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Results for “Proliferation”

Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 1,297 records · Page 72
All sourcesNASA NTRSDOE OSTI
DOE OSTI2017

Overexpression of DBC1, correlated with poor prognosis, is a potential therapeutic target for hepatocellular carcinoma

Highlights: • DBC1 was upregulated in HCC tissues and cell lines. • Overexpression of DBC1 was correlated with clinicopathological parameters in HCC. • Overexpression of DBC1 predicts poor disease-free survival (DFS) and overall survival (OS) in HCC. • Knockdown of DBC1 inhibits HCC cell lines proliferation. Deleted in Breast Cancer 1 (DBC1) is a regulatory protein involved in cell metabolism and cancer progression. Nevertheless, the expression and prognostic values of DBC1 in hepatocellular carcinoma (HCC) are still not well understood. The following study investigated the clinical significance and biological function of DBC1 in HCC. Briefly, overexpression of DBC1 at transcriptional and translational levels in human HCC tissues compared to adjacent normal tissues was observed using quantitative real-time polymerase chain reaction (qRT-PCR), western blot (WB) and immunohistochemistry (IHC) approach. Furthermore, upregulated DBC1 was significantly correlated with tumor size (p = 0.005), N stage (p = 0.016), M stage (p = 0.011), tumor differentiation (p in vitro. To conclude, these findings demonstrated that DBC1 was essential in tumorigenesis and proliferation. Moreover, it was identified as a potential therapeutic target for HCC.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Galangin enhances TGF-β1-mediated growth inhibition by suppressing phosphorylation of threonine 179 residue in Smad3 linker region

Highlights: • Galangin significantly induced apoptosis in the presence of TGF-β1. • Galangin inhibits phosphorylation of the Thr-179 site at the Smad3 linker region. • Galangin suppresses CDK4-mediated Smad3 linker phosphorylation. Smad3 linker phosphorylation is a candidate target for several kinases that play important roles in cancer cell initiation, proliferation and progression. Also, Smad3 is an essential intracellular mediator of TGF-β1-induced transcriptional responses during carcinogenesis. Therefore, it is highly advantageous to identify and develop inhibitors targeting Smad3 linker phosphorylation for the treatment of cancers. Galangin (3,5,7-trihydroxyflavone) has been known to be an active flavonoid showing a cytotoxic effect on several cancer cells. However, the mechanism of action of galangin in various cancers remains unclear, and there has been no report concerning regulation of Smad3 phosphorylation by galangin. In the present study, we show that galangin significantly induced apoptosis and inhibited cell proliferation in the presence of TGF-β1 in both human prostate and pancreatic cancer cell lines. Particularly, galangin effectively inhibits phosphorylation of the Thr-179 site at Smad3 linker region through suppression of CDK4 phosphorylation. Thus, galangin can be a promising candidate as a selective inhibitor to suppress phosphorylation of Smad3 linker region.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

CD1d is a novel cell-surface marker for human monocytic myeloid-derived suppressor cells with T cell suppression activity in peripheral blood after allogeneic hematopoietic stem cell transplantation

Highlights: • High-content screening identified a set of cell-surface marker candidates expressed in HLA-DR{sup -}CD14{sup +} M-MDSCs. • CD1d and CD226 are novel markers for the human M-MDSC subset. • CD1d-expressing M-MDSC showed the suppressive activity of T cell proliferation and could be a valuable marker for of human M-MDSCs. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that regulate immune responses in cancer and various pathological conditions. However, the phenotypic and functional heterogeneity of human MDSCs represents a major hurdle for the development of therapeutic strategies targeting or regulating MDSCs in tumor progression, inflammation, and graft-versus-host disease (GVHD). We previously shown that circulating HLA-DR{sup -}CD14{sup +} monocytic MDSCs are a major contributor to clinical outcomes after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In this study, we identified, using high-throughput screening, a set of surface markers that are strongly expressed in HLA-DR{sup -}CD14{sup +} monocytic MDSCs isolated from the peripheral blood (PB) of patients receiving allo-HSCT. Subsequent experiments showed the consistent dominant expression of CD1d in monocytic MDSCs of allo-HSCT PB in comparison with granulocytic MDSCs. In addition, CD1d-expressing cells isolated from PB of allo-HSCT patients showed the suppressive activity of T cell proliferation and higher expression of MyD88 and IDO compared with CD1d{sup −} cells. Our results suggest that CD1d could be a valuable marker for further therapeutic evaluation of human monocytic MDSCs for immune-related diseases, including GVHD.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Hsa{sub c}irc{sub 0}009910 promotes carcinogenesis by promoting the expression of miR-449a target IL6R in osteosarcoma

