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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 1,351 records · Page 75
All sourcesNASA NTRSDOE OSTI
DOE OSTI2015

MiR-218 Mediates tumorigenesis and metastasis: Perspectives and implications

MicroRNAs (miRNAs) are a class of small non-coding RNAs that negatively regulate gene expression at the post-transcriptional level. As a highly conserved miRNA across a variety of species, microRNA-218 (miR-218) was found to play pivotal roles in tumorigenesis and progression. A group of evidence has demonstrated that miR-218 acts as a tumor suppressor by targeting many oncogenes related to proliferation, apoptosis and invasion. In this review, we provide a complex overview of miR-218, including its regulatory mechanisms, known functions in cancer and future challenges as a potential therapeutic target in human cancers. - Highlights: • miR-218 is frequently down regulated in multiple cancers. • miR-218 plays pivotal roles in carcinogenesis. • miR-218 mediates proliferation, apoptosis, metastasis, invasion, etc. • miR-218 mediates tumorigenesis and metastasis via multiple pathways.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

The novel HSP90 inhibitor NVP-AUY922 shows synergistic anti-leukemic activity with cytarabine in vivo

HSP90 is a molecular chaperone essential for stability, activity and intracellular sorting of many proteins, including oncoproteins, such as tyrosine kinases, transcription factors and cell cycle regulatory proteins. Therefore, inhibitors of HSP90 are being investigated for their potential as anti-cancer drugs. Here we show that the HSP90 inhibitor NVP-AUY922 induced degradation of the fusion oncoprotein FOP2-FGFR1 in a human acute myeloid leukemia (AML) cell line, KG-1a. Concordantly, downstream signaling cascades, such as STAT1, STAT3 and PLCγ were abrogated. At concentrations that caused FOP2-FGFR1 degradation and signaling abrogation, NVP-AUY922 treatment caused significant cell death and inhibition of proliferation of KG-1a cells in vitro. In an animal model for AML, NVP-AUY922 administrated alone showed no anti-leukemic activity. However, when NVP-AUY922 was administered in combination with cytarabine, the two compounds showed significant synergistic anti-leukemic activity in vivo. Thus NVP-AUY922 and cytarabine combination therapy might be a prospective strategy for AML treatment. - Highlights: • NVP-AUY922 induces degradation of the oncoprotein FOP2-FGFR1 in KG-1a leukemia cells. • NVP-AUY922 induces cell death and inhibition of proliferation of KG-1a cells. • NYP-AUY922 combined with cytarabine shows synergistic anti-leukemic activity in vivo.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Down-regulation of hTERT and Cyclin D1 transcription via PI3K/Akt and TGF-β pathways in MCF-7 Cancer cells with PX-866 and Raloxifene

Human telomerase reverse transcriptase (hTERT) is the catalytic and limiting component of telomerase and also a transcription factor. It is critical to the integrity of the ends of linear chromosomes and to the regulation, extent and rate of cell cycle progression in multicellular eukaryotes. The level of hTERT expression is essential to a wide range of bodily functions and to avoidance of disease conditions, such as cancer, that are mediated in part by aberrant level and regulation of cell cycle proliferation. Value of a gene in regulation depends on its ability to both receive input from multiple sources and transmit signals to multiple effectors. The expression of hTERT and the progression of the cell cycle have been shown to be regulated by an extensive network of gene products and signaling pathways, including the PI3K/Akt and TGF-β pathways. The PI3K inhibitor PX-866 and the competitive estrogen receptor ligand raloxifene have been shown to modify progression of those pathways and, in combination, to decrease proliferation of estrogen receptor positive (ER+) MCF-7 breast cancer cells. We found that combinations of modulators of those pathways decreased not only hTERT transcription but also transcription of additional essential cell cycle regulators such as Cyclin D1. By evaluating known expression profile signatures for TGF-β pathway diversions, we confirmed additional genes such as heparin-binding epidermal growth factor-like growth factor (HB EGF) by which those pathways and their perturbations may also modify cell cycle progression. - Highlights: • PX-866 and raloxifene affect the PI3K/Akt and TGF-β pathways. • PX-866 and raloxifene down-regulate genes up-regulated in cancer. • PX-866 and raloxifene decrease transcription of hTERT and Cyclin D1. • Pathological transcription signatures can identify new defense mechanisms.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

