scholarly journals A Novel Long Non-Coding RNA-01488 Suppressed Metastasis and Tumorigenesis by Inducing miRNAs That Reduce Vimentin Expression and Ubiquitination of Cyclin E

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1504
Author(s):  
Syuan-Ling Lin ◽  
Yang-Hsiang Lin ◽  
Hsiang-Cheng Chi ◽  
Tzu-Kang Lin ◽  
Wei-Jan Chen ◽  
...  
Keyword(s):  
Human Cancer ◽  
Cyclin E ◽  
Survival Rates ◽  
Negative Regulator ◽  
Vimentin Expression ◽  
Protein Coding ◽  
Tumorigenic Activity ◽  
Underlying Mechanisms

Long intergenic non-coding RNAs (lincRNAs) play important roles in human cancer development, including cell differentiation, apoptosis, and tumor progression. However, their underlying mechanisms of action are largely unknown at present. In this study, we focused on a novel suppressor lincRNA that has the potential to inhibit progression of human hepatocellular carcinoma (HCC). Our experiments disclosed long intergenic non-protein coding RNA 1488 (LINC01488) as a key negative regulator of HCC. Clinically, patients with high LINC01488 expression displayed greater survival rates and better prognosis. In vitro and in vivo functional assays showed that LINC01488 overexpression leads to significant suppression of cell proliferation and metastasis in HCC. Furthermore, LINC01488 bound to cyclin E to induce its ubiquitination and reduced expression of vimentin mediated by both miR-124-3p/miR-138-5p. Our results collectively indicate that LINC01488 acts as a tumor suppressor that inhibits metastasis and tumorigenesis in HCC via the miR-124-3p/miR-138-5p/vimentin axis. Furthermore, LINC01488 interacts with and degrades cyclin E, which contributes to its anti-tumorigenic activity. In view of these findings, we propose that enhancement of LINC01488 expression could be effective as a potential therapeutic strategy for HCC.

scholarly journals Genetic background-dependent abnormalities of the enteric nervous system and intestinal function in Kif26a-deficient mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yukiko Ohara ◽  
Lisa Fujimura ◽  
Akemi Sakamoto ◽  
Youichi Teratake ◽  
Shuichi Hiraoka ◽  
...  
Keyword(s):  
Genetic Background ◽  
Survival Rates ◽  
Gastrointestinal Diseases ◽  
Negative Regulator ◽  
Enteric Neurons ◽  
Enteric Neuron ◽  
Protein Coding ◽  
Underlying Mechanisms ◽  
Functional Gastrointestinal Diseases ◽  
Deficient Mice

AbstractThe Kif26a protein-coding gene has been identified as a negative regulator of the GDNF-Ret signaling pathway in enteric neurons. The aim of this study was to investigate the influence of genetic background on the phenotype of Kif26a-deficient (KO, −/−) mice. KO mice with both C57BL/6 and BALB/c genetic backgrounds were established. Survival rates and megacolon development were compared between these two strains of KO mice. Functional bowel assessments and enteric neuron histopathology were performed in the deficient mice. KO mice with the BALB/c genetic background survived more than 400 days without evidence of megacolon, while all C57BL/6 KO mice developed megacolon and died within 30 days. Local enteric neuron hyperplasia in the colon and functional bowel abnormalities were observed in BALB/c KO mice. These results indicated that megacolon and enteric neuron hyperplasia in KO mice are influenced by the genetic background. BALB/c KO mice may represent a viable model for functional gastrointestinal diseases such as chronic constipation, facilitating studies on the underlying mechanisms and providing a foundation for the development of treatments.

scholarly journals SMPDL3B Predicts Poor Prognosis and Contributes to Development of Acute Myeloid Leukemia

2021 ◽  
Vol 8 ◽  
Author(s):  
Huiqing Qu ◽  
Ye Zhu
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Human Cancer ◽  
Negative Regulator ◽  
Poor Overall Survival ◽  
Clinicopathologic Characteristics ◽  
Acute Myeloid

