scholarly journals Acetylshikonin Suppresses Diffuse Large B-Cell Lymphoma Cell Growth By Targeting The TOPK Signaling Pathway

Author(s):  
Jieke Cui ◽  
Rong Guo ◽  
Yingjun Wang ◽  
Yue Song ◽  
Xuewen Song ◽  
...  

Abstract Background: Diffuse large B-cell lymphoma (DLBCL) is one of the most common causes of cancer death worldwide, and responds badly to the existing treatment. Thus, identifying the novel therapeutic targets of DLBCL are urgent. Methods and results: In this study, we found that the T-lymphokine-activated killer cell-originated protein kinase (TOPK) was highly expressed in DLBCL cells and tissues. The TOPK expression were analyzed by bioinformatics analysis, immunohistochemistry (IHC) and western blot analysis. TOPK knockdown inhibited cell growth and induced apoptosis of DLBCL cells with MTS and flow cytometry. Further experiments demonstrated that acetylshikonin, the targeted compound of TOPK, could attenuate the cell growth and aggravate the cell apoptosis through TOPK/extra cellular signal-regulated kinase (ERK)-1/2 signaling using MTS, flow cytometry and western blot analysis. In addition, we demonstrated that TOPK overexpression significantly reduced the acetylshikonin effect on cell proliferation and apoptosis in U2932 and OCI-LY8 cells using MTS, flow cytometry and western blot analysis. Conclusions: Taken together, the present study suggests that the targeted inhibition of TOPK by acetylshikonin may be a promising approach to the treatment of DLBCL.

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3653-3653
Author(s):  
Xueling Ge ◽  
Xiao Lv ◽  
Peipei Li ◽  
Xin Wang

Abstract Abstract 3653 Introduction: Diffuse large-B-cell lymphoma (DLBCL) is an aggressive malignancy of mature B lymphocytes with variable biological and cytogenetic features, as well as clinical outcomes. Further investigating specific biomarkers and cellular signaling pathways, understanding molecular pathogenesis of DLBCL and developing more targeted and effective treatments are indispensable for significantly increasing the survival and alleviating the suffering of patients. Metadherin (MTDH) has been demonstrated as a potentially crucial mediator of various types of human malignancies. It promotes tumor progression by modulating multiple oncogenic signaling pathways, such as NF-kB, PI3K/Akt and Wnt/b-catenin pathways. However, the expression and role of MTDH in DLBCL have not been reported yet. This study focuses on illuminating the role of MTDH and the relationship between MTDH and Wnt/b-catenin pathway in the pathogenesis of DLBCL. Methods: Sixteen fresh and thirty araffin-embedded tissues from DLBCL patients were collected. The tissues from patients of reactive hyperplasia of lymph node were used as control group. Peripheral blood mononuclear cells (PBMCs) from healthy volunteers served as normal control compared with human DLBCL cell lines LY1 and LY8. LY1 and LY8 cells were treated with tumor necrosis factor-a(TNF-a,250pg/ml) and cultured for 48 hours to induce the upregulation of MTDH protein. The expressions of MTDH and b-catenin mRNA in DLBCL tissues and controls were determined by quantitative PCR. MTDH and b-catenin protein expressions and localizations were examined by Western-blot analysis and immunohistochemical staining. The impacts of MTDH overexpression induced by TNF-a on LY1 and LY8 cells!&hibar; proliferation and apoptosis were assessed by 3H-TdR incorporation method and flow cytometry. The effects of MTDH upregulation on expression of total b-catenin and its nuclear translocation were analyzed by nuclear protein extraction and Western-blot analysis. Results: A remarkable elevation of MTDH and b-catenin on mRNA level was detected in DLBCL tissues (Figure 1A, P<0.001). The expression of MTDH and b-catenin protein, with b-catenin nuclear localization, was also significantly increased in DLBCL cell lines and DLBCL tissues in comparison to their counterparts (Figure 1B, P<0.001). Immunohistochemical analysis showed high expression of MTDH in 23 of 30(76.67%) paraffin-embedded archival DLBCL specimens (Figure 1C). Statistical analysis suggested that the over expression of MTDH was strongly correlated to the clinical staging of patients with DLBCL (Table 1). The expression of MTDH protein in LY1 and LY8 cells was upregulated after treated with TNF- a(MTDH/b-actin: 0.98\!À0.15 v. 1.18\!À0.18, P<0.05; 0.95\!À0.13 v. 1.19\!À0.19, P<0.05). Furthermore, we determined that the increase of MTDH in DLBCL cells could distinctly enhance cell proliferation and inhibit cell apoptosis (Figure 1D, P<0.05). Upregulation of MTDH elevated the protein level of total b-catenin and translocation of b-catenin to the nucleus (Figure 1E, P<0.05). Conclusion: Our study indicated that MTDH and b-catenin were markedly overexpressed, with b-catenin nuclear localization, in DLBCL. Overexpression of MTDH was correlated with the clinical staging of patients with DLBCL. The effect of MTDH promoting growth and survival of DLBCL cells may be mediated through regulation of Wnt/b-catenin signaling pathway. These results suggest that MTDH contributes to the pathogenesis of DLBCL mediated by activation of Wnt/b-catenin pathway. This novel study may contribute to further investigation on the useful biomarkers and potential therapeutic target in the DLBCL patients. Disclosures: No relevant conflicts of interest to declare.


