The regulation of miR-320a/XBP1 axis through LINC00963 for endoplasmic reticulum stress and autophagy in diffuse large B-cell lymphoma

2021 ◽  
Author(s):  
Yuying Cui ◽  
Hui Xu ◽  
Yu Yang ◽  
Dongmei Zhao ◽  
Yu Wen ◽  
...  
Keyword(s):  
B Cell ◽  
Caspase 3 ◽  
Cell Lymphoma ◽  
Xenograft Model ◽  
B Cell Lymphoma ◽  
Growth Delay ◽  
Apoptosis Pathway ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Introduction: Huge amounts of gene-sequencing data have been used to guide fundamental researches. The study combined bioinformatics tools with basic study to analyze the pathological mechanisms of diffuse large B-cell lymphoma. Methods: A LncRNA-miRNA-mRNA ceRNA network of diffuse large B cell lymphoma was constructed by GTEx combined with TCGA database analysis. qPCR was used to detect the expression of LINC00963 and miR-320a in DLBCL cell lines. The proteins levels of UPR sensors, GRP78, p-IRE1α, IRE1α, active ATF6, ATF4 and XBP1, were assessed through Western blot, along with apoptosis markers (Bcl-2, Bax, caspase 3) and autophagy indicators (Beclin1, LC3II, LC3I and p62) after LINC00963 overexpression or miR-320a overexpression in vitro. Additionally, the expression of LC3 was analyzed through immunofluorescence (IF) assay. Results: Evaluation of SUDHL4 cell showed marked up-regulation of key elements of the UPR (GRP78, p-IRE1α, spliced XBP-1(XBP-1(s))), apoptosis (Bax, cleaved caspase 3) and autophagy (Beclin1, LC3II) after LINC00963 overexpression in vitro, whereas miR-320a mimic reversed the effects. Besides, LINC00963 targeted miR-320a while miR-320a bound to the 3’UTR of XBP1. The work also found that LINC00963 overexpression resulted in significant tumor growth delay in a xenograft model of DLBCL. Conclusion: Mechanistically, LINC00963 / miR-320a regulated XBP1-apoptosis pathway and autophagy, making this pathway an attractive therapeutic target for selective targeting. The data presented here are the first to comprehensively survey the mechanism of LINC00963 / miR-320a/XBP1 in DLBCL.

scholarly journals The regulation of miR-320a/XBP1 axis through LINC00963 for endoplasmic reticulum stress and autophagy in diffuse large B-cell lymphoma

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yuying Cui ◽  
Hui Xu ◽  
Yu Yang ◽  
Dongmei Zhao ◽  
Yu Wen ◽  
...  
Keyword(s):  
B Cell ◽  
Caspase 3 ◽  
Therapeutic Potential ◽  
Cell Lymphoma ◽  
Xenograft Model ◽  
B Cell Lymphoma ◽  
Apoptosis Pathway ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Background This study incorporates fundamental research referring to considerable amounts of gene-sequencing data and bioinformatics tools to analyze the pathological mechanisms of diffuse large B-cell lymphoma (DLBCL). Methods A lncRNA-miRNA-mRNA ceRNA network of DLBCL was constructed through database analysis combining GTEx and TCGA. qPCR was used to detect the expression of LINC00963 and miR-320a in DLBCL cell lines. After LINC00963 or miR-320a overexpression in vitro, western blot was performed to assess the protein levels of UPR sensors (GRP78, p-IRE1, IRE1, active ATF6, ATF4 and XBP1), along with apoptosis markers (Bcl-2, Bax, caspase 3) and autophagy indicators (Beclin1, LC3II, LC3I and p62). Additionally, the expression of LC3 was analyzed through immunofluorescence (IF) assay.  Results Following LINC00963 overexpression in vitro, SUDHL4 cell line showed a marked increase in the level of UPR-related GRP78, p-IRE1 and spliced XBP-1/XBP-1(s), apoptosis-related Bax and cleaved caspase 3, as well as autophagy-related Beclin1 and LC3II, whereas miR-320a mimic greatly diminished the effects of LINC00963 overexpression. Moreover, LINC00963 targeted miR-320a while miR-320a bound to the 3’UTR of XBP1. It was also found that LINC00963 overexpression resulted in significantly delayed tumor growth in a xenograft model of DLBCL.  Conclusion Mechanistically, LINC00963/miR-320a regulated XBP1-apoptosis pathway and autophagy, implying the therapeutic potential of this pathway for selective targeting. The data presented here illustrated the mechanism of LINC00963/miR-320a/XBP1 in DLBCL for the first time.