ERα inhibited myocardin-induced differentiation in uterine fibroids

Uterine fibroids, also known as uterine leiomyomas, are a benign tumor of the human uterus and the commonest estrogen-dependent benign tumor found in women. Myocardin is an important transcriptional regulator in smooth and cardiac muscle development. The role of myocardin and its relationship with ERα in uterine fibroids have barely been addressed. We noticed that the expression of myocardin was markedly reduced in human uterine fibroid tissue compared with corresponding normal or adjacent myometrium tissue. Here we reported that myocardin induced the transcription and expression of differentiation markers SM22α and alpha smooth muscle actin (α-SMA) in rat primary uterine smooth muscle cells (USMCs) and this effect was inhibited by ERα. Notably, we showed that, ERα induced expression of proliferation markers PCNA and ki-67 in rat primary USMCs. We also found ERα interacted with myocardin and formed complex to bind to CArG box and inhibit the SM22α promoter activity. Furthermore, ERα inhibited the transcription and expression of myocardin, and reduced the levels of transcription and expression of downstream target SM22α, a SMC differentiation marker. Our data thus provided important and novel insights into how ERα and myocardin interact to control the cell differentiation and proliferation of USMCs. Thus, it may provide potential therapeutic target for uterine fibroids.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Combination of exogenous cell transplantation and 5-HT{sub 4} receptor agonism induce endogenous enteric neural crest-derived cells in a rat hypoganglionosis model

Enteric neural crest-derived cells (ENCCs) can migrate into endogenous ganglia and differentiate into progeny cells, and have even partially rescued bowel function; however, poor reliability and limited functional recovery after ENCC transplantation have yet to be addressed. Here, we investigated the induction of endogenous ENCCs by combining exogenous ENCC transplantation with a 5-HT{sub 4} receptor agonist mosapride in a rat model of hypoganglionosis, established by benzalkonium chloride treatment. ENCCs, isolated from the gut of newborn rats, were labeled with a lentiviral eGFP reporter. ENCCs and rats were treated with the 5-HT{sub 4} receptor agonist/antagonist. The labeled ENCCs were then transplanted into the muscular layer of benzalkonium chloride-treated colons. At given days post-intervention, colonic tissue samples were removed for histological analysis. ENCCs and neurons were detected by eGFP expression and immunoreactivity to p75{sup NTR} and peripherin, respectively. eGFP-positive ENCCs and neurons could survive and maintain levels of fluorescence after transplantation. With longer times post-intervention, the number of peripherin-positive cells gradually increased in all groups. Significantly more peripherin-positive cells were found following ENCCs plus mosapride treatment, compared with the other groups. These results show that exogenous ENCCs combined with the 5-HT{sub 4} receptor agonist effectively induced endogenous ENCCs proliferation and differentiation in a rat hypoganglionosis model. - Highlights: • Survival and differentiation of exogenous ENCCs in treated colons. • With longer times post-intervention, the number of ENCCs and their progeny cells gradually increased. • Exogenous ENCCs combined with the 5-HT4 receptor agonist ffectively induced ENCCs proliferation and differentiation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

The atypical Rho GTPase RhoD is a regulator of actin cytoskeleton dynamics and directed cell migration

RhoD belongs to the Rho GTPases, a protein family responsible for the regulation and organization of the actin cytoskeleton, and, consequently, many cellular processes like cell migration, cell division and vesicle trafficking. Here, we demonstrate that the actin cytoskeleton is dynamically regulated by increased or decreased protein levels of RhoD. Ectopic expression of RhoD has previously been shown to give an intertwined weave of actin filaments. We show that this RhoD-dependent effect is detected in several cell types and results in a less dynamic actin filament system. In contrast, RhoD depletion leads to increased actin filament-containing structures, such as cortical actin, stress fibers and edge ruffles. Moreover, vital cellular functions such as cell migration and proliferation are defective when RhoD is silenced. Taken together, we present data suggesting that RhoD is an important component in the control of actin dynamics and directed cell migration. - Highlights: • Increased RhoD expression leads to loss of actin structures, e.g. stress fibers and gives rise to decreased actin dynamics. • RhoD knockdown induces various actin-containing structures such as edge ruffles, stress fibers and cortical actin, in a cell-type specific manner. • RhoD induces specific actin rearrangements depending on its subcellular localization. • RhoD knockdown has effects on cellular processes, such as directed cell migration and proliferation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Modulation of hepatic stellate cells and reversibility of hepatic fibrosis