Highlights: • Hsa{sub c}irc{sub 0}009910 plays oncogenic role in osteosarcoma cells. • Circ{sub 0}009910 acted as a sponge of miR-449a. • Inhibition of miR-449a impairs the tumor suppressor role of circ{sub 0}009910 silencing. • IL6R was a functional target of miR-449a. • JAK1/STAT3 signaling involves in circ{sub 0}009910/miR-449a/IL6R related tumorigenesis. Circular RNAs (circRNAs) have recently shown capabilities as gene regulators in mammals. Some of them interact with microRNAs (miRNAs) and function as sponges to affect related miRNAs' activities. In this study, the molecular function of circRNA{sub 0}009910 and its potential downstream miRNA targets were explored. The expression levels of hsa{sub c}irc{sub 0}009910 were found to be overexpressed in osteosarcoma (OS) cells. Knockdown of circ{sub 0}009910 induced cell proliferation inhibition, cell cycle arrest, and apoptosis in OS cells. The target miRNA was predicted to be miR-449a, whose expression was downregulated in OS cells. Inhibition of miR-449a abolished the effect of circ{sub 0}009910 knockdown on cell growth and apoptosis. The expression of miR-449a were found to be negatively correlated with that of circ{sub 0}009910 in OS tissues. Direct interaction of circ{sub 0}009910 and miR-449a was confirmed through dual-luciferase assays. Moreover, IL6R was predicted as a potential target of miR-449a. Overexpression of miR-449a decreased the mRNA and protein levels of IL6R. Restoration of IL6R impaired the miR-449a induced inhibition of cell proliferation, cell cycle arrest, and apoptosis. The mRNA expression of IL6R was inversely correlated with miR-449a in OS tissues. In addition, JAK1/STAT3 signaling pathway was regulated by circ{sub 0}009910/miR-449a/IL6R axis. Taken together, we suggested that circ{sub 0}009910 acted as a sponge of miR-449a and upregulated miR-449a functional target IL6R, thereby contributed to carcinogenesis of OS.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Elevated O-GlcNAcylation stabilizes FOXM1 by its reduced degradation through GSK-3β inactivation in a human gastric carcinoma cell line, MKN45 cells

Highlights: • FOXM1 protein level and the cell proliferation were upregulated in a human gastric cancer cell line, MKN45 cells. • The ubiquitination and degradation of FOXM1 protein were both suppressed by high glucose and TMG treatment. • However, the O-GlcNAcylation was not detected on FOXM1 but not on GSK-3β. • The degradation of FOXM1 protein were suppressed by the treatment of GSK-3β inhibitors. • The higher risk of gastric cancer in diabetic patients could be due to O-GlcNAcylation-mediated FOXM1 stabilization. O-GlcNAcylation is a dynamic post-translational modification of cytonuclear proteins for intracellular signaling. Elevated O-GlcNAcylation is a general feature of cancer and contributes to cancer progression, and recent studies indicate the contribution to increasing incidence of various types of cancer in diabetic patients. However, the role of O-GlcNAcylation in tumor progression is not fully elucidated. Forkhead box M1 (FOXM1), a master mitotic transcription factor, has been implicated in all major hallmarks of cancer, and is wildly expressed in solid tumors. Given that FOXM1 expression was reported to be elevated in gastric cancer, we examined the effect of high glucose or an inhibitor of O-GlcNAc hydrolase, Thiamet G (TMG), on FOXM1 protein expression in a human gastric cancer cell line, MKN45 cells, and confirmed that FOXM1 protein level and the cell proliferation were upregulated. To investigate the molecular mechanisms by which FOXM1 protein expression is regulated by O-GlcNAcylation, the effect of high glucose and TMG on FOXM1 ubiquitination was examined in MKN45 cells. As a result, the ubiquitination and degradation of FOXM1 protein were both suppressed by high glucose and TMG treatment. However, the O-GlcNAcylation was not detected on FOXM1 but not on GSK-3β. High glucose and TMG treatment increased phospho-serine 9 GSK-3β, an inactive form, and the degradation of FOXM1 protein was suppressed by treatment of GSK-3β inhibitors in MKN45 cells. Taken together, we suggest that high glucose and elevated O-GlcNAcylation stabilize FOXM1 protein by its reduced degradation via GSK-3β inactivation in MKN45 cells, suggesting that the higher risk of gastric cancer in diabetic patients could be partially due to O-GlcNAcylation-mediated FOXM1 stabilization.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Harmine promotes molar root development via SMAD1/5/8 phosphorylation

