal status (p=0.0126). To further explore its biological roles, we knocked down CARMA3 expression in CAPAN2 cell line using small interfering RNA (siRNA). MTT growth assay, wound healing assay, and Transwell assay showed that CARMA3 depletion inhibited cell proliferation, migration, and invasion. We also showed that CARMA3 depletion inhibited EGF-induced nuclear factor-kappaB (NF-κB) activation and its target genes' expression. The effect of CARMA3 depletion on NF-κB signaling was significantly reduced in Bcl10-depleted cells. In conclusion, CARMA3 is overexpressed in pancreatic cancer and regulates malignant cell growth, invasion, and NF-κB signaling, which was dependent on its association with Bcl10.

Agarwal NK, Zhu X, Gagea M, et al.
PHLPP2 suppresses the NF-κB pathway by inactivating IKKβ kinase.
Oncotarget. 2014; 5(3):815-23 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
The NF-κB growth pathway is constitutively activated in many cancers but its activation mechanism is unclear in most cases. We show that PHLPP2 interacts with IKKβ kinase, decreases its phosphorylation and the subsequent NF-κB activation in cancer cells. PHLPP2 is progressively lost in glioma and colorectal cancer and acts as a bona fide tumor suppressor, depending on IKKβ expression in cells. Physiologically, IKKβ activation by growth factors requires the formation of the Bcl10-MALT1 ubiquitin-ligase complex leading to NEMO/IKKγ non-degradative ubiquitination and IKKβ phosphorylation. PHLPP2 opposes the formation of this complex through interaction with Bcl10 and competitive displacement of MALT1 from Bcl10. Conversely, PHLPP2 loss enhances Bcl10-MALT1 complex formation, NEMO ubiquitination and subsequent IKKβ phosphorylation, resulting in increased NF-κB-dependent transcription of multiple target genes. Our results reveal PHLPP2 as a new biomarker of cancer progression, and implicate it as major negative regulator of NF-κB signaling.

Fares F, Azzam N, Fares B, et al.
Benzene-poly-carboxylic acid complex, a novel anti-cancer agent induces apoptosis in human breast cancer cells.
PLoS One. 2014; 9(2):e85156 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Some cases of breast cancer are composed of clones of hormonal-independent growing cells, which do not respond to therapy. In the present study, the effect of Benzene-Poly-Carboxylic Acid Complex (BP-C1) on growth of human breast-cancer cells was tested. BP-C1 is a novel anti-cancer complex of benzene-poly-carboxylic acids with a very low concentration of cis-diammineplatinum (II) dichloride. Human breast cancer cells, MCF-7 and T47D, were used. Cell viability was detected by XTT assay and apoptosis was detected by Flow Cytometry and by annexin V/FITC/PI assay. Caspases were detected by western blot analysis and gene expression was measured by using the Applied Biosystems® TaqMan® Array Plates. The results showed that exposure of the cells to BP-C1 for 48 h, significantly (P<0.001) reduced cell viability, induced apoptosis and activated caspase 8 and caspace 9. Moreover, gene expression experiments indicated that BP-C1 increased the expression of pro-apoptotic genes (CASP8AP1, TNFRSF21, NFkB2, FADD, BCL10 and CASP8) and lowered the level of mRNA transcripts of inhibitory apoptotic genes (BCL2L11, BCL2L2 and XIAP. These findings may lead to the development of new therapeutic strategies for treatment of human cancer using BP-C1 analog.

Scudiero I, Vito P, Stilo R
The three CARMA sisters: so different, so similar: a portrait of the three CARMA proteins and their involvement in human disorders.
J Cell Physiol. 2014; 229(8):990-7 [PubMed] Related Publications
Initially identified by their ability to modulate the functional activity of BCL10, the three CARMA proteins, CARMA1, -2, and -3, have recently themselves taken a leading role on the stage of molecular medicine. Although considered for some time as simple ancillary proteins, increasingly accumulating recent data evidently indicate a role of primary importance for these three proteins in the pathophysiology of several human tumors and inflammatory disorders. In fact, recent scientific literature clearly establishes that CARMA1 is one of the most mutated genes in a subtype of B-cell lymphoma and, at the same time, responsible for some rare human immunodeficiency conditions. On the other hand, mutations in CARMA2 are responsible for the hereditary transmission of some inflammatory disorders of the skin, including familial psoriasis and ptiriasis; whereas expression of CARMA3 appears to be deregulated in different human tumors. Here we describe and summarize the mutations found in the genes coding for the three CARMA proteins in these different human pathological conditions, and offer an interpretation of the molecular mechanisms from which arise the biological outcomes in which these proteins are involved.

