scholarly journals The ubiquitin ligase HERC4 mediates c-Maf ubiquitination and delays the growth of multiple myeloma xenografts in nude mice

Blood ◽  
2016 ◽  
Vol 127 (13) ◽  
pp. 1676-1686 ◽  
Author(s):  
Zubin Zhang ◽  
Jiefei Tong ◽  
Xiaowen Tang ◽  
Jiaxiang Juan ◽  
Biyin Cao ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Ubiquitin Ligase ◽  
Nude Mice ◽  
Key Points

Key Points HERC4 is the first identified ubiquitin ligase that mediates c-Maf ubiquitination and degradation. HERC4 suppresses MM cell proliferation and delays MM tumor growth.

LncRNA SNHG14 Promotes Progression of Ovarian Cancer by Regulating miR-206 Expression

2021 ◽  
Vol 7 (5) ◽  
pp. 3997-4004
Author(s):  
Zhibo Zou ◽  
Lin Peng
Keyword(s):  
Ovarian Cancer ◽  
Flow Cytometry ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Cancer Progression ◽  
Nude Mice ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Qrt Pcr ◽  
Research Objects

Objective: This study aimed to probe into the effect of LncRNA SNHG14 on ovarian cancer progression by regulating miR-206.Methods: Fifty-seven ovarian cancer (OC) patients who were treated in our hospital from December 2017 to December 2019 were collected as the research objects. During the operation, OC tissues and paracancerous tissues of patients were collected, and the effect of SNHG14 on OC tumor growth in nude mice was detected, and SNHG14 inhibitor was transfected into OC cells. The relative expression of SNHG14 in tissues and cells was detected by qRT-PCR, cell proliferation was testedvia CCK8, migration and invasion were detected through Transwell, apoptosis was assessedvia flow cytometry, and the targeted relationship between SNHG14 and miR-206 was detected by dual luciferase reporter gene.Results: SNHG14 is highly expressed in OC tissues, cells and nude mice. Down-regulating it can inhibit the biological ability of OC cells and inhibit the growth of nude mice tumors. It can directly target miR-206 to regulate CCND1 expression and promote OC progression.Conclusion: LncRNA SNHG14 can act as miR-206 sponge to regulate CCND1 expression downstream of miR-206 and promote OC progression.

LncRNA NCRNA00173 is down-regulated in pediatric osteosarcoma and suppresses cell metastasis of osteosarcoma cells through regulating PI3k/Akt pathway

2019 ◽  
Author(s):  
Zhongquan Zhao ◽  
Jiechao Chen ◽  
Dezhi Xia
Keyword(s):  
Cell Proliferation ◽  
Protein Expression ◽  
Tumor Growth ◽  
Nude Mice ◽  
Akt Pathway ◽  
Migration And Invasion ◽  
Kaplan Meier ◽  
Disability Rate ◽  
Cell Metastasis ◽  
The Impact

Abstract Background: Osteosarcoma (OS) is a primary malignant tumor with high mortality and disability rate in childhood and adolescent, whereas the influence of LncRNA00173 (NCRNA00173) on pediatric OS progression is not obvious yet. Therefore, this study aimed to investigate the expression of NCRNA00173 in pediatric OS and its effect on OS progression. Methods: In our study, qRT-PCR was adopted to test the NCRNA00173 expression in 40 pairs of pediatric OS tissues and OS cell lines. Kaplan-Meier method and Cox proportional hazard model were performed to analyze the prognosis of pediatric OS patients. The cell proliferation, apoptosis, migration and invasion of U2OS and HOS cells were test by MTT assay, flow cytometry, wound-healing, and transwell assay, respectively. The protein expression levels of PI3K/Akt pathway were measured by western blot. In addition, tumor growth in nude mice was also detected. Results: The expression of NCRNA00173 was down-regulated and relevant with poor prognosis in pediatric OS. Overexpression of NCRNA00713 inhibited cell proliferation, migration and invasion, as well as accelerated cell apoptosis in U2OS and HOS cells. Overexpression of NCRNA00713 suppressed tumor growth in nude mice. The protein expression of p-PI3K and p-Akt were remarkedly decreased in U2OS and HOS cells after transfection with NCRNA00173. In addition, 740 Y-P (PI3K/Akt pathway activator) eliminated the impact of NCRNA00173 in HOS. Conclusions: NCRNA00173 was down-regulated in pediatric OS and suppressed metastasis of OS cells by regulating PI3k/Akt pathway.