Tooth and bone are major tissues involved in physiological calcification in the body, and they use similar molecular pathways for development, homeostasis, and regeneration. Harmine (HMN) is a natural small compound that stimulates osteoblast differentiation in vitro and in vivo. Here we examined the biological effect of HMN on the postnatal development of molar tooth roots and periodontal tissues. HMN supported the formation of tooth roots and periodontal tissues in developing tooth germs. In tooth germ organ culture, HMN promoted the elongation of Hertwig's epithelial root sheath (HERS) and stimulated cell proliferation in HERS and dental follicle-derived tissues, including dental papillae and dental follicles. HMN stimulated cell proliferation and cell movement of HERS-derived cells without mesenchymal cells in vitro and directly induced the phosphorylation of SMAD1/5/8 protein in HERS-derived cells. Our results indicated that HMN was the first natural small compound to stimulate postnatal development of tooth germs.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

ZEB1 stimulates breast cancer growth by up-regulating hTERT expression

Highlights: • hTERT expression is positively correlated with ZEB1 expression in breast cancer. • ZEB1 promotes hTERT expression and telomerase activity in breast cancer cell lines. • ZEB1 increases the transcriptional activity of the hTERT promoter but does not bind to the E-box. • ZEB1 controls hTERT expression by interacting with the co-activator Yes-associated protein (YAP). Dysfunctional cell proliferation and death are the foundation of the malignant biological characteristics of cancers. In this study, we discovered that ZEB1 was positively correlated with hTERT in breast invasive ductal carcinoma samples at both the mRNA and protein levels. Further, our in vitro study in breast cancer cell lines confirmed that ZEB1 regulates hTERT expression at the mRNA and protein levels; thus, hTERT promotes or inhibits telomerase activity, and telomere length is either protected or reduced. Finally, we verified that ZEB1, which mostly functions as a transcriptional repressor, can recruit the co-activator YAP to enhance the transcriptional activation of hTERT. Fascinatingly, instead of acting on E-boxes, the ZEB1/YAP complex tends to function as a transcriptional activator by binding with sequences potentially located in the hTERT promoter. Consequently, our research revealed a new ZEB1-hTERT signaling pathway involved in cell proliferation regulation that has never before been illuminated in breast cancer.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Upregulation of CDCA5 promotes gastric cancer malignant progression via influencing cyclin E1

Highlights: • Upregulation of CDCA5 correlates with more advanced clinical features and worse survival in gastric cancer patients. • Inhibition of CDCA5 suppresses gastric cancer cells proliferation in vitro and tumor growth in vivo. • CDCA5 promotes gastric cancer malignant progression via influencing cyclin E1 expression. The cell division cycle associated 5(CDCA5) was reported to be associated with progression of several human cancers, however, its clinical significance and biological role still remain unknown in gastric cancer(GC). By analyzing The Cancer Genome Atlas(TCGA), we found CDCA5 was significantly upregulated in GC tissues compared to adjacent normal tissues. Tissue microarray(TMA) indicated upregulation of CDCA5 was significantly correlated with more advanced clinicopathological features, and acts as an independent risk factor for worse overall survival(OS) in GC patients. Moreover, silence of CDCA5 suppresses proliferation of GC cells by inducing G1-phase arrest via downregulating Cyclin E1(CCNE1). Our results demonstrate upregulation of CDCA5 promotes GC malignant progression, which may offer a potential prognostic and therapeutic strategy.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

PMN inhibits colorectal cancer cells through inducing mitotic arrest and p53-dependent apoptosis via the inhibition of tubulin polymerization

Highlights: • PMN inhibits CRC cell proliferation through inducing mitotic arrest and apoptosis. • PMN induces mitotic arrest via the inhibition of microtubule polymerization. • PMN-induced mitotic arrest results in apoptosis and p53 upregulation. • PMN-induced apoptosis is partially mediated by p53. Colorectal cancer (CRC) is the third most prevalent malignancy worldwide. New understandings about this disease are urgently required to guide clinical therapies. In this study, we focused on the effects of the small molecule PMN on CRC cells. PMN dose-dependently inhibited CRC cell proliferation through inducing mitotic arrest and apoptosis. PMN induced mitotic arrest via the disruption of spindle apparatus by inhibiting microtubule polymerization. PMN-induced mitotic arrest resulted in apoptosis and p53 upregulation. Furthermore, p53 upregulation sensitized PMN-induced mitotic cells to apoptosis. This study deepens the understanding of the effects of p53 on the response of CRC cells to PMN, providing the basis for the potential development of PMN as a lead compound of microtubule-destabilizers for p53-positive CRC treatment.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