Zheng H, Wang X, Ma Y, et al.
The TCR γδ repertoire and relative gene expression characteristics of T-ALL cases with biclonal malignant Vδ1 and Vδ2 T cells.
DNA Cell Biol. 2014; 33(1):49-56 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Despite significant improvement in our understanding of T-cell acute lymphoblastic leukemia (T-ALL) biology and pathogenesis, many questions remain unanswered. In previous studies, we found a T-ALL case with two malignant T-cell clones with Vδ1Dδ2Dδ3Jδ1 and Vδ2Dδ3Jδ2 rearrangements. In this study, we further characterized T-ALL cases with two malignant clones containing Vδ1Dδ3Jδ1 and Vδ2Dδ1Jδ1 rearrangements using fine-tiling array comparative genomic hybridization, ligation-mediated polymerase chain reaction (LM-PCR), sequencing, and reverse transcription polymerase chain reaction (RT-PCR) analysis. We further analyzed the distribution and clonality of the T-cell receptor (TCR) Vγ and Vδ subfamily T cells in the two T-ALL cases by RT-PCR and GeneScan. Monoclonal Vδ1 and Vδ2 subfamilies were confirmed in both samples, the Vδ3 through Vδ7 subfamilies could not be detected in the T-ALL samples, whereas the oligoclonal Vδ8 subfamily could be identified. Based on the clinical finding that both of the T-ALL cases with two malignant T-cell clones had a poor outcome, we attempted to compare the expression pattern of genes related to T-cell activation and proliferation between cases with the malignant Vδ1 and Vδ2 T-cell clones and T-ALL cases with a mono-malignant Vα T-cell clone. We selected two T-ALL cases with VαJα rearrangements and analyzed the expression level of Notch1, TAL1, and the CARMA-BCL10-MALT-A20-NF-κB pathway genes by real-time PCR. A20 had significantly higher expression in the biclonal compared with the monoclonal T-ALL group (p=0.0354), and there was a trend toward higher expression for the other genes in the biclonal group with the exception of TAL1, although the differences were not statistically significant. In conclusion, we identified two T-ALL cases with biclonal malignant T-cell clones and described the characteristics of the biclonal T-ALL subtype and its gene expression pattern. Thus, our findings may improve the understanding of biclonal T-ALL.

Gomez-Martin C, Plaza JC, Pazo-Cid R, et al.
Level of HER2 gene amplification predicts response and overall survival in HER2-positive advanced gastric cancer treated with trastuzumab.
J Clin Oncol. 2013; 31(35):4445-52 [PubMed] Related Publications
PURPOSE: Previous studies have highlighted the importance of an appropriate human epidermal growth factor receptor 2 (HER2) evaluation for the proper identification of patients eligible for treatment with anti-HER2 targeted therapies. Today, the relationship remains unclear between the level of HER2 amplification and the outcome of HER2-positive gastric cancer treated with first-line chemotherapy with trastuzumab. The aim of this study was to determine whether the level of HER2 gene amplification determined by the HER2/CEP17 ratio and HER2 gene copy number could significantly predict some benefit in overall survival and response to therapy in advanced gastric cancer treated with trastuzumab-based chemotherapy.
PATIENTS AND METHODS: Ninety patients with metastatic gastric cancer treated with first-line trastuzumab-based chemotherapy were studied. The optimal cutoff values for HER2/CEP17 ratio and HER2 gene copy number (GCN) for discriminating positive results in terms of response and prolonged survival were determined using receiver operating characteristic curves analyses.
RESULTS: In this study, a median HER2/CEP17 ratio of 6.11 (95% CI, 2.27 to 21.90) and a median HER2 gene copy number of 11.90 (95% CI, 3.30 to 43.80) were found. A mean HER2/CEP17 ratio of 4.7 was identified as the optimal cutoff value discriminating sensitive and refractory patients (P = .005). Similarly, the optimal cutoff for predicting survival longer than 12 months was 4.45 (P = .005), and for survival longer than 16 months was 5.15 (P = .004). For HER2 GCN, the optimal cutoff values were 9.4, 10.0, and 9.5, respectively (P = .02).
CONCLUSION: The level of HER2 gene amplification significantly predicts sensitivity to therapy and overall survival in advanced gastric cancer treated with trastuzumab-based chemotherapy.

