Search

Turk J. Biol. 44, (1), 1-14. 10.3906/biy-1908-23 3 Fuertes, T., Ramiro, A. R., de Yebenes, V. G., (2020). miRNA-Based Therapies in B Cell Non-hodgkin Lymphoma. Keywords: B lymphoma; tumor microenvironment; NHL - Non-Hodgkin lymphomas; immune cells; Epigenetic alteration EN B lymphoma tumor microenvironment NHL - Non-Hodgkin lymphomas immune cells Epigenetic alteration 1 3 3 05/23/22 20220519 NES 220519 Non-Hodgkin B Lymphoma (B-NHL) is the seventh most common cancer of the lymphatic system. B lymphoma, tumor microenvironment, NHL - Non-Hodgkin lymphomas, immune cells, Epigenetic alteration Genetic Alterations in B Cell Lymphoma Subtypes as Potential Biomarkers for Noninvasive Diagnosis, Prognosis, Therapy, and Disease Monitoring. [Extracted from the article]

High plasma lactate is associated with poor prognosis of many malignancies, but its role in virally mediated cancer progression and underlying molecular mechanisms are unclear. Epstein-Barr virus (EBV), the first human oncogenic virus, causes several cancers, including B-cell lymphoma. Here, we report that lactate dehydrogenase A (LDH-A) expression and lactate production are elevated in EBV-immortalized B lymphoblastic cells, and lactic acid (LA; acidic lactate) at low concentration triggers EBV-infected B-cell adhesion, morphological changes and proliferation in vitro and in vivo. Moreover, LA-induced responses of EBV-infected B cells uniquely occurs in viral latency type III, and it is dramatically associated with the inhibition of global viral microRNAs, particularly the miR-BHRF1 cluster, and the high expression of SMAD3, JUN, and COL1A genes. The introduction of miR-BHRF1-1 blocks the LA-induced effects of EBV-infected B cells. Thus, this may be a novel mechanism to explain EBV-immortalized B lymphoblastic cell malignancy in an LA microenvironment. IMPORTANCE The tumor microenvironment is complicated, and lactate, which is created by cell metabolism, contributes to an acidic microenvironment that facilitates cancer progression. However, how LA operates in virus-associated cancers is unclear. Thus, we studied how EBV (the first tumor virus identified in humans; it is associated with many cancers) upregulates the expression of LDH-A and lactate production in B lymphoma cells. Elevated LA induces adhesion and the growth of EBVinfected B cells by inhibiting viral microRNA transcription. Thus, we offer a novel understanding of how EBV utilizes an acidic microenvironment to promote cancer development. [ABSTRACT FROM AUTHOR]

Background Identification of novel genetic risk factors is imperative for a better understanding of B lymphomagenesis and for the development of novel therapeutic strategies. TRAF3, a critical regulator of B cell survival, was recently recognized as a tumor suppressor gene in B lymphocytes. The present study aimed to identify novel oncogenes involved in malignant transformation of TRAF3-deficient B cells. Methods We used microarray analysis to identify genes differentially expressed in TRAF3-/- mouse splenic B lymphomas. We employed lentiviral vector-mediated knockdown or overexpression to manipulate gene expression in human multiple myeloma (MM) cell lines. We analyzed cell apoptosis and proliferation using flow cytometry, and performed biochemical studies to investigate signaling mechanisms. To delineate protein-protein interactions, we applied affinity purification followed by mass spectrometry-based sequencing. Results We identified mutated in colorectal cancer (MCC) as a gene strikingly up-regulated in TRAF3-deficient mouse B lymphomas and human MM cell lines. Aberrant up-regulation of MCC also occurs in a variety of primary human B cell malignancies, including non-Hodgkin lymphoma (NHL) and MM. In contrast, MCC expression was not detected in normal or premalignant TRAF3-/- B cells even after treatment with B cell stimuli, suggesting that aberrant up-regulation of MCC is specifically associated with malignant transformation of B cells. In elucidating the functional roles of MCC in malignant B cells, we found that lentiviral shRNA vector-mediated knockdown of MCC induced apoptosis and inhibited proliferation in human MM cells. Experiments of knockdown and overexpression of MCC allowed us to identify several downstream targets of MCC in human MM cells, including phospho-ERK, c- Myc, p27, cyclin B1, Mcl-1, caspases 8 and 3. Furthermore, we identified 365 proteins (including 326 novel MCC-interactors) in the MCC interactome, among which PARP1 and PHB2 were two hubs of MCC signaling pathways in human MM cells. Conclusions Our results indicate that in sharp contrast to its tumor suppressive role in colorectal cancer, MCC functions as an oncogene in B cells. Our findings suggest that MCC may serve as a diagnostic marker and therapeutic target in B cell malignancies, including NHL and MM. [ABSTRACT FROM AUTHOR]

