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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 181 records · Page 10
All sourcesNASA NTRSDOE OSTI
DOE OSTI2016

NAMPT regulates senescence, proliferation, and migration of endothelial progenitor cells through the SIRT1 AS lncRNA/miR-22/SIRT1 pathway

The importance of endothelial progenitor cells (EPCs) in cardiovascular diseases has been demonstrated by numerous studies. Previous studies have shown that Nicotinamide phosphoribosyltransferase (NAMPT) plays a role in EPC development by regulating Sirtuin 1 (SIRT1), but the specific mechanism has not yet been elucidated. After stimulating EPCs with NAMPT, expression of SIRT1 and SIRT1 antisense long non-coding RNA (AS lncRNA) was upregulated. Upon transfection of an SIRT1 AS lncRNA overexpression vector into EPCs, SIRT1 expression was upregulated. Upon transfection of a small interfering RNA (siRNA) that targets SIRT1 AS lncRNA along with NAMPT, SIRT1 AS lncRNA was downregulated and NAMPT-induced SIRT1 expression was reduced. We used software analyses and a dual-luciferase reporter assay to demonstrate that microRNA (miR)-22 regulated SIRT1 and SIRT1 AS lncRNA. Our data suggest that SIRT1 AS lncRNA relieves miR-22-induced SIRT1 downregulation by competitively sponging miR-22. By measuring EPC senescence, proliferation, and migration, we found that NAMPT inhibited EPC senescence through an SIRT1 AS lncRNA/miR-22/SIRT1 pathway and promoted EPC proliferation and migration. These findings provide a new theoretical basis for the prevention and treatment of atherosclerosis (AS) and other cardiovascular diseases. - Highlights: • NAMPT upregulates expression of SIRT1 AS lncRNA, which regulates SIRT1 expression in EPCs. • NAMPT regulates SIRT1 expression through an SIRT1 AS lncRNA/miR-22 pathway. • NAMPT regulates EPC senescence through an SIRT1 AS lncRNA/miR-22/SIRT1 pathway. • NAMPT regulates EPC proliferation and migration through an SIRT1 AS lncRNA/miR-22/SIRT1 pathway.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

MicroRNA-215 suppresses cell proliferation, migration and invasion of colon cancer by repressing Yin-Yang 1

Colorectal cancer is one of the most common malignant tumors worldwide with rising incidence. MicroRNAs are small non-coding RNAs that implicate in multiple physiological or pathological processes. The aberrant expression of miRNA-215 (miR-215) has been illustrated in various types of cancers. However, the expression of miR-215 in human colon cancer and the biological roles of it remain largely unknown. We conducted this study to explore the expression and the function of miR-215 in human colon cancer. The results showed that miR-215 was remarkably downregulated in colon cancer tissues and cell lines. Overexpression of miR-215 by miR-215 mimic significantly inhibited colon cancer cell proliferation, migration and invasion while knockdown of miR-215 by miR-215 inhibitor exerted reverse effects. Furthermore, we newly identified Yin-Yang 1(YY1) as a direct target of miR-215 which could rescue the effects of miR-215 on colon cancer cells. In summary, our investigation revealed that miR-215 was downregulated in colon cancer and it suppressed colon cancer cell proliferation, migration and invasion by directly targeting YY1. - Highlights: • MiR-215 expression was decreased in colon cancer tissues and cell lines. • Mir-215 inhibited colon cancer cell proliferation, migration and invasion. • MiR-215 targeted YY1 directly. • The effects of miR-215 on colon cancer cells were mediated by YY1.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

1, 25(OH){sub 2}D{sub 3}-induced interaction of vitamin D receptor with p50 subunit of NF-κB suppresses the interaction between KLF5 and p50, contributing to inhibition of LPS-induced macrophage proliferation