Rajasekaran K, Kumar P, Schuldt KM, et al.
Signaling by Fyn-ADAP via the Carma1-Bcl-10-MAP3K7 signalosome exclusively regulates inflammatory cytokine production in NK cells.
Nat Immunol. 2013; 14(11):1127-36 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Inflammation is a critical component of the immune response. However, acute or chronic inflammation can be highly destructive. Uncontrolled inflammation forms the basis for allergy, asthma and various autoimmune disorders. Here we identified a signaling pathway that was exclusively responsible for the production of inflammatory cytokines but not for cytotoxicity. Recognition of tumor cells expressing the NK cell-activatory ligands H60 or CD137L by mouse natural killer (NK) cells led to efficient cytotoxicity and the production of inflammatory cytokines. Both of those effector functions required the kinases Lck, Fyn and PI(3)K (subunits p85α and p110δ) and the signaling protein PLC-γ2. However, a complex of Fyn and the adaptor ADAP exclusively regulated the production of inflammatory cytokines but not cytotoxicity in NK cells. That unique function of ADAP required a Carma1-Bcl-10-MAP3K7 signaling axis. Our results have identified molecules that can be targeted to regulate inflammation without compromising NK cell cytotoxicity.

Lee MO, Moon SH, Jeong HC, et al.
Inhibition of pluripotent stem cell-derived teratoma formation by small molecules.
Proc Natl Acad Sci U S A. 2013; 110(35):E3281-90 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
The future of safe cell-based therapy rests on overcoming teratoma/tumor formation, in particular when using human pluripotent stem cells (hPSCs), such as human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs). Because the presence of a few remaining undifferentiated hPSCs can cause undesirable teratomas after transplantation, complete removal of these cells with no/minimal damage to differentiated cells is a prerequisite for clinical application of hPSC-based therapy. Having identified a unique hESC signature of pro- and antiapoptotic gene expression profile, we hypothesized that targeting hPSC-specific antiapoptotic factor(s) (i.e., survivin or Bcl10) represents an efficient strategy to selectively eliminate pluripotent cells with teratoma potential. Here we report the successful identification of small molecules that can effectively inhibit these antiapoptotic factors, leading to selective and efficient removal of pluripotent stem cells through apoptotic cell death. In particular, a single treatment of hESC-derived mixed population with chemical inhibitors of survivin (e.g., quercetin or YM155) induced selective and complete cell death of undifferentiated hPSCs. In contrast, differentiated cell types (e.g., dopamine neurons and smooth-muscle cells) derived from hPSCs survived well and maintained their functionality. We found that quercetin-induced selective cell death is caused by mitochondrial accumulation of p53 and is sufficient to prevent teratoma formation after transplantation of hESC- or hiPSC-derived cells. Taken together, these results provide the "proof of concept" that small-molecule targeting of hPSC-specific antiapoptotic pathway(s) is a viable strategy to prevent tumor formation by selectively eliminating remaining undifferentiated pluripotent cells for safe hPSC-based therapy.