Hepatic fibrosis (HF) is the pathological component of a variety of chronic liver diseases. Hepatic stellate cells (HSC) are the main collagen-producing cells in the liver and their activation promotes HF. If HSC activation and proliferation can be inhibited, HF occurrence and development can theoretically be reduced and even reversed. Over the past ten years, a number of studies have addressed this process, and here we present a review of HSC modulation and HF reversal. - Highlights: • We present a review of the modulation of hepatic stellate cells (HSC) and reversibility of hepatic fibrosis (HF). • HSC are the foci of HF occurrence and development, HF could be prevented and treated by modulating HSC. • If HSC activation and proliferation can be inhibited, HF could theoretically be inhibited and even reversed. • Prevention or reversal of HSC activation, or promotion of HSC apoptosis, immune elimination, and senescence may prevent, inhibit or reverse HF.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

The role of cardiac energy metabolism in cardiac hypertrophy and failure

In mammalian heart, incessant production of cellular energy is vital for maintaining continuous mechanical pumping function providing the body for oxygen and nutrients. To ensure this essential function, cardiac muscle adapt to increased energy demand or compromised energy supply by reprogramming the network of genes whose products are necessary to match the production of energy to consumption. Failure in this regulation leads to severe cardiac dysfunction and has been associated with cardiac pathogenesis including cardiac hypertrophy, failure and diabetes. Metabolic adaptations are induced by network of transcriptional pathways that are activated by a variety of factors such as hormones, nutrients, second messengers and oxygen. The metabolic phenotype of the heart is maintained by pathways controlling transcriptional regulators, which include peroxisome proliferator-activated receptors, estrogen-related receptors and nuclear respiratory factors, as well as their common coactivator protein peroxisome proliferator-activated receptor γ coactivator 1. These central regulators of gene expression are complemented with factors such as hypoxia inducible factor 1, which is activated in insufficient oxygenation of the tissue. Here, we discuss how these pathways relate to the cardiac metabolism and how they interact with pathways controlling the contractile phenotype of the heart. - Highlights: • Energy metabolic changes are associated with cardiac adaptation and pathogenesis. • Cardiac energy substrate utilisation is controlled by complex transcriptional networks. • Transcriptional pathways controlling heart metabolic and contractile phenotype overlap.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

miR-429 inhibits metastasis by targeting KIAA0101 in Soft Tissue Sarcoma

Soft tissue sarcomas (STS) are a heterogeneous group of rare tumors with high metastatic potential. There being only a handful of publication on metastasis of STS, we investigated the miRNA mediated target gene regulations in modulating the metastatic processes in this cancer. In this study, we amalgamated gene and miRNA expression profiles of high-grade STS samples with miRNA target predictions and identified miR-429 targeting KIAA0101 as a novel pair, which remain unexplored in STS metastasis. We validated their expression in metastatic fibrosarcoma cell line, HT1080 and performed several functional assays using miRNA mimics and KIAA0101 over-expression vector to confirm their role in metastasis. We observed miR-429 is downregulated in HT1080 cells and acting as an anti-metastatic miRNA that inhibited proliferation, migration, anchorage independent growth and invasion by de-repressing KIAA0101. Moreover, the renilla luciferase reporter assay confirmed that miR-429 targets KIAA0101 by binding to its 3{sup /}UTR and influence its expression. Taken together, our work demonstrated miR-429 mediates deregulation of KIAA0101 by acting as an anti-metastatic miRNA that targets KIAA0101 pro-metastatic gene during metastasis of STS. - Highlights: • miR-429 inhibits metastasis by targeting KIAA0101 in Soft Tissue Sarcoma. • miR-429 suppresses proliferation, migration, anchorage independent growth and invasion in HT1080. • We validated targeting of miR-429 and KIAA0101 by reporter assay. • KIAA0101 overexpression is involved in decreased survival of STS patients.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Function and regulation of LAG3 on CD4{sup +}CD25{sup -} T cells in non-small cell lung cancer