2016 ◽  
Vol 36 (2) ◽  
pp. 1069-1075 ◽  
Author(s):  
Wenxiu Yang ◽  
Yi Li ◽  
Pinhao Li ◽  
Lingling Wang

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4656-4656
Author(s):  
Fernando Cavallin ◽  
Giovanni Vicario ◽  
Paolo Manente ◽  
Rosa Di Gaetano ◽  
Giuseppe Tagariello

Abstract Diffuse Large B Cell Lymphoma (DLBCL) and Follicular Lymphoma (FL) are the most common adult low-grade non Hodgkin’s lymphomas. The influence of these diseases in peripheral blood lymphocytes is not well defined. Indeed the lymphocytic arrangement can be altered on account of the leukaemic form (although it slightly ever occurs); on the other hand the cause of occasional anomalies can be the involvement of the immune system against neoplasm. In order to contribute to the knowledge of these conditions we have analysed, at diagnosis, the lymphocytic immunophenotype in peripheral blood of 61 subjects: 27 were affected by DLBCL, average age 68, and 34 by FL, average age 61 years. Therefore we quantified the number of lymphocytes and evaluated essential markers, using flow cytometry, to define T, B, NK subsets by: CD3, CD4, CD8, CD19, SIgk, Sigl, CD56, and expression of CD11a molecule on T CD8. The absolute peripheral blood lymphocytes count presented a reduction in 51% and in 32% of the cases with an increase in 4% and in 3% of the subjects respectively considering DLBCL and FL. On the contrary T cells (CD3) had similar decrease, 33% and 32%, and different augmentation 15% and 3%. T cells ratio CD4/CD8 was under normal in 23% and in 12% of the patients but over normal in 12% and 29% always in DLBCL and FL. B cells (CD19) were reduced in 35% and in 12% of the subjects but increased in 8% and in 14%, whereas clonal restriction was present in 8% and in 20% of the components of the two groups. Natural Killer lymphocytes (CD56) were under normal in 12% and in 6% of bthe cases but over in 40% and 20%. Finally CD11a was over-expressed in 87% and in 68% of the patients of the respective pathologies. After selecting patients aged over 60 years, following four parameters that showed a significant variability was obtained: 1) lymphopenia in 50% of the cases in both groups; 2) similar results 11% and 15% about clonal restriction; 3) increase of the NK population 42% and 30% in DLBCL and FL; 4) very high over-expression of CD11a on T CD8 of 90% and 80%. Therefore DLBCL and FL are lymphoproliferative diseases where there is an important subtraction of lymphocytes, particularly in elderly people, from peripheral blood (perhaps because of accumulation in lymphnodes). These lesions present clonal restriction of B cells only in few cases (confirming the low known leukaemic form) while Natural Killer population are well represented especially in DLBCL. The over-expression of CD11a is the most altered parameter and seems almost a typical marker of these diseases above all in over 60 years subjects. Consequently if rarely happens that a leukaemic form of DLBCL and FL are found by flow cytometry however immunological defined alterations are very frequent in most of the cases of old patients.


Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5037-5037
Author(s):  
Sonia González de Villambrosia ◽  
Mercedes Colorado ◽  
Andres Insunza ◽  
Ana Batlle ◽  
Brenda López-Pereira ◽  
...  