Background: Acute myeloid leukemia (AML), characterized by the low cure rate and high relapse, urgently needs novel diagnostic or prognostic biomarkers and potential therapeutic targets. Sphingomyelin Phosphodiesterase Acid Like 3B (SMPDL3B) is a negative regulator of Toll-like receptor signaling that plays important roles in the interface of membrane biology and innate immunity. However, the potential role of SMPDL3B in human cancer, especially in AML, is still unknown.Methods: The expression of SMPDL3B in AML samples was investigated through data collected from Gene Expression Omnibus (GEO). Association between SMPDL3B expression and clinicopathologic characteristics was analyzed with the chi-square test. Survival curves were calculated by the Kaplan–Meier method. Cox univariate and multivariate analyses were used to detect risk factors for overall survival. The biological functions of SMPDL3B in human AML were investigated both in vitro and in vivo.Results: Expression of SMPDL3B mRNA was significantly upregulated in human AML samples and closely correlated to cytogenetics risk and karyotypes. Elevated expression of SMPDL3B was associated with poor overall survival and emerged as an independent predictor for poor overall survival in human AML. Blocked SMPDL3B expression inhibited AML cells growth both in vitro and in vivo via promoting cell apoptosis.Conclusion: Taken together, our results demonstrate that SMPDL3B could be used as an efficient prognostic biomarker and represent a potential therapeutic target for human AML.

550 An Axl-targeting monoclonal antibody that inhibits Axl activity and potently stimulates the innate immune response

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A587-A587
Author(s):  
Diego Alvarado ◽  
Laura Vitale ◽  
Mike Murphy ◽  
Thomas O’Neill ◽  
Edward Natoli ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
T Cell ◽  
Tumor Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Human Cancer ◽  
Cell Activity ◽  
Negative Regulator

BackgroundAxl is a member of the TAM (Tyro3/Axl/MerTK) family of receptor tyrosine kinases and a negative regulator of innate immunity. Activation of Axl through its ligand Gas6 leads to suppression of myeloid cell activity, while its activation in tumor cells drives tumor growth, metastasis, and is associated with acquired resistance to targeted therapies, radiotherapy and chemotherapy.MethodsPurified monoclonal antibodies and variants thereof were tested in human cancer lines and primary human myeloid cells for effects on Axl signaling and immune activation, respectively.ResultsWe describe a humanized IgG1 Axl-targeting monoclonal antibody (mAb), CDX-0168, that binds to the ligand-binding domain of Axl with sub-nanomolar affinity and potently inhibits Gas6 binding. In tumor cells, CDX-0168 inhibits Gas6-dependent Axl phosphorylation and signaling and elicits tumor cell killing via ADCC in vitro and in vivo. In primary human immune cells, CDX-0168 treatment induces potent release of pro-inflammatory cytokines and chemokines from dendritic cells, monocytes and macrophages through an Fc receptor-dependent mechanism and enhanced T cell activation in mixed lymphocyte reactions. Axl inhibition may further enhance antitumor activity associated with PD-(L)1 blockade. To this end, we generated a tetravalent bispecific Axl x PD-L1 antibody combining CDX-0168 with a potent anti-PD-L1 mAb (9H9) using an IgG-scFv format. The bispecific antibody elicits greater cytokine release and T cell activation in vitro than the combination of the parental antibodies, while maintaining robust Axl and PD-L1 blockade.ConclusionsAdditional studies investigating simultaneous blockade of the Axl and PD-L1 pathways with other agents may further exploit the potential for this novel anti-cancer therapeutic approach.

SNHG5 inhibits the progression of EMT through the ubiquitin-degradation of MTA2 in oesophageal cancer

2020 ◽  
Author(s):  
Sisi Wei ◽  
Shiping Sun ◽  
Xinliang Zhou ◽  
Cong Zhang ◽  
Xiaoya Li ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Survival Rates ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Underlying Mechanisms ◽  
And Function