LAG3 is a surface molecule found on a subset of immune cells. The precise function of LAG3 appears to be context-dependent. In this study, we investigated the effect of LAG3 on CD4{sup +}CD25{sup -} T cells from non-small cell lung cancer (NSCLC) patients. We found that in the peripheral blood mononuclear cells of NSCLC patients, LAG3 was significantly increased in CD4{sup +} T cells directly ex vivo and primarily in the CD4{sup +}CD25{sup -} fraction, which was regulated by prolonged TCR stimulation and the presence of IL-27. TCR stimulation also increased CD25 expression, but not Foxp3 expression, in LAG3-expressing CD4{sup +}CD25{sup -} cells Compared to LAG3-nonexpressing CD4{sup +}CD25{sup -} cells, LAG3-expressing CD4{sup +}CD25{sup -} cells presented significantly higher levels of PD1 and TIM3, two inhibitory receptors best described in exhausted CD8{sup +} T effector cells. LAG3-expressing CD4{sup +}CD25{sup -} cells also presented impaired proliferation compared with LAG3-nonexpressing CD4{sup +}CD25{sup -} cells but could be partially rescued by inhibiting both PD1 and TIM3. Interestingly, CD8{sup +} T cells co-incubated with LAG3-expressing CD4{sup +}CD25{sup -} cells at equal cell numbers demonstrated significantly lower proliferation than CD8{sup +} T cells incubated alone. Co-culture with CD8{sup +} T cell and LAG3-expressing CD4{sup +}CD25{sup -} T cell also upregulated soluble IL-10 level in the supernatant, of which the concentration was positively correlated with the number of LAG3-expressing CD4{sup +}CD25{sup -} T cells. In addition, we found that LAG3-expressing CD4{sup +}CD25{sup -} T cells infiltrated the resected tumors and were present at higher frequencies of in metastases than in primary tumors. Taken together, these data suggest that LAG3-expressing CD4{sup +}CD25{sup -} T cells represent another regulatory immune cell type with potential to interfere with anti-tumor immunity.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

1,25(OH)2D3 attenuates pulmonary arterial hypertension via microRNA-204 mediated Tgfbr2/Smad signaling

Highlights: • miRNA-204 is significantly lower in hypoxic pulmonary hypertension. • miRNA-204 is involved in the development of pulmonary hypertension. • 1,25(OH){sub 2}D{sub 3} significantly prevented the development of PAH by blocking the Tgfbr2/Smad signaling. • 1,25(OH){sub 2}D{sub 3} reduced pulmonary hypertension mediated by increased the level of miRNA-204. • miRNA-204 strengthened the anti-PAH function of 1,25(OH){sub 2}D{sub 3} by targeting Tgfbr2. Pulmonary arterial hypertension (PAH) is a devastating disease characterized by high pulmonary artery pressure. It is reported that microRNA-204 (miR-204) plays an important role in the development of PAH. Calcitriol [1,25-dihydroxyvitamin D3, 1,25(OH){sub 2}D{sub 3}] mediates multiple pathophysiological processes. The aim of the current study was to explore the role of 1,25(OH){sub 2}D{sub 3} in PAH. PAH was induced in rats and rat pulmonary arterial endothelial cells (PAECs) were isolated as in vitro PAH model. The mean pulmonary artery pressure, morphologic changes, and expressions of transforming growth factor-beta1 (Tgfbr2), Smad2/7, alpha smooth muscle actin (α-SMA), and p21 were then measured. Furthermore, the effect of 1,25(OH){sub 2}D{sub 3} on rat PAECs with or without hypoxia treatment was also assessed by measuring the proliferation, migration, and cell cycle distribution of PAECs. The potential targets of miR-204 were also predicted and validated with a dual-luciferase reporter system. Then the role of miR-204 and Tgfbr2 in the anti-PAH effect of 1,25(OH){sub 2}D{sub 3} was further explored by modulating the expression of the two genes. The overall pulmonary hypertension and hypoxia-induced proliferation and migration of PAECs were attenuated by administration of 1,25(OH){sub 2}D{sub 3}, which was associated with the suppressed expressions of Tgfbr2, α-SMA, and Smad7 and induced expressions of miR-204, p21 and Smad2 both in vitro and in vivo. Moreover, the luciferase reporter assay identified Tgfbr2 as a novel direct target of miR-204. Both overexpression of miR-204 and inhibition of Tgfbr2 would strengthen the effect of 1,25(OH){sub 2}D{sub 3} administration. Findings outlined in the current study demonstrated that 1,25(OH){sub 2}D{sub 3} was a promising therapeutic modality for treatment of PAH, function of which was exerted through miR-204 mediated Tgfbr2 signaling.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Potential role of MG53 in the regulation of transforming-growth-factor-β1-induced atrial fibrosis and vulnerability to atrial fibrillation