PPM1B depletion in U2OS cells supresses cell growth through RB1-E2F1 pathway and stimulates bleomycin-induced cell death

Highlights: • PPM1B depletion causes growth suppression in U2OS cells. • PPM1B depletion causes RB1 phosphorylation. • PM1B depletion up-regulates E2F1 target genes in a p38 dependent manner. • PPM1B depletion stimulates bleomycin-induced cell death. PPM1B is a metal-dependent serine/threonine protein phosphatase, with a similar structure and function to the well-known oncogene in breast cancer, PPM1D (WIP1). However, clinical significance of PPM1B as a pharmacological target in cancer therapy has not been explored. To test if PPM1B can be a drug target in the cellular proliferation and death pathway, the lentiviral PPM1B shRNA was stably expressed in cancer cell lines and its regulatory function in the RB1-E2F1 pathway was examined. We found that PPM1B depletion suppressed cellular proliferation of U2OS cells, accompanied by hyper-phosphorylation of RB1 and up-regulation of E2F1 target genes, p27 and caspase 7. Notably, PPM1B depletion significantly sensitised U2OS cells to bleomycin-induced cell death at a minimal effective concentration. Our results suggest that PPM1B plays a negative role in the activation of the p38-RB1-E2F1 pathway and that targeting PPM1B could be useful in certain types of cancer by stimulating chemotherapy-induced cell death.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Silencing LncRNA LOXL1-AS1 attenuates mesenchymal characteristics of glioblastoma via NF-κB pathway

Highlights: • LncRNA LOXL1-AS1 expression is increased in mesenchymal subtype of GBM. • Knocking down LOXL1-AS1 could suppresse GBM cell proliferation. • Silencing LncRNA LOXL1-AS1 Attenuates Mesenchymal Characteristics of Glioblastoma via reducing NF-κB transcription activity. The mesenchymal (MES) subtype of glioblastoma (GBM) suggested worse prognosis and a more malignant phenotype in comparison with their proneural (PN) counterpart. The plasticity between PN and MES transcriptome signatures provided clinical intervention with an manner. Few LncRNA, however, have been discovered to take part in the shift between subtypes. Here, we used transcriptomic data and experimental evidences to demonstrate that silencing LncRNA LOXL1-AS1 was a new regulator of NF-κB signaling pathway through repressing RELB directly, resulting in increased marker genes of PN subtype and decreased those of MES.GBM cell proliferation was functionally suppressed by LOXL1-AS1's knockdown expression,. Furthermore, RELB's rescue could reverse LOXL1-AS1's effects partially in GBM malignant behaviors. LOXL1-AS1 could clinically serve as a poor prognostic indicator for GBM patients. In conclusion, our results suggest that LOXL1-AS1 contributes to aggressive biological processes that are related with MES phenotype via NF-κB signaling, which expand our perceptions into the underlying mechanisms in LOXL1-AS1-based and subtype transition adapted medicine for GBM management.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Identifying the SUMO1 modification of FAM122A leading to the degradation of PP2A-Cα by ubiquitin-proteasome system

Highlights: • FAM122A can be modified by SUMO1 and the sumoylation is desumoylated by SENP1. • The SUMO1 modification site of FAM122A is lysine 89. • The sumoylated FAM122A degrades PP2A-Cα protein by ubiquitin-proteasome system. • The sumoylated FAM122A reduces the activity of PP2A and suppresses cell proliferations. FAM122A is a highly conserved protein in mammals. Here, we identify that FAM122A can be sumoylated at lysine 89, which can be de-conjugated by SENP1. Furthermore, the sumoylation of FAM122A reduces the PP2A-Cα protein level together with the reduced phosphatase activity of PP2A, which suppresses cell proliferation. Collectively, our results suggest that the sumoylation of FAM122A may have a significant role in cellular function.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

ShRNA-mediated knock-down of CXCL8 inhibits tumor growth in colorectal liver metastasis