Abstract A substantial fraction of transcripts are known as long noncoding RNAs (lncRNAs), and these transcripts play pivotal roles in the development of cancer. However, little information has been published regarding the functions of lncRNAs in oesophageal squamous cell carcinoma (ESCC) and the underlying mechanisms. In our previous studies, we demonstrated that small nucleolar RNA host gene 5 (SNHG5), a known lncRNA, is dysregulated in gastric cancer (GC). In this study, we explored the expression and function of SNHG5 in development of ESCC. SNHG5 was found to be downregulated in human ESCC tissues and cell lines, and this downregulation was associated with cancer progression, clinical outcomes and survival rates of ESCC patients. Furthermore, we also found that overexpression of SNHG5 significantly inhibited the proliferation, migration and invasion of ESCC cells in vivo and in vitro. Notably, we found that metastasis-associated protein 2 (MTA2) was pulled down by SNHG5 in ESCC cells using RNA pulldown assay. We also found that SNHG5 reversed the epithelial–mesenchymal transition by interacting with MTA2. In addition, overexpression of SNHG5 downregulated the transcription of MTA2 and caused its ubiquitin-mediated degradation. Thus, overexpression of MTA2 partially abrogated the effect of SNHG5 in ESCC cell lines. Furthermore, we found that MTA2 mRNA expression was significantly elevated in ESCC specimens, and a negative correlation between SNHG5 and MTA2 expression was detected. Overall, this study demonstrated, for the first time, that SNHG5-regulated MTA2 functions as an important player in the progression of ESCC and provide a new potential therapeutic strategy for ESCC.

Regulation of TLR4, p38 MAPkinase, IκB and miRNAs by inactivated strains of lactobacilli in human dendritic cells

2012 ◽  
Vol 3 (2) ◽  
pp. 91-98 ◽  
Author(s):  
L. Giahi ◽  
E. Aumueller ◽  
I. Elmadfa ◽  
A.G. Haslberger
Keyword(s):  
Immune Response ◽  
Dendritic Cells ◽  
Lactobacillus Rhamnosus ◽  
Human Monocyte ◽  
Lactobacillus Delbrueckii ◽  
Negative Regulator ◽  
Transcriptional Level ◽  
Underlying Mechanisms

Strain specific properties of probiotics in providing supportive health effects in the immune system and the gastrointestinal tract have been widely investigated in vivo and in vitro. However, the underlying responsible mechanism is poorly described. By unravelling the probiotic-induced responses in a complex network of interacting signalling pathways, we investigated the effect of heat-inactivated Lactobacillus rhamnosus GG (LGG) and Lactobacillus delbrueckii subsp. bulgaricus (L.del) on the expression of TLR4 and signalling factors such as p38 MAPK and I?B at transcription level in human monocyte-derived dendritic cells (DCs). Our findings demonstrated that even inactivated probiotic strains can affect TLR4 expression in a down-regulatory direction as with lipopolysaccharides after 12 hours. LGG significantly down-regulated expression of p38 while I?B expression was significantly reduced in L.del-treated DCs. Moreover, we found these Lactobacillus strains could even modify the immune response at post-transcriptional level by modifying miRNAs expression. Based on our results LGG induced a significant down-regulatory effect on miR-146a expression which is known as a novel fine negative regulator of immune response targeting NFκB. On the other hand, miR-155 was up-regulated by LGG which is consistent with down-regulation of p38 and in LGG-treated DCs. These findings provide genetic and epigenetic explanations for the responsible underlying mechanisms by which probiotics influence immune response by targeting DCs.

scholarly journals LINC00518 Promotes Cell Proliferation by Regulating the Cell Cycle of Lung Adenocarcinoma Through miR-185-3p Targeting MECP2

2021 ◽  
Vol 11 ◽  
Author(s):  
Xu Han ◽  
Jixiang Wu ◽  
Yajun Zhang ◽  
Jianxiang Song ◽  
Zhan Shi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Growth ◽  
Lung Adenocarcinoma ◽  
Human Cancer ◽  
Survival Rates ◽  
Bioinformatic Analysis ◽  
Luciferase Reporter