Elevated expression of the antiapoptotic protein Bfl-1 (A1) was previously reported in several cancer cell lines. Recently, molecular profiling of large B-cell lymphoma identified Bfl-1 as a gene signature in ‘OxPhos’ diffuse large B-cell lymphoma subtype and in primary mediastinal large B-cell lymphoma, suggesting that in addition to Bcl-2, Bcl-xL and Mcl-1, Bfl-1 may be a relevant target in the design of new strategies for cancer therapy. Using short hairpin RNA strategy, we show here that Bfl-1 silencing in one lymphoblastoid B-cell line and in two diffuse large B-cell lymphoma cell lines potently induces their apoptosis and sensitizes those cell lines to anti-CD20 (Rituximab)-mediated cell death as well as to apoptosis induced by chemotherapeutic molecules such as doxorubicin, vincristine, cisplatin and fludarabine. These results demonstrate for the first time that Bfl-1 is an essential protein for survival of malignant B cells and suggest Bfl-1 may represent a potential target for future drug development against B cell lymphoma.Oncogene (2007) 26, 5828–5832; doi:10.1038/sj.onc.1210363; published online 12 March 2007 [ABSTRACT FROM AUTHOR]

The protein levels of β-catenin are tightly regulated by the ubiquitin/proteasome system. We provide evidence that two distinct ubiquitin-dependent degradation pathways for β-catenin are active in the same Burkitt's lymphoma cells: Along with the classical glycogen-synthase kinase 3β-dependent destruction machinery, degradation of β-catenin through seven in absentia homolog 1 (Siah-1) ubiquitin ligase is functional in these cells. We show that inhibition of endogenous Siah-1 stabilizes and activates β-catenin in B cells. The principal Epstein-Barr virus oncoprotein, latent membrane protein 1, is involved in β-catenin up-regulation, and expression of latent membrane protein 1 in B lymphoma cells is associated with decreased Siah-1 RNA and protein levels. Thus, we demonstrate the significance of the endogenous Siah-1-dependent ubiquitin/proteasome pathway for β-catenin degradation in malignant human cells and its regulation by a viral oncogene. [ABSTRACT FROM AUTHOR]

Abstract: The B cell antigen receptor (BCR) composed of the ligand-binding membrane IgM (mIgM) and the signaling component, Ig-α/β, is known to inducibly associate with membrane microdomains rich in cholesterol and sphingolipids, termed lipid rafts. In this study we tested whether the Ig-α/β portion of the BCR has targeting information that allows it to be localized in lipid rafts. In order to do this, we cross-linked the Ig-α/β on the cell surface of the variant B cell line, WEHI 303.1.5, a derivative of the immature murine B cell line WEHI 231 that lacks μ heavy chain and expresses the Ig-α/β on the cell surface by itself. Using two methods to isolate detergent-insoluble, lipid raft-like fractions, we found that Ig-α/β without accompanying mIgM was constitutively located in these raft-like fractions and that the amount was marginally increased after Ig-α/β cross-linking. These results suggest that the Ig-α/β portion of the BCR has the ability to be compartmentalized into raft-like membrane domains even when not associated with mIgM and perhaps this targeting information is normally regulated by the presence of the mIgM portion of the receptor. [Copyright &y& Elsevier]