Abstract Background: Diffuse large B-cell lymphoma (DLBCL) is a clinically and molecularly heterogeneous disease. We can identify two subgroups with aggressive clinical course and higher risk of treatment failure after standard therapy: B cell lymphoma unclassifiable (BCLU) with features intermediate between DLBCL and Burkitt lymphoma (BL) and B-cell lymphomas with double/triple translocation (DHL/THL). Previous reports suggest that these types of lymphomas may show a common immunophenotype, providing another tool in the challenge of their diagnosis. Objetives: To analyze the immnunophenotype (IF) of BCLU and DH/TH lymphomas by multiparametric flow cytometry and compare it with the IF of a series of cases with DLBCL and BL. Methods: we analyzed the inmunophenotype (four-color flow cytometry on a FACSCalibur flow cytometer) and cytogenetic studies (FISH to detect MYC, BCL2 and/or BCL6 rearrangement) of cases diagnosed of BCLU and DH/TH lymphomas. Control cases of DLBCL and BL were consecutively collected from our database. Fisher`s Exact test was used to compare proportions between two groups. P-values <0.05 were considered statistically significant. Results: We analyzed 23 controls (14 DLBCL and 9 BL) and 17 cases: 9 DHL (8 BCL2/MYC+ and 1 BCL6/MYC+), 3 THL (BCL2/BCL6/MYC+) and 5 BCLU (1 IGH-MYC+, 3 MYC+ and 1 unknown). Six of the 17 cases (35.3%) had decreased expression of CD19 while this was exceptional in DLBCL (1/10 P=0.073) and BL (0/9 P=0.054). All of the cases were positive for CD20 but with different intensities: only 5.9% expressed high CD20 compared to 42.9% of DLBCL (p=0.021) and 55.6% of BL (P=0.010). Most of the cases (12/17) had intermediate expression of CD20 and only 4/17 had weak expression. CD10 expression was typical in BL (100%) and frequent in the cases (82.4%), while it was only present in 20% of DLBCL (P<0.0001). CD38 expression was high in 100% of BL, 6.3% of the cases and none of DLBCL. It was intermediate in 64.7% of the cases and in 35.7% of DLBCL (P=0.015). BCL2 overexpression was detected in 57.1% of the cases; neither DLBCL nor BL (P= 0.009) had BCL2 overexpression. Conclusions: We identify a common immunophenotype in DH/TH lymphomas and BCLU: decreased expression of CD19 and CD20, CD10 expression, overexpression of BCL2 and intermediate expression of CD38. This immuphenotype may be useful for identifying cases for confirmatory cytogenetic studies. Larger studies are needed to validate these results. Disclosures No relevant conflicts of interest to declare.


2009 ◽  
Vol 133 (8) ◽  
pp. 1233-1237 ◽  
Author(s):  
Kirtee Raparia ◽  
Chung-Che(Jeff) Chang ◽  
Patricia Chévez-Barrios

AbstractContext.—Diagnosis and classification of primary intraocular lymphoma can be challenging because of the sparse cellularity of the vitreous specimens.Objective.—To classify and clinically correlate intraocular lymphoma according to the World Health Organization (WHO) classification by using vitrectomy specimens.Design.—Clinical history, cytologic preparations, flow cytometry reports, and outcome of 16 patients diagnosed with intraocular lymphoma were reviewed.Results.—The study group included 10 women and 6 men. The mean age of the patients was 63 years (range, 19–79 years). Eleven patients had central nervous system involvement and 6 patients had systemic involvement. All cases were adequately diagnosed and classified according to the WHO classification by using combination of cytologic preparations and 4-color flow cytometry with a limited panel of antibodies to CD19, CD20, CD5, CD10, and κ and λ light chains. The cases included 9 primary diffuse large B-cell lymphomas of the CNS type; 2 diffuse large B-cell lymphomas, not otherwise specified; 1 extranodal, low-grade, marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT); 1 precursor B-lymphoblastic lymphoma; and 3 peripheral T-cell lymphomas, not otherwise specified. Of note, all 11 cases of diffuse large B-cell lymphoma were CD10−. All the patients received systemic chemotherapy and radiation therapy. Only 4 patients were free of disease at last follow-up (range, 18 months to 8 years), with severe visual loss.Conclusions.—Intraocular lymphoma cases can be adequately classified according to the WHO classification. Diffuse large B-cell lymphoma, CD10− and most likely of non–germinal center B-cell–like subgroup, is the most common subtype of non-Hodgkin lymphoma in this site, in contrast to ocular adnexal lymphoma for which MALT lymphoma is the most common subtype.


2018 ◽  
Vol 98 (2) ◽  
pp. 391-399 ◽  
Author(s):  
Zihang Chen ◽  
Xueqin Deng ◽  
Yunxia Ye ◽  
Limin Gao ◽  
Wenyan Zhang ◽  
...  

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