Previous studies have shown that long intergenic non-protein coding RNA 00518 (LINC00518) are essential for the cell growth and metastasis of human cancer. However, the role of LINC00518 in lung adenocarcinoma (LUAD) is still unknown. This research put emphasis on the function of LINC00518 on the cell growth of LUAD. The lncRNA, miRNA and mRNA expression were measured by using qRT-PCR. Protein levels were measured by using Western blotting. CCK-8, colony formation assays and transwell assay were performed to evaluate the cell proliferation ability and invasion. Bioinformatic analysis and luciferase reporter assays were chosen to confirm the mechanism of LINC00518 in LUAD. We found that LINC00518 was highly expressed in LUAD specimens and the high-expression was negatively correlated with the overall survival rates. This finding was also proved in the LUAD cell lines. Through a series of in vitro and in vivo experiments, we proved that LICN00518 promoted the cell growth of LUAD by regulating the cell cycle. Moreover, LICN00518 upregulated the expression of MECP2 by mutagenesis of miR-185-3p. The results suggested that LICN00518 could be used as a survival indicator and potential therapeutic target for LUAD patients.

Phytosomal Curcumin Elicits Anti-tumor Properties Through Suppression of Angiogenesis, Cell Proliferation and Induction of Oxidative Stress in Colorectal Cancer

2019 ◽  
Vol 24 (39) ◽  
pp. 4626-4638 ◽  
Author(s):  
Reyhaneh Moradi-Marjaneh ◽  
Seyed M. Hassanian ◽  
Farzad Rahmani ◽  
Seyed H. Aghaee-Bakhtiari ◽  
Amir Avan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Colorectal Cancer ◽  
Therapeutic Potential ◽  
Vegf Signaling ◽  
Anticancer Effects ◽  
Inhibition Of Angiogenesis ◽  
Underlying Mechanisms ◽  
Apoptotic Activity

Background: Colorectal cancer (CRC) is one of the most common causes of cancer-associated mortality in the world. Anti-tumor effect of curcumin has been shown in different cancers; however, the therapeutic potential of novel phytosomal curcumin, as well as the underlying molecular mechanism in CRC, has not yet been explored. Methods: The anti-proliferative, anti-migratory and apoptotic activity of phytosomal curcumin in CT26 cells was assessed by MTT assay, wound healing assay and Flow cytometry, respectively. Phytosomal curcumin was also tested for its in-vivo activity in a xenograft mouse model of CRC. In addition, oxidant/antioxidant activity was examined by DCFH-DA assay in vitro, measurement of malondialdehyde (MDA), Thiol and superoxidedismutase (SOD) and catalase (CAT) activity and also evaluation of expression levels of Nrf2 and GCLM by qRT-PCR in tumor tissues. In addition, the effect of phytosomal curcumin on angiogenesis was assessed by the measurement of VEGF-A and VEGFR-1 and VEGF signaling regulatory microRNAs (miRNAs) in tumor tissue. Results: Phytosomal curcumin exerts anti-proliferative, anti-migratory and apoptotic activity in-vitro. It also decreases tumor growth and augmented 5-fluorouracil (5-FU) anti-tumor effect in-vivo. In addition, our data showed that induction of oxidative stress and inhibition of angiogenesis through modulation of VEGF signaling regulatory miRNAs might be underlying mechanisms by which phytosomal curcumin exerted its antitumor effect. Conclusion: Our data confirmed this notion that phytosomal curcumin administrates anticancer effects and can be used as a complementary treatment in clinical settings.

Novel Findings of Anti-cancer Property of Propofol

2018 ◽  
Vol 18 (2) ◽  
pp. 156-165 ◽  
Author(s):  
Jiaqiang Wang ◽  
Chien-shan Cheng ◽  
Yan Lu ◽  
Xiaowei Ding ◽  
Minmin Zhu ◽  
...  
Keyword(s):  
General Anesthesia ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Intravenous Anesthetic ◽  
The Past ◽  
Anti Cancer ◽  
Underlying Mechanisms ◽  
Recent Attention

Background: Propofol, a widely used intravenous anesthetic agent, is traditionally applied for sedation and general anesthesia. Explanation: Recent attention has been drawn to explore the effect and mechanisms of propofol against cancer progression in vitro and in vivo. Specifically, the proliferation-inhibiting and apoptosis-inducing properties of propofol in cancer have been studied. However, the underlying mechanisms remain unclear. Conclusion: This review focused on the findings within the past ten years and aimed to provide a general overview of propofol's malignance-modulating properties and the potential molecular mechanisms.