KLF5 and nuclear factor κB (NF-κB) regulate cell proliferation and inflammation. Vitamin D signaling through vitamin D receptor (VDR) exerts anti-proliferative and anti-inflammatory actions. However, an actual relationship between KLF5, NF-κB and VDR in the inflammation and proliferation of macrophages is still unclear. Here, we showed that LPS and proinflammatory cytokines stimulate KLF5 gene expression in macrophages, and that 1, 25(OH){sub 2}D{sub 3} suppresses LPS-induced KLF5 expression and cell proliferation via upregulation of VDR expression. Mechanistic studies suggested that KLF5 interacts with p50 subunit of NF-κB to cooperatively induce the expressions of positive cell cycle regulators cyclin B1 and Cdk1/Cdc2 in LPS-treated macrophages. Further studies revealed that 1, 25(OH){sub 2}D{sub 3}-induced interaction of VDR with p50 decreases LPS-induced interaction of KLF5 with p50. Collectively, we identify a novel regulatory pathway in which 1, 25(OH){sub 2}D{sub 3} induces VDR expression and promotes VDR interaction with p50 subunit of NF-κB, which in turn attenuates the association of KLF5 with p50 subunit of NF-κB and thus exerts anti-inflammatory and anti-proliferative effects on macrophages. - Highlights: • 1, 25(OH){sub 2}D{sub 3} suppresses LPS-induced KLF5 expression via upregulation of VDR expression. • KLF5 interacts with NF-κB-p50 to cooperatively induce the expressions of positive cell cycle regulators cyclin B1 and Cdk1/Cdc2 in LPS-treated macrophages. • 1,25(OH){sub 2}D{sub 3} induces interaction of VDR with p50.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Highly expressed lncRNA CCND2-AS1 promotes glioma cell proliferation through Wnt/β-catenin signaling

Glioma is the most common and aggressive primary brain tumor in adults. Long-non coding RNAs (lncRNAs) have been recently shown to play important roles in regulating numerous biological processes both in physiologic and pathologic condition. However, the role of lncRNAs in glioma remains largely unknown. In this study, we firstly found that lncRNA CCND2-AS2 is significantly up regulated in malignant glioma tissues and cell lines. Both loss- and gain-functions assays show that CCND2-AS1 promotes glioma cells proliferation and growth. In addition, we also revealed that highly expressed CCND2-AS1 could enhance Wnt/β-catenin signaling in glioma. Taken together, our findings revealed a novel lncRNA CCND2-AS1 promotes glioma cell proliferation through Wnt/β-catenin signaling and CCND2-AS1 might function as a potential novel therapeutic target for the treatment of glioma. - Highlights: • LncRNA CCND2-AS1 was significantly upregulated in glioma cancer tissues and cell lines. • Overexpression CCND2-AS1 confers a poor prognosis in glioma patients. • Knockdown of CCND2-AS1 inhibited glioma cell proliferation and induced cell cycle arrest. • Overexpression CCND2-AS1 promotes cell growth in Normal human astrocyte (NHA). • LncRNA CCND2-AS1 regulates the activation of Wnt/β-catenin signaling in glioma cells.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

MiR-141-3p promotes prostate cancer cell proliferation through inhibiting kruppel-like factor-9 expression

Evidence has revealed that some microRNAs play a critical role in tumor proliferation. We demonstrated that miR-141-3p appears to be a novel oncogene miRNA, which promotes prostate tumorigenesis and facilitates the stemness of prostate cancer cells via suppressing a key transcription factor kruppel-like factor-9 (KLF9). KLF9 is the core effector protein that might suppress tumor growth. MiR-141-3p is upregulated in prostate cancer cells and tissues compared to non-tumorigenic prostate epithelial cells and prostate tissues. MiR-141-3p positively regulated proliferation, spheroid formation, and expression of the stemness factors OCT-4, Nanog, SOX-9, Bmil, CCND1, and CD44 in PC-3 cells. Restoration of miR-141-3p suppresses the expression of the transcription factor KLF9 in PC-3 and accelerates prostate tumorigenesis via targeted binding with its 3′-UTR. Downregulation of KLF9 enhances spheres formation of prostate cancer cells. Our results suggest that miR-141-3p/KLF9 may play an important role in regulating the growth of prostate cancer and is a potential target of prevention and therapy. - Highlights: • MiR-141-3p is upregulated in human prostate cancer. • MiR-141-3p induces cell proliferation and apoptosis resistance. • KLF9 is a direct and functional target of miR-141-3p.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