Highlights: • MG53 is expressed in human atrium and associated with AF. • MG53 could regulate TGF-β1/Smad pathway to induce atrial fibrosis. • Exogenous TGF-β1 suppresses expression of MG53. • MG53 could serve as a promising target agent for atrial fibrosis induced by the TGF-β1/Smad pathway in patients with AF. Atrial fibrosis plays a critical role in atrial fibrillation (AF) by the transforming growth factor (TGF)-β1/Smad pathway. The disordered differentiation, proliferation, migration and collagen deposition of atrial fibroblasts play significant roles in atrial fibrosis. Mitsugumin (MG)53 is predominantly expressed in myocardium of rodents and has multiple biological functions. However, the role of MG53 in cardiac fibrosis remains unclear. This study provided clinical and experimental evidence for the involvement of MG53 in atrial fibrosis in humans and atrial fibrosis phenotype in cultured rat atrial fibroblasts. In atrial tissue from patients we demonstrated that MG53 was expressed in human atrium. Expression of MG53 increased with the extent of atrial fibrosis, which could induce AF. In cultured atrial fibroblasts, depletion of MG53 by siRNA caused down-regulation of the TGF-β1/Smad pathway, while overexpression of MG53 by adenovirus up-regulated the pathway. MG53 regulated the proliferation and migration of atrial fibroblasts. Besides, exogenous TGF-β1 suppressed expression of MG53. In conclusion, we demonstrated that MG53 was expressed in human atrium, and may be a potential upstream of the TGF-β1/Smad pathway in human atrium and rat atrial fibroblasts. This suggests that MG53 is a potential regulator of atrial fibrosis induced by the TGF-β1/Smad pathway in patients with AF.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Abrogation of Fam20c altered cell behaviors and BMP signaling of immortalized dental mesenchymal cells

Highlights: • Fam20c deficiency decreases the proliferation, mobility and mineralization of mouse immortalized dental mesenchymal cells. • Fam20c deficiency decreases the tooth mineralization, as well as the gene expression on dental mesenchymal differentiation. • Canonical and non-canonical BMP signaling pathways are declined in the mouse Fam20c-deficient dental mesenchyaml cell line. FAM20C mutations compromise the mineralization of skeleton and tooth in both human and mouse. Putatively, the mineralization disorder is attributed to the elevated fibroblast growth factor 23 (FGF23), which reduced the serum phosphorus by suppressing the reabsorption of phosphorus in kidney. Besides the regulation on systemic phosphorus homeostasis, FAM20C was also implicated to regulate cell behaviors and gene expression through a cell-autonomous manner. To identify the primary effects of Fam20c on dental mesenchymal cells, mouse Fam20c-deficient dental mesenchymal cells were generated by removing the floxed alleles from the immortalized mouse Fam20c{sup f/f} dental mesenchymal cells with Cre-expressing lentivirus. The removal of Fam20c exerted no impact on cell morphology, but suppressed the proliferation and mobility of the dental mesenchymal cells. Fam20c deficiency also significantly reduced the expression of Osterix, Runx2, type I Collagen a 1 (Col1a1), Alkaline phosphatase (Alpl) and the members of the small integrin-binding ligand, N-linked glycoprotein (SIBLING) family, but increased Fgf23 expression. Consistently, the in vitro mineralization of Fam20c-deficient dental mesenchymal cells was severely disabled. However, supplements of the non-collagenous proteins from wild type rat dentin failed to rescue the compromised mineralization, suggesting that the roles of FAM20C in tooth mineralization are more than phosphorylating local matrices and regulating systemic phosphorus metabolism. Moreover, the down-regulated BMP signaling pathways in the Fam20c deficient dental mesenchymal cells revealed that the kinase activity of FAM20C might be required to maintain BMP signaling. In summary, our study discloses that Fam20c indeed regulates cell behaviors and cell signaling pathway in a cell-autonomous manner.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Silencing of Kangai 1 C-terminal interacting tetraspanin suppresses progression of cholangiocarcinoma