scholarly journals Anti-Cancer Effects of CKD-581, a Potent Histone Deacetylase Inhibitor against Diffuse Large B-Cell Lymphoma

2020 ◽  
Vol 21 (12) ◽  
pp. 4377
Author(s):  
Soo Jin Kim ◽  
U Ji Kim ◽  
Hae Yong Yoo ◽  
Yong June Choi ◽  
Keon Wook Kang
Keyword(s):  
B Cell ◽  
Histone Deacetylase ◽  
Cell Lymphoma ◽  
Hdac Inhibitors ◽  
Xenograft Model ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Mouse Xenograft Model ◽  
Anti Cancer ◽  
Large B Cell

Double-hit lymphoma (DHL) and double-expressor lymphoma (DEL) are aggressive forms of lymphoma that require better treatments to improve patient outcomes. CKD-581 is a new histone deacetylase (HDAC) inhibitor that exhibited a better safety profile in clinical trials compared to other HDAC inhibitors. Here, we demonstrate that CKD-581 inhibited the class I–II HDAC family via histone H3 and tubulin acetylation. CKD-581 treatment also up-regulated the phosphorylation of histone H2AX (γH2AX, DNA double-strand break marker), and reduced levels of MYC and anti-apoptotic proteins such as BCL-2, BCL-6, BCL-XL, and MCL-1 in DH/DE-diffuse large B cell lymphoma (DLBCL) cell lines. Ultimately, CKD-581 also induced apoptosis via poly(ADP ribose) polymerase 1 (PARP1) cleavage. In a DLBCL SCID mouse xenograft model, CKD-581 exhibited anti-cancer effects comparable with those of rituximab (CD20 mAb). Our findings suggest that CKD-581 could be a good candidate for the treatment of DLBCL.

Novel cyclophosphamide of natural products osalmide and pterostilbene induces cytotoxicity and cell cycle arrest in diffuse large B-cell lymphoma cells

2020 ◽  
Vol 52 (4) ◽  
pp. 401-410
Author(s):  
Mengyu Xi ◽  
Wan He ◽  
Bo Li ◽  
Jinfeng Zhou ◽  
Zhijian Xu ◽  
...  
Keyword(s):  
Natural Products ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Underlying Mechanism ◽  
Anticancer Activities ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Diffuse large B-cell lymphoma (DLBCL) is the most common category and disease entity of non-Hodgkin lymphoma. Osalmide and pterostilbene are natural products with anticancer activities via different mechanism. In this study, using a new synthetic strategy for the two natural products, we obtained the compound DCZ0801, which was previously found to have anti-multiple myeloma activity. We performed both in vitro and in vivo assays to investigate its bioactivity and explore its underlying mechanism against DLBCL cells. The results showed that DCZ0801 treatment gave rise to a dose- and time-dependent inhibition of cell viability as determined by CCK-8 assay and flow cytometry assay. Western blot analysis results showed that the expression of caspase-3, caspase-8, caspase-9 and Bax was increased, while BCL-2 and BCL-XL levels were decreased, which suggested that DCZ0801 inhibited cell proliferation and promoted intrinsic apoptosis. In addition, DCZ0801 induced G0/G1 phase arrest by downregulating the protein expression levels of CDK4, CDK6 and cyclin D1. Furthermore, DCZ0801 exerted an anti-tumor effect by down-regulating the expressions of p-PI3K and p-AKT. There also existed a trend that the expression of p-JNK and p-P38 was restrained. Intraperitoneal injection of DCZ0801 suppressed tumor development in xenograft mouse models. The preliminary metabolic study showed that DCZ0801 displayed a rapid metabolism within 30 min. These results demonstrated that DCZ0801 may be a new potential anti-DLBCL agent in DLBCL therapy.