MicroRNA-340 inhibits the proliferation and invasion of hepatocellular carcinoma cells by targeting JAK1

Increasing evidence indicates that dysregulation of microRNAs (miRNAs) contributes to tumorigenesis. MicroRNA-340 (miR-340) is downregulated in several types of cancer. However, the functional mechanism of miR-340 in hepatocellular carcinoma (HCC) remains unclear. Here, we showed that miR-340 was significantly downregulated in HCC tissues and cell lines. Gain-of-function experiments demonstrated that miR-340 overexpression inhibited HCC cell proliferation, migration, and invasion in vitro, and suppressed tumor growth in vivo. Janus kinase 1 (JAK1) was identified as a direct target of miR-340 in HCC cells. Ectopic expression of JAK1 reversed the inhibitory effects of miR-340. Further investigations showed that miR-340 dramatically inhibited the expression of signal transducer and activator of transcription (STAT)3 downstream molecules including Bcl-2, cyclin D1, and matrix metalloprotease (MMP)-2. The present findings indicated that miR-340 suppressed HCC cell proliferation and invasion by regulating the JAK1/STAT3 pathway, suggesting its potential as a novel therapeutic target for HCC. - Highlights: • miR-340 is downregulated in HCC and suppresses HCC cell proliferation, migration, and invasion. • miR-340 overexpression on HCC xenograft tumor growth in nude mice. • miR-340 directly targets JAK1. • miR-340 regulates the JAK1/STAT3 signaling pathway.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

CG13250, a novel bromodomain inhibitor, suppresses proliferation of multiple myeloma cells in an orthotopic mouse model

Multiple myeloma (MM) is characterized by the clonal proliferation of neoplastic plasma cells. Despite a stream of new molecular targets based on better understanding of the disease, MM remains incurable. Epigenomic abnormalities contribute to the pathogenesis of MM. bromodomain 4 (BRD4), a member of the bromodomain and extraterminal (BET) family, binds to acetylated histones during M/G1 transition in the cell cycle promoting progression to S phase. In this study, we investigated the effects of a novel BET inhibitor CG13250 on MM cells. CG13250 inhibited ligand binding to BRD4 in a dose-dependent manner and with an IC{sub 50} value of 1.1 μM. It inhibited MM proliferation in a dose-dependent manner and arrested cells in G1, resulting in the induction of apoptosis through caspase activation. CG13250 inhibited the binding of BRD4 to c-MYC promoter regions suppressing the transcription of the c-MYC gene. Administered in vivo, CG13250 significantly prolonged survival of an orthotopic MM-bearing mice. In conclusion, CG13250 is a novel bromodomain inhibitor that is a promising molecular targeting agent against MM. - Highlights: • A novel bromodomain inhibitor CG13250 suppresses MM cell proliferation. • CG13250 decreases C-MYC expression, resulting in the induction of apoptosis. • CG13250 prolongs the survivals of MM-bearing mice.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

RNA interference influenced the proliferation and invasion of XWLC-05 lung cancer cells through inhibiting aquaporin 3

Objective: The objective of this study was to construct a recombinant vector expressing siRNA targetedly inhibiting aquaporin 3 (AQP3), and to evaluate the effects of AQP3 inhibition on the proliferation and invasion of XWLC-05 human lung cancer cells. Methods: We obtained human AQP3 sequence from the Genbank and established the recombinant vector expressing siRNA targeting AQP3. After the transfection of the recombinant vectors, the expression of AQP3 was determined by RT-PCR and western blot. The MTS assay, flow cytometry and Transwell assay were conducted to detect the proliferation, cell cycle process, apoptosis and invasion of XWLC-05 cells. Then the activity of metal matrix proteinase (MMP) 2 was determined by gelatin zymography. Tumor formation in vivo experiments were also conducted in nude mice. Results: RNA interference (RNAi) of AQP3 substantially suppressed the XWLC-05 cell proliferation and invasion, blocked the cell cycle progressing and promoted cell apoptosis. In addition, the activity of MMP2 was remarkably attenuated in RNAi group. AQP3 RNAi did not affect the tumor formation rate in nude mice but reduced the tumor growth. Conclusion: The inhibition of AQP3 retarded the growth and invasiveness of XWLC-05 lung cancer cells and decreased the activity of MMP2.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Hypotonic stress promotes ATP release, reactive oxygen species production and cell proliferation via TRPV4 activation in rheumatoid arthritis rat synovial fibroblasts