scholarly journals KDM2A Targets PFKFB3 for Ubiquitylation to Inhibit the Proliferation and Angiogenesis of Multiple Myeloma Cells

2021 ◽  
Vol 11 ◽  
Author(s):  
Xinling Liu ◽  
Jiaqiu Li ◽  
Zhanju Wang ◽  
Jie Meng ◽  
Aihong Wang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Proliferation ◽  
Ubiquitin Ligase ◽  
Biological Processes ◽  
Potential Mechanism ◽  
Histone Demethylation ◽  
Ubiquitin Ligase Activity ◽  
Lysine Demethylase ◽  
Worse Prognosis ◽  
Demethylation Activity

The lysine demethylase KDM2A (also known as JHDM1A or FBXL11) demethylates histone H3 at lysine K36 which lead to epigenetic regulation of cell proliferation and tumorigenesis. However, many biological processes are mediated by KDM2A independently by its histone demethylation activity. In the present study, we aimed to characterize the functional significance of KDM2A in multiple myeloma (MM) disease progression. Specifically, we defined that one of the key enzymes of glycolysis PFKFB3 (6-phosphofructo-2-kinase) is ubiquitylated by KDM2A which suppresses MM cell proliferation. Previous study showed that KDM2A and PFKFB3 promoted angiogenesis in various tumor cells. We further reveal that KDM2A targets PFKFB3 for ubiquitination and degradation to inhibit angiogenesis. Several angiogenic cytokines are also downregulated in MM. Clinically, MM patients with low KDM2A and high PFKFB3 levels have shown worse prognosis. These results reveal a novel function of KDM2A through ubiquitin ligase activity by targeting PFKFB3 to induce proliferation, glycolysis and angiogenesis in MM cells. The data provides a new potential mechanism and strategy for MM treatment.

scholarly journals Hsa_Circular RNA_0001013 Exerts Oncogenice Effects in Gastric Cancer Via the microRNA-136/TWSG1 Axis

2022 ◽  
Author(s):  
Zhaofeng Gao ◽  
Lingyu Hu ◽  
Fei Chen ◽  
Chunhua He ◽  
Biwen Hu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Microarray Analysis ◽  
Nude Mice ◽  
Critical Role ◽  
Luciferase Reporter ◽  
Clinical Samples ◽  
Circular Rnas

Abstract Background：Gastric cancer (GC) is one of the most principle malignant cancers in the digestive system. Moreover, the critical role of circular RNAs (circRNAs) has been identified in GC development. Methods：In this context, the purpose of research was to explore the regulatory mechanism circ_0001013, a novel circRNAs predicted by our research, in GC. The differential circRNAs and related mechanism in GC were predicted by microarray analysis. Circ_0001013, miR-136, and TWSG1 expression in GC clinical samples and cells was detected by RT-qPCR. The relationship among circ_0001013, miR-136, and TWSG was assessed by dual-luciferase reporter assay, biotin coupled probe pull-down assay, and biotin coupled miRNA capture. After gain- and loss-of-function assays in GC cells, cell proliferation, migration, invasion, and cell cycle and apoptosis were measured by EdU assay, scratch test, Transwell assay, and flow cytometry respectively. The effect of circ_0001013 on tumor growth was detected by xenograft tumor in nude mice. Results ：Microarray analysis predicted a novel circRNA, circ_0001013, was upregulated in GC, which was confirmed by RT-qPCR detection in GC tissues and cells. Besides, miR-136 was downregulated but TWSG1 was highly expressed in GC tissues. Mechanically, circ_0001013 could bind to miR-136, and miR-136 negatively targeted TWSG1 in GC cells. Silencing circ_0001013 or TWSG1 or overexpressing miR-136 decreased GC cell proliferation, migration, invasion, and cell cycle arrest and accelerated cell apoptosis. Circ_0001013 silencing decreased TWSG1 expression and inhibited transplanted tumor growth in nude mice. Conclusion：Circ_0001013 elevated TWSG1 expression by binding to miR-136, thereby exerting oncogenic effect in GC.

scholarly journals Hsa_Circular RNA_0001013 Exerts Oncogenice Effects in Gastric Cancer via the MicroRNA-136/TWSG1 Axis

2021 ◽  
Author(s):  
Zhaofeng Gao ◽  
Lingyu Hu ◽  
Fei Chen ◽  
Chunhua He ◽  
Biwen Hu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Microarray Analysis ◽  
Nude Mice ◽  
Critical Role ◽  
Luciferase Reporter ◽  
Clinical Samples ◽  
Circular Rnas