scholarly journals Repurposing dasatinib for diffuse large B cell lymphoma

2019 ◽  
Vol 116 (34) ◽  
pp. 16981-16986 ◽  
Author(s):  
Claudio Scuoppo ◽  
Jiguang Wang ◽  
Mirjana Persaud ◽  
Sandeep K. Mittan ◽  
Katia Basso ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
Kinase Inhibitor ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Multikinase Inhibitor ◽  
Large B Cell Lymphoma ◽  
Large B Cell

To repurpose compounds for diffuse large B cell lymphoma (DLBCL), we screened a library of drugs and other targeted compounds approved by the US Food and Drug Administration on 9 cell lines and validated the results on a panel of 32 genetically characterized DLBCL cell lines. Dasatinib, a multikinase inhibitor, was effective against 50% of DLBCL cell lines, as well as against in vivo xenografts. Dasatinib was more broadly active than the Bruton kinase inhibitor ibrutinib and overcame ibrutinib resistance. Tumors exhibiting dasatinib resistance were commonly characterized by activation of the PI3K pathway and loss of PTEN expression as a specific biomarker. PI3K suppression by mTORC2 inhibition synergized with dasatinib and abolished resistance in vitro and in vivo. These results provide a proof of concept for the repurposing approach in DLBCL, and point to dasatinib as an attractive strategy for further clinical development in lymphomas.

Loss of IRF8 Inhibits the Growth of Diffuse Large B-Cell Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3004-3004
Author(s):  
Yulian Xu ◽  
Lei Jiang ◽  
Rachel R. Fang ◽  
Jeff Xiwu Zhou ◽  
Herbert Morse
Keyword(s):  
Cell Proliferation ◽  
B Cell ◽  
Cell Lymphoma ◽  
Critical Role ◽  
B Cell Lymphoma ◽  
Expression Levels ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract IRF8 is a transcription factor with a critical role in B lymphocyte development and biological functions. Although it has been reported that IRF8 is highly expressed in human diffuse large B-cell lymphoma (DLBCL) and the translocation of IRF8-IgH loci occurs in DLBCL, little information is available regarding the function and mechanisms for the role of IRF8 in DLBCL. In this study, by using several human DLBCL cell lines with shRNA-mediated decrease in IRF8 expression levels, we found that the loss of IRF8 significantly reduced the proliferation of lymphoma cells (Figure 1). Mechanistically, decreasing the levels of IRF8 led to a decrease in p38 and ERK phosphorylation (Figure 2), molecular events critical for B cell proliferation. Furthermore, using a xenograft lymphoma mice model, we found that the loss of IRF8 significantly inhibited the growth of lymphomas in vivo (n=5 for each group) (Figure 3). Analysis of public available data also suggested that the expression levels of IRF8 mRNA in human DLBCL tissues were inversely correlated patientsÕ overall survival time. Taken together, this study showed that IRF8 may play an oncogenic role in human DLBCL by promoting cell proliferation. Figure 1. Loss of IRF8 decreased the proliferation of DLBCL cells in vitro. Figure 1. Loss of IRF8 decreased the proliferation of DLBCL cells in vitro. Figure 2. Loss of IRF8 decreased the phosphorylation of p38 and ERK in DLBCL cells. Figure 2. Loss of IRF8 decreased the phosphorylation of p38 and ERK in DLBCL cells. Figure 3. Loss of IRF8 decreased the growth of DLBCL in vivo. Figure 3. Loss of IRF8 decreased the growth of DLBCL in vivo. Disclosures No relevant conflicts of interest to declare.