Studies on the mechanism of acute inhibition of thyroglobulin hydrolysis by iodine

1985 ◽  
Vol 108 (4) ◽  
pp. 511-517 ◽  
Author(s):  
Nandalal Bagchi ◽  
Birdie Shivers ◽  
Thomas R. Brown
Keyword(s):  
Time Course ◽  
Period 2 ◽  
Iodotyrosine Deiodinase ◽  
Rate Of Hydrolysis ◽  
Underlying Mechanisms ◽  
Excess Iodide ◽  
Sites Of Action ◽  
Hydrolysis Of

Abstract. Iodine in excess is known to acutely inhibit thyroidal secretion. In the present study we have characterized the time course of the iodine effect in vitro and investigated the underlying mechanisms. Labelled thyroid glands were cultured in vitro in medium containing mononitrotyrosine, an inhibitor of iodotyrosine deiodinase. The rate of hydrolysis of labelled thyroglobulin was measured as the proportion of labelled iodotyrosines and iodothyronines recovered at the end of culture and was used as an index of thyroidal secretion. Thyrotrophin (TSH) administered in vivo acutely stimulated the rate of thyroglobulin hydrolysis. Addition of Nal to the culture medium acutely inhibited both basal and TSH-stimulated thyroglobulin hydrolysis. The effect of iodide was demonstrable after 2 h, maximal after 6 h and was not reversible upon removal of iodide. Iodide abolished the dibutyryl cAMP induced stimulation of thyroglobulin hydrolysis. Iodide required organic binding of iodine for its effect but new protein or RNA synthesis was not necessary. The inhibitory effects of iodide and lysosomotrophic agents such as NH4C1 and chloroquin on thyroglobulin hydrolysis were additive suggesting different sites of action. Iodide added in vitro altered the distribution of label in prelabelled thyroglobulin in a way that suggested increased coupling in the thyroglobulin molecule. These data indicate that 1) the iodide effect occurs progressively over a 6 h period, 2) continued presence of iodide is not necessary once the inhibition is established, 3) iodide exerts its action primarily at a post cAMP, prelysosomal site and 4) the effect requires organic binding of iodine, but not new RNA or protein synthesis. Our data are consistent with the hypothesis that excess iodide acutely inhibits thyroglobulin hydrolysis by increasing the resistance of thyroglobulin to proteolytic degradation through increased iodination and coupling.

scholarly journals A New Smoothened Antagonist Bearing the Purine Scaffold Shows Antitumour Activity In Vitro and In Vivo

2021 ◽  
Vol 22 (16) ◽  
pp. 8372
Author(s):  
Ana María Zárate ◽  
Christian Espinosa-Bustos ◽  
Simón Guerrero ◽  
Angélica Fierro ◽  
Felipe Oyarzún-Ampuero ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Human Cancer ◽  
Antitumour Activity ◽  
Anticancer Compounds ◽  
Human Cancer Cells ◽  
Cycle Arrest ◽  
Apoptosis Inducer ◽  
Purine Ring

The Smoothened (SMO) receptor is the most druggable target in the Hedgehog (HH) pathway for anticancer compounds. However, SMO antagonists such as vismodegib rapidly develop drug resistance. In this study, new SMO antagonists having the versatile purine ring as a scaffold were designed, synthesised, and biologically tested to provide an insight to their mechanism of action. Compound 4s was the most active and the best inhibitor of cell growth and selectively cytotoxic to cancer cells. 4s induced cell cycle arrest, apoptosis, a reduction in colony formation and downregulation of PTCH and GLI1 expression. BODIPY-cyclopamine displacement assays confirmed 4s is a SMO antagonist. In vivo, 4s strongly inhibited tumour relapse and metastasis of melanoma cells in mice. In vitro, 4s was more efficient than vismodegib to induce apoptosis in human cancer cells and that might be attributed to its dual ability to function as a SMO antagonist and apoptosis inducer.

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