Highlights: • Showed an up regulation of chemokines (1, 2, 3, 5 and 8) in the tumor invasion front compared to inner parts of the tumor in a xenograft model of colorectal liver metastasis. • Upregulation of CXCL8 in the invasion front of tumor cells is able to promote colorectal liver metastasis. • ShRNA mediated knockdown of CXCL8 in LS174T cells resulted in significantly decreased cell proliferation, migration and invasion in vitro and in a near complete reduction of tumor growth in vivo. • Results suggest an association between CXCL8 expression and progression of colorectal carcinoma and the development of colorectal liver metastases. • CXCL8 may serve as a potential therapeutic target for the treatment of colorectal liver metastasis. CXCL8 belongs to proinflammatory chemokines that are predominantly involved in neutrophil chemotaxis and degranulation. Several studies have suggested that secretion of CXCL8 from cancer cells have a profound effect on tumor microenvironment. In this study, in continuation to our previous work of understanding the global picture of invasion related genes in colorectal liver metastases, we clearly show an up-regulation of CXCL8 expression in the tumor cells at the invasion front as compared to the tumor cells in the inner parts of the tumor. Furthermore, ShRNA mediated down-regulation of CXCL8 resulted in inhibition of cell proliferation, viability and invasion in vitro and a near complete growth reduction of tumor in vivo. We showed that CXCL8 secreted by tumor cells at the invasion front were able to promote migration through angiogenesis by upregulating VEGFA and invasion via the AKT/GSK3β/β-catenin/MMP7 pathway by upregulating BCL-2 confirming the key role of CXCL8 during tumor progression.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Mutual suppression of miR-125a and Lin28b in human hepatocellular carcinoma cells

MicroRNA-125a exhibits an antiproliferative activity and is downregulated in several types of tumors, including hepatocellular carcinoma where it targets sirtuin-7, matrix metalloproteinase-11, and c-Raf. Another target of miR-125a is Lin28, a pluripotency factor that is generally undetectable in differentiated cells but is often upregulated/reactivated in tumors where it acts as an oncogenic factor promoting cell proliferation and tumor progression. In this study we show that downregulation of Lin28b by miR-125a partially accounts for its antiproliferative activity toward hepatocellular carcinoma cells. We also found that Lin28b is able to bind a conserved GGAG motif of pre-miR-125a and to inhibit its maturation in hepatocellular carcinoma cells. Reciprocal inhibition between miR-125a and Lin28b reasonably generates a positive feedback loop where reactivation of Lin-28b inhibits the expression of both miR-125a and let-7, reinforcing its own expression and leading to a marked overexpression of the mitogenic targets of the two miRNAs. On the other hand, perturbation of these circuits by overexpression of miR-125a suppresses Lin28b leading to a decreased cell proliferation. Overall, these data support a tumor suppressive role for miR-125a and contribute to the elucidation of its molecular targets.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Circular RNA hsa{sub c}ircRNA{sub 1}03809 promotes lung cancer progression via facilitating ZNF121-dependent MYC expression by sequestering miR-4302

Lung cancer characterized with malignant cell growth is the leading cause of cancer-related deaths. In recent years, several circular RNAs (circRNAs) have been reported to participate in lung cancer progression. However, the correlation between circular RNA (circRNA) and lung cancer still remains to be further investigated. In this study, we screened out a highly expressed circular RNA hsa{sub c}ircRNA{sub 1}03809 in lung cancer tissues. We showed hsa{sub c}ircRNA{sub 1}03809 could serve as a prognostic biomarker for patients with lung cancer. Furthermore, we found that hsa{sub c}ircRNA{sub 1}03809 knockdown significantly suppressed lung cancer cell proliferation and invasion in vitro and delayed tumor growth in vivo. In mechanism, we identified hsa{sub c}ircRNA{sub 1}03809 as a sponge of miR-4302 targeting ZNF121. By sequestering miR-4302, hsa{sub c}ircRNA{sub 1}03809 promoted the expression of ZNF121 which consequently enhanced MYC protein level in lung cancer cells. Through rescue assays, we demonstrated hsa{sub c}ircRNA{sub 1}03809 contributed to lung cancer cell proliferation and invasion via facilitating ZNF121-dependent MYC expression by sponging miR-4302. In conclusion, our findings illustrated a novel hsa{sub c}ircRNA{sub 1}03809/miR-4302/ZNF121/MYC regulatory signaling pathway in lung cancer progression.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

circRNA{sub 0}084043 promote malignant melanoma progression via miR-153-3p/Snail axis