Rheumatoid arthritis (RA) is a chronic and systemic autoimmune-disease with complex and unclear etiology. Hypotonicity of synovial fluid is a typical characteristic of RA, which may play pivotal roles in RA pathogenesis. In this work, we studied the responses of RA synovial fibroblasts to hypotonic stress in vitro and further explored the underlying mechanisms. Data showed that hyposmotic solutions significantly triggered increases in cytosolic calcium concentration ([Ca{sup 2+}]{sub c}) of synoviocytes. Subsequently, it caused rapid release of ATP, as well as remarkable production of intracellular reactive oxygen species (ROS). Meanwhile, hypotonic stimulus promoted the proliferation of synovial fibroblasts. These effects were almost abolished by calcium-free buffer and significantly inhibited by gadolinium (III) chloride (a mechanosensitive Ca{sup 2+} channel blocker) and ruthenium red (a transient receptor potential vanilloid 4 (TRPV4) blocker). 4α-phorbol 12,13-didecanoate, a specific agonist of TRPV4, also mimicked hypotonic shock-induced responses shown above. In contrast, voltage-gated channel inhibitors verapamil and nifedipine had little influences on these responses. Furthermore, RT-PCR and western blotting evidently detected TRPV4 expression at mRNA and protein level in isolated synoviocytes. Taken together, our results indicated that hypotonic stimulus resulted in ATP release, ROS production, and cell proliferation depending on Ca{sup 2+} entry through activation of TRPV4 channel in synoviocytes. - Highlights: • Hypotonic stress evokes Ca{sup 2+} entry in rheumatoid arthritis synovial fibroblasts. • Hypotonic stress induces rapid ATP release and ROS production in synoviocytes. • Hypotonic stimulation promotes the proliferation of synovial fibroblasts. • TRPV4 controls hypotonic-induced responses in synoviocytes.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Overexpression of microRNA-125b inhibits human acute myeloid leukemia cells invasion, proliferation and promotes cells apoptosis by targeting NF-κB signaling pathway

microRNA-125b has been reported to play an novel biological function in the progression and development of several kinds of leukemia. However, the detail role of miR-125b in acute myeloid leukemia (AML) is remains largely unknown. The present study aimed to investigate the biological role of miR-125b in AML and the potential molecular mechanism involved in this process. Our results showed that overexpression of miR-125b suppressed AML cells proliferation, invasion and promotes cells apoptosis in a dose-dependent manner, while the miR-NC did not show the same effect. In addition, miR-125b induced AML cells G2/M cell cycle arrest in vitro. Overexpression of miR-125b resulted in a significant decrease of the expression of p-IκB-α and inhibition of IκB-α degradation, and the nuclear translocation of NF-κB subunit p65 was abrogated by miR-125b simutaneously. To further verify that miR-125b targeted NF-κB signaling pathway, the NF-κB-regulated downstream genes that were associated with cell cycle arrest and apoptosis was also determined. The results showed that, miR-125b also affect NF-κB-regulated genes expression involved in cell cycle arrest and apoptosis. In conclusion, the present work certificates that miR-125b can significantly inhibit human AML cells invasion, proliferation and promotes cells apoptosis by targeting the NF-κB signaling pathway, and thus it can be viewed as an promising therapeutic target for AML. - Highlights: • Overexpression of miR-125b suppressed AML cells proliferation, invasion and promotes cells apoptosis. • miR-125b induced AML cells G2/M cell cycle arrest in vitro. • miR-125b suppressed AML cells tumorigenicity and promoted cells apoptosis by targeting NF-κB pathway.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Graphene modified titanium alloy promote the adhesion, proliferation and osteogenic differentiation of bone marrow stromal cells