Cerrone M, Collina F, De Chiara A, et al.
BCL10 expression and localization in ocular adnexa MALT lymphomas: a comparative cytogenetic and immunohistochemical study.
Histol Histopathol. 2014; 29(1):77-87 [PubMed] Related Publications
T(1;14) (p22;q32) involving BCL10 and IGH genes is a rare but recurrent chromosomal aberration in MALT-type lymphoma. It is rarely described in ocular adnexa B cell lymphomas, although nuclear BCL10 shuttling seems to be critical for disease progression in this district. We have evaluated the translocations MALT lymphoma-related in a series of 45 ocular adnexa cases, focusing in particular on their relation with BCL10 expression and its cellular topographic distribution. A prognostic tissue microarray (TMA) with ocular adnexa MALT lymphomas was designed. A study of BCL10 expression and its topographic distribution was performed through immunohistochemistry. In addition the assessment of t(14;18) (q32;q21), t(1;14) (p22;q32) and t(11;18) (q21;q21) was determined by Fluorescent In Situ Hybridization (FISH). Our series revealed t(14;18) (q32;q21) in 6/43 cases (14,3%). t(1;14) (p22;q32), never described in ocular adnexa MALT lymphomas, was observed in 3/31 (9,7%), two of which exhibited the gain of 3' upstream BCL10 gene signal (4%), whereas no case showed t(11;18) (q21;q21). Moreover, BCL10 expression was observed in 18/45 cases. In particular its nuclear expression was revealed in 12/45 cases, cytoplasmic expression in 5/45 and both cytoplasmic and nuclear expression in 1/45. Statistical analysis demonstrated that while BCL10 cytoplasmic expression is significantly related to the presence of the investigated chromosomal aberrations, in particular with t(14;18) (q32;q21), BCL10 nuclear shuttling does not show any correlation with these translocations. Our data support that BCL10 nuclear distribution is neither related to BCL10 rearrangement nor to other known translocations.

Huh JH, Kim TH, Kim K, et al.
Dysregulation of miR-106a and miR-591 confers paclitaxel resistance to ovarian cancer.
Br J Cancer. 2013; 109(2):452-61 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
BACKGROUND: MicroRNAs are noncoding regulatory RNAs strongly implicated in carcinogenesis, cell survival, and chemosensitivity. Here, microRNAs associated with chemoresistance in ovarian carcinoma, the most lethal of gynaecological malignancies, were identified and their functional effects in chemoresistant ovarian cancer cells were assessed.
METHODS: MicroRNA expression in paclitaxel (PTX)-resistant SKpac sublines was compared with that of the PTX-sensitive, parental SKOV3 ovarian cancer cell line using microarray and qRT-PCR. The function of differentially expressed microRNAs in chemoresistant ovarian cancer was further evaluated by apoptosis, cell proliferation, and migration assays.
RESULTS: Upregulation of miR-106a and downregulation of miR-591 were associated with PTX resistance in ovarian cancer cells and human tumour samples. Transfection with anti-miR-106a or pre-miR-591 resensitized PTX-resistant SKpac cells to PTX by enhancing apoptosis (23 and 42% increase), and inhibited their cell migration (43 and 56% decrease) and proliferation (64 and 65% decrease). Furthermore, ZEB1 was identified as a novel target gene of miR-591, and BCL10 and caspase-7 were target genes of miR-106a, as identified by immunoblotting and luciferase assay.
CONCLUSION: MiR-106a and miR-591 have important roles in conferring PTX resistance to ovarian cancer cells. Modulation of these microRNAs resensitizes PTX-resistant cancer cells by targeting BCL10, caspase-7, and ZEB1.

Zhu J, Wei RL, Pi YL, Guo Q
Significance of Bcl10 gene mutations in the clinical diagnosis of MALT-type ocular adnexal lymphoma in the Chinese population.
Genet Mol Res. 2013; 12(2):1194-204 [PubMed] Related Publications
We investigated the expression of Bcl10 gene mutations in mucosa-associated lymphoid tissue-type ocular adnexal lymphoma (OAL), atypical lymphoid hyperplasia (ALH), and reactive lymphoid hyperplasia (RLH) in the Chinese population and its role in clinical diagnosis and pathogenesis. Forty-three samples were collected during patient surgeries. Pathological diagnosis confirmed OAL in 23 cases, ALH in 10 cases, and RLH in 10 cases. Normal peripheral lymph tissues from 12 cases were used as negative controls. Bcl10 gene expression was examined using molecular biological methods, and DNA sequences and mutations were compared with published data. The protein expression of Bcl10 and nuclear factor kappaB (NF-κB) were detected with immunohistological and immunofluorescence colocalization. Bcl10 gene expression was detected in 15 OAL cases. Novel mutations were found in 11 cases. Notably, 1 mutation, which matched a published mutation, was detected in 1 ALH case; 1 novel mutation was found in 1 RLH case; and no Bcl10 gene mutation was found in controls. Most novel mutations were truncation mutations, resulting in a truncated protein product of 99 amino acids (compared to the full-length 233 amino acids; GenBank accession No. EF189176). Results of tests for abnormal Bcl10 gene expression in nuclei or cytoplasm were consistent with changes in NF-κB translocation. This report is the first of newly discovered mutations in the Bcl10 gene in the Chinese population. The distribution of the mutations is consistent with and more sensitive than that of the pathological diagnosis. These mutations can be used to identify the stage and clinical characteristics even when morphological changes are absent.