Abstract Background：Gastric cancer (GC) is one of the most principle malignant cancers in the digestive system. Moreover, the critical role of circular RNAs (circRNAs) has been identified in GC development. Methods：In this context, the purpose of research was to explore the regulatory mechanism circ_0001013, a novel circRNAs predicted by our research, in GC. The differential circRNAs and related mechanism in GC were predicted by microarray analysis. Circ_0001013, miR-136, and TWSG1 expression in GC clinical samples and cells was detected by RT-qPCR. The relationship among circ_0001013, miR-136, and TWSG was assessed by dual-luciferase reporter assay, biotin coupled probe pull-down assay, and biotin coupled miRNA capture. After gain- and loss-of-function assays in GC cells, cell proliferation, migration, invasion, and cell cycle and apoptosis were measured by EdU assay, scratch test, Transwell assay, and flow cytometry respectively. The effect of circ_0001013 on tumor growth was detected by xenograft tumor in nude mice. Results ：Microarray analysis predicted a novel circRNA, circ_0001013, was upregulated in GC, which was confirmed by RT-qPCR detection in GC tissues and cells. Besides, miR-136 was downregulated but TWSG1 was highly expressed in GC tissues. Mechanically, circ_0001013 could bind to miR-136, and miR-136 negatively targeted TWSG1 in GC cells. Silencing circ_0001013 or TWSG1 or overexpressing miR-136 decreased GC cell proliferation, migration, invasion, and cell cycle arrest and accelerated cell apoptosis. Circ_0001013 silencing decreased TWSG1 expression and inhibited transplanted tumor growth in nude mice. Conclusion：Circ_0001013 elevated TWSG1 expression by binding to miR-136, thereby exerting oncogenic effect in GC.

scholarly journals Functional role and therapeutic targeting of p21-activated kinase 4 in multiple myeloma

Blood ◽  
2017 ◽  
Vol 129 (16) ◽  
pp. 2233-2245 ◽  
Author(s):  
Mariateresa Fulciniti ◽  
Joaquin Martinez-Lopez ◽  
William Senapedis ◽  
Stefania Oliva ◽  
Rajya Lakshmi Bandi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Proliferation ◽  
Functional Role ◽  
Myeloma Cell ◽  
Therapeutic Targeting ◽  
Growth And Survival ◽  
Survival Pathways ◽  
Molecule Inhibitor ◽  
Key Points ◽  
P21 Activated Kinase

Key Points High expression of PAK4 promotes myeloma cell proliferation through activation of MM antiapoptotic and survival pathways. Targeting PAK4 with a novel small molecule inhibitor, KPT-9274, has significant impact on MM cell growth and survival.

Platelet Factor 4 Potently Inhibits Tumor Cell Growth and Angiogenesis In Multiple Myeloma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4173-4173
Author(s):  
Pei Liang ◽  
Suk-Hang Cheng ◽  
Chi-Keung Cheng ◽  
Kin-Mang Lau ◽  
Natalie Pui Ha Chan ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Proliferation ◽  
Endothelial Cells ◽  
Survival Rate ◽  
Cell Growth ◽  
Tumor Growth ◽  
Platelet Factor ◽  
Rabbit Bone