We studied the effects of graphene coating on improving the biological activity of a titanium alloy (Ti{sub 6}Al{sub 4}V) widely used in hip and knee joint replacements. The experiments included immunofluorescence staining for observing cellular adhesion, Cell Counting Kit-8 (CCK-8) for evaluating cellular proliferation and reverse transcription-polymerase chain reaction (RT-PCR) for detecting the differentiation of bone marrow stromal cells on different scaffolds. The results showed that G-Ti{sub 6}Al{sub 4}V exhibited a higher mean integrated optical density (IOD) for vinculin and resulted in a higher cell proliferation rate and higher osteoblast-specific gene transcription levels. In summary, graphene could be used as a new nanocoating material for Ti{sub 6}Al{sub 4}V scaffolds to enhance their surface bioactivity. - Highlights: • Graphene coating could promote the adhesion and proliferation of SD rats' BMSCs. • Graphene coating could accelerate BMSCs specific differentiation into osteogenic lineages. • Graphene coating could enhance the surface bioactivity of Ti-based alloys.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

miR-217 suppresses proliferation and promotes apoptosis in cardiac myxoma by targeting Interleukin-6

Cardiac myxoma (CM) is a prevalent primary cardiac tumor. miR-217 plays a vital role in tumorigenesis of various cancers, however, its role and underlying molecular mechanism in human CM remain poorly understood. Here, we reported that the expression of miR-217 was downregulated in CM tissues and inversely correlated with the expression of Interleukin-6 (IL-6) mRNA. Gain-of-function analysis indicated that overexpression of miR-217 inhibited the proliferation and promoted the apoptosis of the primary CM cells. Bioinformatics analysis showed that IL-6 was a direct target gene of miR-217, which is confirmed by the dual luciferase assays. Moreover, downregulation of IL-6 by small interference RNA (siRNA) mimicked the tumor-suppressive effects of miR-217 in CM. Furthermore, rescue experiments pointed out that restoration of IL-6 expression abrogated the anti-proliferative and pro-apoptotic effect induced by miR-217 overexpression in CM cells. Taken together, we validated that miR-217 could act as a tumor suppressor in CM by directly targeting 3′UTR of IL-6 gene, indicating that manipulation of miR-217 may be a potential therapeutic strategy for CM patients. - Highlights: • Lower expression of miR-217 and higher expression of IL-6 mRNA was observed in CM tissues. • miR-217 overexpression suppressed proliferation and promoted apoptosis of primary CM cells. • miR-217 targeted IL-6 3′-UTR to inhibit its expression. • Reintroduction of IL-6 reversed the effect of miR-217 overexpression on CM cell proliferation and apoptosis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

The NAMPT/E2F2/SIRT1 axis promotes proliferation and inhibits p53-dependent apoptosis in human melanoma cells

Melanoma is the most common primary malignant neoplasm in adults, causing more deaths than any other skin cancer, necessitating the development of new target-based approaches. Current evidence suggests SIRT1, the mammalian nicotinamide adenine dinucleotide (NAD{sup +})-dependent protein deacetylase, and nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting NAD{sup +} biosynthetic enzyme, together comprise a novel systemic regulatory network to play a pivotal role in cell proliferation and apoptosis. Nevertheless, how the regulation of this cofactor interfaces with signal transduction network remains poorly understood in melanoma. Here, we report NAMPT is highly expressed in melanomaassociated with poor overall survival in patients. Pharmacological and genetic inhibition of NAMPT decreased NAD{sup +} levels and melanoma cell proliferation capacity, and NAMPT knockdown induced apoptosis through the activity of the tumor suppressor p53. Next, we demonstrate NAMPT regulates the transcription factor E2F family member 2 (E2F2) in the apoptosis process. Downstream, E2F2 control the mRNA and protein levels of SIRT1. Finally, we find NAMPT mediates the apoptosis resistance of melanoma cells through NAMPT-E2F2-SIRT1 axis, more than NAD{sup +}-driven transcriptional program. Accordingly, our results demonstrated that NAMPT is a prognostic marker in melanoma, and the identificationofNAMPT-E2F2-SIRT1 pathway establishes another link between NAMPT and apoptosis events in melanoma, with therapeutic implications for this deadly cancer. - Highlights: • The expression of NAMPT is remarkably high in melanoma tumors and associated with poor overall survival in patients. • NAMPT is required for E2F2 and SIRT1 expression for regulating p53 and apoptosis levels in human melanoma cells. • NAMPT/E2F2/SIRT1 is a novel regulatory pathway that governs melanoma cells proliferation and apoptosis resistance.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