An J, Liu H, Magyar CE, et al.
Hyperactivated JNK is a therapeutic target in pVHL-deficient renal cell carcinoma.
Cancer Res. 2013; 73(4):1374-85 [PubMed] Related Publications
Clear cell renal cell carcinomas (RCC), the major histologic subtype of RCC accounting for more than 80% of cases, are typified by biallelic inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene. Although accumulation of hypoxia-inducible factor alpha (HIF-α) is the most well-studied effect of VHL inactivation, direct inhibition of HIFα or restoration of wild-type pVHL protein expression has not proved readily feasible, given the limitations associated with pharmacologic targeting of transcription factors (i.e., HIF-α) and gene replacement therapy of tumor suppressor genes (i.e., VHL). Here, we have established that phosphorylated c-Jun, a substrate of the c-Jun-NH(2)-kinase (JNK), is selectively activated in clear cell RCC patient specimens. Using multiple isogenic cell lines, we show that HIF-α-independent JNK hyperactivation is unique to the pVHL-deficient state. Importantly, pVHL-deficient RCCs are dependent upon JNK activity for in vitro and in vivo growth. A multistep signaling pathway that links pVHL loss to JNK activation involves the formation of a CARD9/BCL10/TRAF6 complex as a proximal signal to sequentially stimulate TAK1 (MAPKKK), MKK4 (MAPKK), and JNK (MAPK). JNK stimulates c-Jun phosphorylation, activation, and dimerization with c-Fos to form a transcriptionally competent AP1 complex that drives transcription of the Twist gene and induces epithelial-mesenchymal transition. Thus, JNK represents a novel molecular target that is selectively activated in and drives the growth of pVHL-deficient clear cell RCCs. These findings can serve as the preclinical foundation for directed efforts to characterize potent pharmacologic inhibitors of the JNK pathway for clinical translation.

Liu GY, Liu KH, Li Y, et al.
Novel cancerization marker, TP53, and its role in distinguishing normal tissue adjacent to cancerous tissue from normal tissue adjacent to benign tissue.
World J Surg Oncol. 2012; 10:252 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
BACKGROUND: The histopathological and molecular heterogeneity of normal tissue adjacent to cancerous tissue (NTAC) and normal tissue adjacent to benign tissue (NTAB), and the availability of limited specimens make deciphering the mechanisms of carcinogenesis challenging. Our goal was to identify histogenetic biomarkers that could be reliably used to define a transforming fingerprint using RNA in situ hybridization.
METHODS: We evaluated 15 tumor-related RNA in situ hybridization biomarkers using tumor microarray and samples of seven tumor-adjacent normal tissues from 314 patients. Biomarkers were determined using comprehensive statistical methods (significance of support vector machine-based artificial intelligence and area under curve scoring of classification distribution).
RESULTS: TP53 was found to be a most reliable index (P <10(-7); area under curve >87%) for distinguishing NTAC from NTAB, according to the results of a significance panel (BCL10, BECN1, BRCA2, FITH, PTCH11 and TP53).
CONCLUSIONS: The genetic alterations in TP53 between NTAC and NTAB may provide new insight into the field of cancerization and tumor transformation.