Highlights: • circRNA{sub 0}084043 was significantly up-regulated in melanoma tissue. • circRNA{sub 0}084043 promotes melanoma cell proliferation, invasion and migration. • circRNA{sub 0}084043 directly binds to miR-153-3p, and Snail is directly targeted by miR-153-3p. • circRNA{sub 0}084043 act as the sponge of miR-153-3p to up-regulate Snail expression, and consequently function as an oncogene in melanoma. Circular RNAs (circRNAs) has been found to play an important role in the regulation of multiple diseases, and participate in cancer development. However, the role of circRNA in malignant melanoma has not been reported. In this study, human circRNA microarray was used to screen the dysregulated circRNA in melanoma. We found that circRNA{sub 0}084043 was significantly up-regulated in melanoma tissue, and the result was replicated in a larger sample size. High circRNA{sub 0}084043 expression was an independent risk factor of overall survival in melanoma patients. circRNA{sub 0}084043 promotes melanoma cell proliferation, invasion and migration. Bioinformatics and luciferase reporter assays confirmed that circRNA{sub 0}084043 directly binds to miR-153-3p, and Snail is directly targeted by miR-153-3p. We also demonstrated that circRNA{sub 0}084043 may act as the sponge of miR-153-3p to up-regulate Snail expression, and consequently function as an oncogene in melanoma. Overall, this result elucidates a new mechanism for circRNA{sub 0}084043 in melanoma development and provides a potential therapeutic target for melanoma patients.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

The long non-coding RNA PCSEAT exhibits an oncogenic property in prostate cancer and functions as a competing endogenous RNA that associates with EZH2

Highlights: • PCSEAT is specifically overexpressed in prostate cancer. • PCSEAT promotes the growth and motility of prostate cancer cells. • PCSEAT regulates EZH2 by competitively ‘sponge’ miRNA-143-3p and miRNA-24-2-5p. • PCSEAT may serve as a biomarker for EZH2 inhibitors. • PCSEAT can be transmitted via exosomes and function in recipient cell. Prostate cancer (PCa) is the most common malignancy and the leading cause of cancer deaths in males. Recent studies demonstrate that long non-coding RNAs (lncRNAs) are involved in many aspects of PCa. However, their biological roles in PCa remain imperfectly understood. Here, we characterized an lncRNA, PCa specific expression and EZH2-associated transcript (PCSEAT, annotated as PRCAT38), which is specifically overexpressed in PCa. We further demonstrated that knockdown of PCSEAT results in the reduction of PCa cell growth and motility, and overexpression of PCSEAT reverses these phenotypes. Furthermore, bioactive PCSEAT is incorporated into exosomes and transmitted to adjacent cells, thus promoting cell proliferation and motility. Mechanistically, we found that PCSEAT promotes cell proliferation, at least in part by affecting miR-143-3p- and miR-24-2-5p-mediated regulation of EZH2, suggesting that PCSEAT and EZH2 competitively ‘sponge’ miR-143-3p and miR-24-2-5p. Overall, our results reveal that PCSEAT is specifically overexpressed in PCa patients and a potential oncogene in PCa cells via mediating EZH2 activity, indicating that PCSEAT may be a potential therapeutic target in PCa.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Inhibition of TBK1 reduces choroidal neovascularization in vitro and in vivo

Highlights: • The expression of TBK1 and VEGF is up-regulated in CNV model. • Knockdown of TBK1 alleviates CNV formation via inhibiting VEGF expression. • TBK1 plays a critical role in the development of CNV. choroidal neovascularization (CNV), a characteristic of wet age-related macular degeneration (AMD), causes severe vision loss among elderly patients. TANK-binding kinase 1 (TBK1) is a ubiquitously expressed serine–threonine kinase and is found to induce endothelial cells proliferation, represent a novel mediator of tumor angiogenesis and exert pro-inflammatory effect. However, the role of TBK1 in choroidal neovascularization has not been investigated so far. In this study, we found that the expression of TBK1 and VEGF was up-regulated in RF/6 A cells chemical hypoxia model and laser-induced mouse CNV model. Silencing of TBK1 suppressed the proliferation and tube formation activity of RF/6 A cells. Intravitreal injection of anti-TBK1 monoclonal antibody ameliorates CNV formation. Taken together, these findings exhibit a proangiogenic role for TBK1 via upregulating the expression of VEGF, and may suggest that TBK1 inhibition offers a unique and alternative method for prevention and treatment of AMD.

60 APPLIED LIFE SCIENCES↗