Prognostic implications of caspase-3 expression in patients with diffuse large B-cell lymphoma (DLBCL)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 17500-17500 ◽  
Author(s):  
W. H. Elsawy ◽  
M. Abdel Kader ◽  
A. Elfar ◽  
A. Gharib ◽  
S. Eltrhony ◽  
...  
Keyword(s):  
B Cell ◽  
Tumor Cells ◽  
Poor Prognosis ◽  
Caspase 3 ◽  
Cell Lymphoma ◽  
International Prognostic Index ◽  
B Cell Lymphoma ◽  
Serum Lactate Dehydrogenase ◽  
Large B Cell Lymphoma ◽  
Large B Cell

17500 Background: Caspase-3 activation is an essential step in programmed cell death (apoptosis) and cytotoxic drug-induced apoptosis is mediated by caspase-2 and caspase-3. The following study was designed to evaluate the correlation between Caspase-3 and the clinical outcome in patients with diffuse large B-cell lymphoma. Methods: Caspase-3 was determined by both immunohistochemistry and by quantitative reverse-transcription PCR in 49 previously untreated patients with diffuse large B-cell lymphoma. Results: Caspase-3 was positive in 69.4% of the patients by immunostaining and Tumor cells displayed a diffuse cytosolic expression in 51% of patients. The median value of Caspase-3mRNA within the group by quantitative PCR was 1. Caspase-3mRNA level was μ1 in 28 patients and <1 in 21 patients. Caspase-3 expression was associated with higher tumor stage (P = 0.03), elevated serum lactate dehydrogenase levels (P = 0.02), and the International Prognostic Index (P = 0.0001). Patients with Caspase-3-positive immunostaining had a significantly higher complete response rate to chemotherapy and a longer overall survival than Caspase-3-negative patients. Also, patients with tumor cells expressing diffuse cytosolic immunostaining for caspase-3 had a poor prognosis when compared with those expressing a punctate staining (P > 0.0004 log-rank). A low caspase-3 mRNA expression by quantitative RT-PCR was also associated with a poor prognosis, although this was not statistically significant. In addition, patients with a high TUNEL positivity had a low survival probability (P > 0.02). Conclusions: Our results suggest that Caspase-3 activation or its lack may be a powerful independent predictor of response and survival in previously untreated diffuse large B-cell lymphomas. No significant financial relationships to disclose.

scholarly journals Identification of PLA2G7 as a novel biomarker of diffuse large B cell lymphoma

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Weili Zheng ◽  
Qiaochu Lin ◽  
Mohammed Awal Issah ◽  
Ziyuan Liao ◽  
Jianzhen Shen
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Specific Inhibitor ◽  
B Cell Lymphoma ◽  
Clinical Samples ◽  
Cancer Type ◽  
Dlbcl Patient ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Background Diffuse large B-cell lymphoma is the most common form of non-Hodgkin lymphoma globally, and patients with relapsed or refractory DLBCL typically experience poor long-term outcomes. Methods Differentially expressed genes associated with DLBCL were identified using two GEO datasets in an effort to detect novel diagnostic or prognostic biomarkers of this cancer type, after which receiver operating characteristic curve analyses were conducted. Genes associated with DLBCL patient prognosis were additionally identified via WCGNA analyses of the TCGA database. The expression of PLA2G7 in DLBCL patient clinical samples was further assessed, and the functional role of this gene in DLBCL was assessed through in vitro and bioinformatics analyses. Results DLBCL-related DEGs were found to be most closely associated with immune responses, cell proliferation, and angiogenesis. WCGNA analyses revealed that PLA2G7 exhibited prognostic value in DLBCL patients, and the upregulation of this gene in DLBCL patient samples was subsequently validated. PLA2G7 was also found to be closely linked to tumor microenvironmental composition such that DLBCL patients expressing higher levels of this gene exhibited high local monocyte and gamma delta T cell levels. In vitro experiments also revealed that knocking down PLA2G7 expression was sufficient to impair the migration and proliferation of DLBCL cells while promoting their apoptotic death. Furthmore, the specific inhibitor of PLA2G7, darapladib, could noticeably restrained the DLBCL cell viability and induced apoptosis. Conclusions PLA2G7 may represent an important diagnostic, prognostic, or therapeutic biomarker in patients with DLBCL.

Sign in / Sign up

Export Citation Format

Share Document