Chan W, Schaffer TB, Pomerantz JL
A quantitative signaling screen identifies CARD11 mutations in the CARD and LATCH domains that induce Bcl10 ubiquitination and human lymphoma cell survival.
Mol Cell Biol. 2013; 33(2):429-43 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Antigen receptor signaling to NF-κB, essential for normal lymphocyte activation, is dysregulated in several types of lymphoma. During normal signaling, the multidomain adapter CARD11 transitions from a closed, inactive state to an open, active scaffold that assembles a multiprotein complex, leading to NF-κB activation. The regulation of CARD11 scaffold function is bypassed by lymphoma-associated oncogenic CARD11 mutations that induce spontaneous signaling. We report an unbiased high-throughput quantitative signaling screen that identifies new CARD11 hyperactive variants and defines a LATCH domain that functions with the CARD to promote CARD11 autoinhibition. Gain-of-function mutations in the LATCH or CARD disrupt inhibitory domain binding, promote Bcl10 association, and induce Bcl10 ubiquitination, NF-κB activation, and human lymphoma cell survival. Our results identify CARD11 mutations with oncogenic potential, provide a mechanistic explanation for their signaling potency, and offer a straightforward method for the discovery of variants that promote the tumorigenesis of NF-κB-dependent lymphomas.

Kozanoglu I, Yandim MK, Cincin ZB, et al.
New indication for therapeutic potential of an old well-known drug (propranolol) for multiple myeloma.
J Cancer Res Clin Oncol. 2013; 139(2):327-35 [PubMed] Related Publications
PURPOSE: Propranolol, a non-selective β-adrenergic receptor blocker, has been used for the treatment of the patients with hypertension for more than 50 years. There are several in vitro and in vivo evidences that β-adrenergic receptor antagonists inhibit proliferation and angiogenesis and also increase apoptosis in breast, skin, and colon cancers. The aim of this study was to investigate the cytotoxic and apoptotic effects of propranolol and the genes involved in propranolol-induced apoptosis in multiple myeloma cells.
METHODS: Time-dependent antiproliferation and apoptotic effects of propranolol were subsequently determined by MTT cell proliferation assay, changes in caspase-3 activity, loss of mitochondrial membrane potential (MMP), and also the localization of phosphatidylserine in the plasma membrane. Changes in expression levels of NF-ΚB pathway were examined by qRT-PCR array.
RESULTS: IC50 values of propranolol on U266 cells were calculated as 141, 100, and 75 μM after 24-, 48-, and 72-h propranolol exposure, respectively. There were significant increases in caspase-3 activity, loss of MMP, and increases in apoptotic cell population in response to propranolol in U266 cells in a time- and dose-dependent manner. There were increases in expression levels of BCL10, TRAF family members, interleukins, TLR1-4, TNFRSF10B, NF-κB, and the inhibitors of NF-κB genes, and significant decreases in expression levels of Bcl-2 in response to propranolol treatment were observed.
CONCLUSION: These results revealed that propranolol has antiproliferative and apoptotic effects on multiple myeloma cells. Being supported with in vivo analyses, propranolol can be a good and economical way to treat multiple myeloma patients.

Marsit C, Christensen B
Blood-derived DNA methylation markers of cancer risk.
Adv Exp Med Biol. 2013; 754:233-52 [PubMed] Related Publications
The importance of somatic epigenetic alterations in tissues targeted for carcinogenesis is now well recognized and considered a key molecular step in the development of a tumor. Particularly, alteration of gene-specific and genomic DNA methylation has been extensively characterized in tumors, and has become an attractive biomarker of risk due to its specificity and stability in human samples. It also is clear that tumors do not develop as isolated phenomenon in their target tissue, but instead result from altered processes affecting not only the surrounding cells and tissues, but other organ systems, including the immune system. Thus, alterations to DNA methylation profiles detectable in peripheral blood may be useful not only in understanding the carcinogenic process and response to environmental insults, but can also provide critical insights in a systems biological view of tumorigenesis. Research to date has generally focused on how environmental exposures alter genomic DNA methylation content in peripheral blood. More recent work has begun to translate these findings to clinically useful endpoints, by defining the relationship between DNA methylation alterations and cancer risk. This chapter highlights the existing research linking the environment, blood-derived DNA methylation alterations, and cancer risk, and points out how these epigenetic alterations may be contributing fundamentally to carcinogenesis.