TRIP6 promotes cell proliferation in hepatocellular carcinoma via suppression of FOXO3a

Highlights: • TRIP6 was upregulated in HCC cells and tissue. • TRIP6 expression was correlated with HCC patients’ clinical stage and poor survival. • TRIP6 enhanced the proliferation of HCC cells via suppression of FOXO3a. • TRIP6 may serve as a novel prognostic biomarker and therapeutic target in HCC. Thyroid hormone receptor-interacting protein 6 (TRIP6), a member of LIM family, acts as an adaptor protein and is overexpressed in several tumor types. However, the clinical significance and biological role of TRIP6 in HCC remains unknown. In our study, we found that TRIP6 was markedly overexpressed in HCC cells and clinical specimens compared with normal hepatocytes and adjacent non-tumor tissues. Immunohistochemical and statistical analysis showed that the expression of TRIP6 significantly correlated with HCC patients' clinical stage and poor survival. Moreover, we demonstrated that overexpressing TRIP6 significantly enhanced, whereas silencing endogenous TRIP6 inhibited, the proliferation and the anchorage-independent growth ability of HCC cells. In addition, overexpression of TRIP6 accelerated, while inhibition of TRIP6 retarded, G1-S phase transition in HCC cells. We further found that overexpression of TRIP6 increased the activation of AKT and suppressed the transactivity of FOXO3a. Meanwhile, overexpression of TRIP6 leaded to the decreased expression of cyclin-dependent kinase inhibitors p21{sup Cip1} and p27{sup Kip1} and increased expression of the cell cycle regulator cyclin D1. While silencing TRIP6 triggered the opposite effect. Taken together, these findings showed that TRIP6 plays an important role in promoting HCC cells proliferation and may serve as a novel prognostic biomarker and therapeutic target in HCC.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Involvement of mitochondrial fission in calcium sensing receptor-mediated vascular smooth muscle cells proliferation during hypertension

Hyperproliferation of vascular smooth muscle cells (VSMC) is a major risk factor for cardiovascular diseases. Proper mitochondrial fission and fusion is involved with VSMC function. However, the role and mechanism of mitochondrial morphological changes in VSMC proliferation are not well understood. Here, we found that calcium sensing receptor (CaSR) was increased in the aortas from spontaneous hypertensive rats (SHRs) compared with age-matched Wistar Kyoto (WKY) rats. There was also an increase in mitochondrial fission and VSMC proliferation, which was attenuated by Calhex231. In primary rat VMSC, angiotensin II (Ang II) stimulation induced cytosolic [Ca{sup 2+}]{sub i} increase, mitochondrial shortening and proliferation, all of which could be attenuated by pretreatment with mitochondrial division inhibitor-1 (Mdivi-1) and Calhex231. Our data indicate that CaSR-mediated mitochondrial fission could be a therapeutic target for hyperproliferative disorders.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