Abstract Abstract 4173 Multiple myeloma (MM) is a B-cell derived plasma cell malignancy characterized by accumulation of clonal plasma cells in bone marrow (BM). Platelet factor 4 (PF4), a potent antiangiogenic chemokine, not only inhibits endothelial cell proliferation and migration in vitro but also inhibits solid tumor growth in vivo. Our group previously demonstrated loss of PF4 expression in patient multiple myeloma (MM) samples and MM cell lines. Here, we characterized the effects of PF4 on both MM cells and endothelial cells in the BM milieu. We found that PF4 inhibits cell growth in MM cell lines (U266 and NCI-H929) with an IC50 4μM at 96 hours by the WST-1 assay. Cell apoptosis by Annexin V-7 AAD staining showed that percentages of apoptotic cells increased from 15.6% to 16.5%, 23.6% and 39.2% for U266 cells and from 19.8% to 20.1%. 26.8% and 71.0% for NCI-H929 cells when incubated with 2, 4, and 8μM PF4, respectively. PF4 also has direct effects on endothelial cells isolated from patient's BM aspirates (MMECs). Our results showed that PF4 suppresses MMECs proliferation (IC50 8μM) and capillary-like tube formation on matrigel in a dose-dependent manner. It is known that BM endothelial cells promote MM cell growth, survival, and drug resistance in BM microenvironment. Therefore, we further examined whether the proliferation of MM cell is influenced by the presence of endothelial cells. U266 cells were cultured for 96 hours with or without MMECs, in the presence or absence of PF4. We found that adhesion of MM cell to MMECs up regulates cell proliferation (about 1.5 fold), which is markedly inhibited by PF4 (>4uM). Given the ability of PF4 to suppress MM cell growth and angiogenesis in vitro, we evaluated its tumor suppressive function in vivo. In SCID-rab mouse model, 1× 106 U266 MM cells were directly injected into the rabbit bone which was subcutaneously implanted into the NOD-SCID mice. Two weeks after injection, SCID mice were treated with various dose of PF4 (20 or 200 ng per injection, three times per week) or vehicle control by tail vein injection. ELISA assay with hIg (Lambda) showed that tumor growth in PF4-treated mice is markedly reduced by 2.5 fold compared with the control group, which is further confirmed by immunohistochemistry analysis of CD138 staining on rabbit bone section. Consistent with the in vitro results, MM cells' proliferation and angiogenesis are also significantly inhibited by PF4 in vivo, as evidenced by ki67 and CD31 staining on rabbit bone sections from treated versus control mice. Moreover, PF4 improves the survival rate of mice. The survival rate of PBS treated mice was 80% after 3 weeks and less than 30% after 12 weeks, while PF4-treated groups had 100% survival rate after 12 weeks. Taken together, our findings confirm that PF4 is a critical regulator of MM pathogenesis, which targets both MM cells and MMECs in the BM milieu in vitro and in vivo and prolongs survival in the SCID-rab mice model of human MM. These studies provide an important framework for critical clinical studies of PF4 to improve patient treatment outcome in MM. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Pim2 is required for maintaining multiple myeloma cell growth through modulating TSC2 phosphorylation

Blood ◽  
2013 ◽  
Vol 122 (9) ◽  
pp. 1610-1620 ◽  
Author(s):  
Jing Lu ◽  
Tatiana Zavorotinskaya ◽  
Yumin Dai ◽  
Xiao-Hong Niu ◽  
Joseph Castillo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Proliferation ◽  
Cell Growth ◽  
Myeloma Cell ◽  
Multiple Myeloma Cell ◽  
Key Points

Key Points Pim2 expression is highly elevated in multiple myeloma and is required for multiple myeloma proliferation. Pim2 phosphorylates TSC2 and modulates mTOR-C1 activity to promote multiple myeloma cell proliferation.

scholarly journals Positive feedback of SuFu negating protein 1 on Hedgehog signaling promotes colorectal tumor growth

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Zhengwei Yan ◽  
Minzhang Cheng ◽  
Guohui Hu ◽  
Yao Wang ◽  
Shaopeng Zeng ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Growth ◽  
Ubiquitin Ligase ◽  
Hedgehog Signaling ◽  
Nuclear Translocation ◽  
Critical Role ◽  
E3 Ubiquitin Ligase ◽  
Hh Signaling ◽  
Proliferation Regulation ◽  
Feedback Regulator

AbstractHedgehog (Hh) signaling plays a critical role in embryogenesis and tissue homeostasis, and its deregulation has been associated with tumor growth. The tumor suppressor SuFu inhibits Hh signaling by preventing the nuclear translocation of Gli and suppressing cell proliferation. Regulation of SuFu activity and stability is key to controlling Hh signaling. Here, we unveil SuFu Negating Protein 1 (SNEP1) as a novel Hh target, that enhances the ubiquitination and proteasomal degradation of SuFu and thus promotes Hh signaling. We further show that the E3 ubiquitin ligase LNX1 plays a critical role in the SNEP1-mediated degradation of SuFu. Accordingly, SNEP1 promotes colorectal cancer (CRC) cell proliferation and tumor growth. High levels of SNEP1 are detected in CRC tissues and are well correlated with poor prognosis in CRC patients. Moreover, SNEP1 overexpression reduces sensitivity to anti-Hh inhibitor in CRC cells. Altogether, our findings demonstrate that SNEP1 acts as a novel feedback regulator of Hh signaling by destabilizing SuFu and promoting tumor growth and anti-Hh resistance.

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