Berger E, Vega N, Vidal H, Geloën A
Gene network analysis leads to functional validation of pathways linked to cancer cell growth and survival.
Biotechnol J. 2012; 7(11):1395-404 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) represents one of the most frequently diagnosed human cancers; however, there are currently few treatment alternatives to surgical resection. In this study we performed bioinformatic analysis of previously published transcriptomic data in order to characterize liver specific networks, including biological functions, signaling pathways and transcription factors, potentially dysregulated in HCC. By incorporating specific signaling inhibitors into real-time proliferation assays using HepG2 cells, we then validated these in silico results. We found that G protein subunits Gi/G0, protein kinase C, Mek1/2, and Erk1/2 (P42/44), JAK1, PPARA and NFκB p65 subunit were the major signaling molecules required for survival and proliferation of human HCC cell lines. We also found that these pathways regulate the expression of key hepatic transcription factors involved in cell differentiation, such as CEBPA, EGR1, FOXM1 and PPARs. By combining bioinformatic and functional analyses, major signaling pathways related to tumorigenicity in HCC are revealed, thereby elucidating potential targets for drug therapies.

Liguori G, Cantile M, Cerrone M, et al.
Breast MALT lymphomas: a clinicopathological and cytogenetic study of 9 cases.
Oncol Rep. 2012; 28(4):1211-6 [PubMed] Related Publications
Primary breast mucosa-associated lymphoid tissue (MALT) lymphomas are uncommon and restricted diagnostic criteria should be used to exclude breast involvement by systemic lymphomas. The molecular pathogenesis of primary breast MALT lymphomas is not clear because of the rarity of the disease. Generally the molecular studies of MALT lymphoma in extranodal sites have shown the presence of different chromosomal aberrations, mutually exclusive with substantial differences in their frequency relatively to topographic localization. Few cases of breast MALT lymphomas in the literature have been assessed for MALT lymphoma-associated translocations and BCL10 expression, underlying their rarity in primary breast MALT lymphomas. In our study, we analyzed a series of nine cases of primary breast MALT lymphomas. FISH results showed evidence of MALT1 gene rearrangements in four primary breast lymphomas, in particular three cases with t(11;18)(q21;q21) and one case with t(14;18)(q32;q21). In addition, BCL10 gene rearrangement was not observed. There was no evidence of BCL10 gene translocation in any of the neoplasms assessed. Our data indicate that MALT1 gene rearrangements are not rare in primary breast MALT lymphoma in contrast with results of previous series. Finally, t(11;18) has been observed to be significantly associated with high intensity cytoplasmic BCL10 expression underlying cross-talk between MALT1 and BCL10 pathways in the pathogenesis of MALT lymphomas.

Rossi M, Agostinelli C, Righi S, et al.
BCL10 down-regulation in peripheral T-cell lymphomas.
Hum Pathol. 2012; 43(12):2266-73 [PubMed] Related Publications
The BCL10 gene encodes for a T-cell receptor signaling downstream protein involved in nuclear factor κB activation. It is expressed in normal lymphoid tissues and in several B-non Hodgkin lymphomas, its aberrant function being related to the pathogenesis of certain subtypes. Conversely, conflicting data are available concerning BCL10 expression in peripheral T cell lymphomas. We analyzed BCL10 expression in peripheral T cell lymphomas and correlated it with NFκB activation, proliferation, phenotypic aberration, and survival. First, gene expression analysis of 40 peripheral T cell lymphomas (28 peripheral T cell lymphomas/not otherwise specified, 6 anaplastic large cell lymphomas, and 6 angioimmunoblastic lymphomas), 4 reactive lymph nodes, and 20 samples of normal T-lymphocytes, showed significantly lower BCL10 gene expression in all tumors in comparison to normal samples, the lowest values being detected in anaplastic large cell lymphoma. Secondly, we studied the immunohistochemical expression of BCL10 in 52 peripheral T cell lymphomas/not otherwise specified on tissue microarrays. BCL10 was expressed in 10/52 cases (19%), not showing any significant correlation with either expression of Ki-67 and the T-cell markers or NFκB activation. Furthermore, BCL10 expression was not associated with peculiar gene expression profiles. Finally, we did not find significant correlations with progression free survival and overall survival, although a favorable trend was recorded in BCL10(+) cases. In conclusion, BCL10 was commonly down-regulated in peripheral T cell lymphomas, suggest the T-cell receptor signaling cascade for future characterization.