GBP3 promotes glioma cell proliferation via SQSTM1/p62-ERK1/2 axis

Highlights: • GBP3, an interferon-inducible large GTPase, is highly elevated in human glioma tumors. • GBP3 promotes glioma cell growth in vitro and in vivo through the SQSTM1/p62-ERK1/2 pathway. • GBP3 expression predicts poor outcome of glioma patients. Guanylate binding proteins (GBPs) are interferon-inducible large GTPases and play a crucial role in cell-autonomous immunity. However, the biology function of GBPs in cancer remains elusive. GBP3 is specifically expressed in adult brain. Here we show that GBP3 is highly elevated in human glioma tumors and glioma cell lines. Overexpression of GBP3 dramatically increased glioma cell proliferation whereas silencing GBP3 by RNA interference produced opposite effects. We further showed that GBP3 expression was able to induce sequestosome-1(SQSTM1, also named p62) expression and activate extracellular signal-regulated kinase (ERK1/2). The SQSTM1-ERK1/2 signaling cascade was essential for GBP3-promoted cell growth because depletion of SQSTM1 markedly reduced the phosphorylated ERK1/2 levels and GBP3-mediated cell growth, and inhibition of mitogen-activated protein kinase/ERK kinase abolished GBP3-induced glioma cell proliferation. Consistently, GBP3 overexpression significantly promoted glioma tumor growth in vivo and its expression was inversely correlated with the survival rate of glioma patients. Taken together, these results for the first time suggest that GBP3 contributes to the proliferation of glioma cells via regulating SQSTM1-ERK1/2 pathway, and GBP3 might represent as a new potential therapeutic target against glioma.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Down-regulation of lncRNA MEG3 promotes hypoxia-induced human pulmonary artery smooth muscle cell proliferation and migration via repressing PTEN by sponging miR-21

Highlights: • Hypoxia induced cell proliferation and migration in PASMCs. • MEG3 expression was down-regulated in PASMCs hypoxia cell models. • MEG3 exerts its role via miR-21/PTEN axis in PASMCs hypoxia cell models. Hypoxia-induced pulmonary hypertension is a life-threatening disease arising from a progressive increase in pulmonary vascular resistance, irreversible pulmonary vascular remodeling and resulting in right ventricular failure. Recent studies suggested that pulmonary artery smooth muscle cell proliferation and migration played an important role in the pathogenesis of hypoxia-induced pulmonary hypertension. However, the mechanisms of hypoxia-induced pulmonary hypertension are complicated and largely unclear. In this study, we discovered that lncRNA MEG3 was down-regulated in human pulmonary artery smooth muscle cell in hypoxia, and inhibition of MEG3 promoted the cell proliferation and cell migration in both normal and hypoxia condition. Further study demonstrated that MEG3 exerted its function via regulation of miR-21 expression in both normal and hypoxia condition. In addition, we displayed the modulation of PTEN by miR-21 and their role in hypoxia. Ultimately, our study illustrated that MEG3 exerts its role via miR-21/PTEN axis in human pulmonary artery smooth muscle cell under both normal and hypoxia conditions.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Inhibition of KLHL21 prevents cholangiocarcinoma progression through regulating cell proliferation and motility, arresting cell cycle and reducing Erk activation

Highlights: • KLHL21 was upregulated in CCA tissues and its expression correlated with tumor histologic grade and prognosis of patient. • Inhibition of KLHL21 reduced proliferation and triggered G0/G1 cell cycle arrest through P21/P27/Cyclin E1 in CCA cells. • KLHL21 knockdown reduced cell motility and inhibited activation of Erk pathway in CCA cells. Kelch-like family member 21 (KLHL21) is involved in cell mitosis and motility. Nevertheless, the clinical significance and biological function of KLHL21 in cholangiocarcinoma (CCA) are elusive. This is the first study to describe a pivotal role for KLHL21 in the progression of CCA. The expression of KLHL21 was elevated in CCA tissues compared with paired normal bile duct tissues. In addition, immunohistochemical and statistical analyses demonstrated that the expression of KLHL21 correlated inversely with tumor histological grade (p < 0.05) and the overall survival of patients (p < 0.01). In CCA cells, we found that the inhibition of KLHL21 significantly reduced proliferation, migration and invasion. Further results indicated that inhibition of KLHL21 triggered G0/G1 cell cycle arrest, leading to the increased expression of P21 and P27 and decreased expression of Cyclin E1, which eventually resulted in proliferation suppression in CCA cells. Furthermore, KLHL21 knockdown alleviated the activation of the Erk signaling pathway via decreasing the expression of phospho-Erk1/2. Our data demonstrated that KLHL21 plays an essential role in the tumorigenesis and progression of CCA, implying that it might serve as a potential therapeutic target for CCA treatment.

60 APPLIED LIFE SCIENCES↗