Lactate dehydrogenase A is implicated in the pathogenesis of B-cell lymphoma through regulation of the FER signaling pathway.

Lactate dehydrogenase A (LDHA) is highly expressed in various tumors. However, the role of LDHA in the pathogenesis of B-cell lymphoma remains unclear. Analysis of data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases revealed an elevated LDHA expression in diffuse large B-cell lymphoma (DLBC) tissues compared with normal tissues. Similarly, our results demonstrated a significant increase in LDHA expression in tumor tissues from the patients with B-cell lymphoma compared with those with lymphadenitis. To further elucidate potential roles of LDHA in B-cell lymphoma pathogenesis, we silenced LDHA in the Raji cells (a B-cell lymphoma cell line) using shRNA techniques. Silencing LDHA led to reduced mitochondrial membrane integrity, adenosine triphosphate (ATP) production, glycolytic activity, cell viability and invasion. Notably, LDHA knockdown substantially suppressed in vivo growth of Raji cells and extended survival in mice bearing lymphoma (Raji cells). Moreover, proteomic analysis identified feline sarcoma-related protein (FER) as a differential protein positively associated with LDHA expression. Treatment with E260, a FER inhibitor, significantly reduced the metabolism, proliferation and invasion of Raji cells. In summary, our findings highlight that LDHA plays multiple roles in B-cell lymphoma pathogenesis via FER pathways, establishing LDHA/FER may as a potential therapeutic target.

Circ-SMARCA5 suppresses progression of multiple myeloma by targeting miR-767-5p.

BACKGROUND: We aimed to investigate the correlation of Circ-SMARCA5 with disease severity and prognosis in multiple myeloma (MM), and its underlying mechanisms in regulating cell proliferation and apoptosis. METHODS: Bone marrow samples from 105 MM patients and 36 healthy controls were collected for Circ-SMARCA5 expression measurement. And the correlation of Circ-SMARCA5 expression with patients' characteristics and survival was determined. In vitro, the effect of Circ-SMARCA5 on MM cell proliferation and apoptosis was evaluated by altering Circ-SMARCA5 expression through transfection. Rescue experiments and luciferase assay were further performed to explore the mechanism of Circ-SMARCA5 as well as its potential target miR-767-5p in regulating MM cell activity. RESULTS: Circ-AMARCA5 was downregulated in MM and presented a good value in distinguishing MM patients from controls and it was also negatively correlated with Beta-2-microglobulin (ß2-MG) level and International Staging System (ISS) stage. Additionally, Circ-SMARCA5 high expression was associated with higher CR as well as better PFS and OS. As for in vitro experiments, Circ-SMARCA5 expression was lower in MM cell lines compared with normal cells, and Circ-SMARCA5 overexpression inhibited cell proliferation but promoted cell apoptosis in RPMI8226 cells. Rescue experiments disclosed that the effect of Circ-SMARCA5 on cell activity was attenuated by miR-767-5p, and luciferase reporter assay revealed direct binding between Circ-SMARCA5 and miR-767-5p. CONCLUSIONS: Circ-SMARCA5 is downregulated and correlated with lower ß2-MG level and ISS stage as well as better prognosis in MM patients, and it inhibits proliferation but promotes apoptosis of MM cells via directly sponging miR-767-5p.

IL-17A Increases Multiple Myeloma Cell Viability by Positively Regulating Syk Expression.

PURPOSE: Elevated IL-17 produced by Th17 cells was reported to promote myeloma cell growth and inhibit immune function in multiple myeloma (MM). IL-17A was also reported to promote MM growth through IL-17 receptors and enhance adhesion to bone marrow stromal cells (BMSCs). Spleen tyrosine kinase (Syk) influences MM cell survival and migration. Herein we aimed to investigate whether Syk was involved in the regulative role of IL-17A in the viability of MM cells. METHODS: Cell viability was determined using CCK8 assay. The production of cytokine including IL-17A was evaluated with ELISA. Western blotting assay was used to determine protein expression levels of Syk and nuclear factor κB (NF-κB) related molecules. mRNA expression level of RORγt was detected with reverse transcription quantitative polymerase chain reaction. RESULTS: IL-17Awas highly expressed in MM patients and was able to induce MM cell viability. Following analysis indicated that the effects of IL-17A were mediated by Syk/ nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway. Immunoprecipitation also indicated that Syk is involved in IL-17A-induced Act1-TRAF6 complex formation and TRAF6 polyubiquitination in MM cells. CONCLUSIONS: Taken together, our study indicated that IL-17A increases MM cell viability through activating NF-κB signal pathway via positively regulating Syk expression. Syk also participates in the formation of IL-17R-proximal signaling complex (IL-17R-Act1-TRAF6), which is essential for IL-17A-mediated NF-kB activation. These investigations highlight that inhibition of Syk may be a potential therapeutic option for neoplastic diseases such as MM.