Chiarini A, Marconi M, Pacchiana R, et al.
Role-shifting PKCζ fosters its own proapoptotic destruction by complexing with Bcl10 at the nuclear envelope of human cervical carcinoma cells: a proteomic and biochemical study.
J Proteome Res. 2012; 11(8):3996-4012 [PubMed] Related Publications
Many features of deadly human cervical cancers (HCCs) still require elucidation. Among HCC-derived cell lines, here we used the C4-I one since its quantitative gene expression pattern most closely mimics invasive HCCs, including protein kinase-Cζ (PKCζ) overexpression. Via proteomic, bioinformatic, and biochemical approaches we identified 31 and 33 proteins co-immunoprecipitating with PKCζ from nuclear membranes (NMs) of, respectively, untreated or VP-16-exposed C4-I cells. Such proteins belonged to eight functional groups, whose compositions and relative sizes changed with either context. Of the 56 proteins identified, only eight were shared between the two subproteomes, including Bcl10. Surprisingly, proteins known to associate with Bcl10, like Carma1/3 and Malt1, in so-called CBM signalosomes were absent. Notably, in VP-16-treated C4-I cells, PKCζ•Bcl10 complexes increasingly accrued at NMs, where PKCζ phosphorylated Bcl10, as PKCζ also did in vitro and in cell-free systems, both processes being thwarted by interfering RNA (iRNA) PKCζ depletion. Caspase-3 was associated with PKCζ•Bcl10 complexes and proteolyzed PKCζ leading to its inactivation/destruction; both events were prevented by Bcl10 iRNA suppression. Thus, PKCζ's molecular interactions and functional roles changed strikingly according to the untreated or apoptogen-treated cells context, and by complexing with Bcl10, PKCζ surprisingly favored its own demise, which suggests both proteins as HCCs therapeutic targets.

Moar-Antelo AR, Pérez-Sayáns M, Suárez-Peñaranda JM, et al.
BCL10 expression is unrelated to clinico-pathological parameters or prognoses for oral squamous cell carcinomas.
Biotech Histochem. 2012; 87(6):423-7 [PubMed] Related Publications
BCL-10 (B-cell lymphoma 10) has been linked to a pro-apoptotic gene in mucosa-associated lymphoid tissue (MALT) lymphomas. We describe the expression of BCL10 in oral squamous cell carcinoma (OSCC) and its relation to clinical, pathological and prognostic parameters. We carried out a retrospective study of 50 patients in Spain who were diagnosed with OSCC. We constructed a tissue microarray of the samples to study the expression of BCL10 using immunohistochemistry. Diffuse and homogeneous staining was observed in the nuclei and cytoplasms of most neoplastic cells of the vast majority of tumors and no significant differences were seen in different areas of the tumors. The expression was unrelated to any clinical or pathological parameters including tumor stage. The intra-class coefficient was 0.97, which indicates the minimal variability among the determinations.

Kirchhofer D, Vucic D
Protease activity of MALT1: a mystery unravelled.
Biochem J. 2012; 444(2):e3-5 [PubMed] Related Publications
Constitutive NF-κB (nuclear factor κB) activation in B-cell lymphomas relies greatly on the CARMA1 [CARD (caspase recruitment domain)-containing MAGUK (membrane-associated guanylate kinase) 1]-Bcl10-MALT1 (mucosa-associated lymphoid tissue translocation gene 1) signalling complex. Within this protein complex, MALT1 possesses a rather unique enzymatic activity, which allows it to cleave Bcl10, RelB and CYLD, among other substrates. The catalytic activity of MALT1 promotes activation of canonical and non-canonical NF-κB as well as other signalling pathways. However, even after a decade of intense research on MALT1, many mechanistic aspects of its enzymatic activity remain elusive. A recent article by Hachmann, Snipas, van Raam, Cancino, Houlihan, Poreba, Kasperkiewicz, Drag and Salvesen [(2012) Biochem. J. 443, 287-295] provides novel insight into the activation mechanism and the substrate specificity of MALT1. These intriguing findings convincingly demonstrate the importance of MALT1 dimerization for its catalytic activity and pave the way for novel therapeutic approaches that target this crucial regulator of lymphoma survival and proliferation.

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