Highlights: • KITENIN is expressed in murine and human cholangiocarcinoma (CC). • Knockdown of KITENIN reduced proliferation, migration, invasion and colony formation in CC cells. • Silencing of KITENIN inhibited the expression of epithelial-mesenchymal transition markers. • Targeting of KITENIN might function as a new therapeutic strategy against CC. Cholangiocarcinoma (CC) is the second most common primary hepatic malignancy. CC treatment options are very limited especially for patients with distant metastasis. Kangai 1 C-terminal interacting tetraspanin (KITENIN) is highly expressed in numerous cancers, but the role of KITENIN in CC remains unknown. Here, we have investigated for the first time the function of KITENIN in human CC cell lines (TFK-1, SZ-1), tissues and a CC mouse model (Alb-Cre/LSL-KRAS{sup G12D}/p53{sup L/L}). KITENIN was expressed in 92.2% of human CC tissues, in murine CC samples and also in human CC cell lines. Knockdown of KITENIN by small interfering RNA (siRNA) effectively reduced proliferation, migration, invasion and colony formation in both intra- and extra-hepatic CC cells. The expression of epithelial-mesenchymal transition (EMT) markers like N-cadherin, Vimentin, Snail and Slug were suppressed in KITENIN knockdown CC cells. Our results indicate that KITENIN is crucial for cholangiocarcinogenesis and it might become a potential therapeutic target for human CC treatment.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Survivin regulated by autophagy mediates hyperglycemia-induced vascular endothelial cell dysfunction

Highlights: • HG did not induce endothelial cell injury directly, but increased cell viability after 72 h. • HG triggered upregulation of survivin expression as well as key components of autophagy pathway. • Survivin regulated HG-induced vascular endothelial cell dysfunction mediated by autophagy pathway. Diabetic vascular complications are often defined by vascular endothelial lesions. However, as a plastic cell type, whether endothelial cells could transit from quiescence to hyper-active status and hamper vascular stability upon hyperglycemia stimulation and whether this process is involved in diabetic vascular complications remain obscure. Survivin has been identified as an anti-apoptotic protein in tumor or epithelial cells by either promoting proliferation or inhibiting apoptosis. Therefore, this study aims at investigating the effects of hyperglycemia on endothelial cell status and the potential involvement of survivin. We found that high glucose (25 mM) did not cause endothelial injuries, instead, it evidently promotes endothelial proliferation and tube formation capacity indicating endothelial cell dysfunction upon hyperglycemia characterized by its preference to hyper-active status. Concomitantly, an upregulation of survivin was detected accompanied by the key component elevations of autophagy pathway including LC3, Beclin1, and p62. YM155, a specific inhibitor of survivin, could abrogate hyperglycemia-induced endothelial hyper-activation. Application of the autophagy inhibitor (3MA) and agonist (rapamycin) supported that survivin could be as a downstream effect or of autophagy. Thus, our results suggested that survivin/autophagy axis a potential therapeutic target in treatment of diabetic vascular complications.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

ISG15 promotes esophageal squamous cell carcinoma tumorigenesis via c-MET/Fyn/β-catenin signaling pathway

Highlights: • ISG15 is highly expressed in ESCC tissues and plasma, representing a promising diagnostic marker. • ISG15 positively regulated the proliferation, invasion and migration in vitro and in vivo. • ISG15 mediates the tumorigenesis via c-MET/Fyn/β-catenin pathway. Esophageal squamous cell carcinoma (ESCC) is one of the most malignant tumors in China with a poor prognosis. Most ESCC patients were diagnosed at advanced stages, losing the opportunity for surgical excision. Hence, it remains a pressing work to identify biomarkers for early detection, prognosis prediction and targeting therapies in ESCC. Interferon-stimulated gene 15 (ISG15) encodes a 15-kDa protein, and is involved in the post-translational modification (PTMs) of multiple proteins. However, the molecular functions of ISG15 in ESCC remain unclear. In this work, we found that ISG15 was aberrantly expressed in ESCC tissues and cell lines. Enhanced protein level of ISG15 promoted cellular malignant phenotypes including proliferation, migration, invasion and tumor formation in vivo. Consistently, reduction of ISG15 attenuated the cellular malignant phenotype in ESCC cell lines. Furthermore, gene-expression profiles suggested that the differentially expressed ISG15 affected the expression of a panel of genes enriched in the cell adherens junction, such as c-MET. Notably, as a secreted protein, the concentration of ISG15 was elevated in ESCC plasma than healthy individuals, acting as a potential diagnostic marker. Taken together, our results suggested a tumor promotion role of ISG15 in ESCC via c-MET/Fyn/β-catenin pathway.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Exosomes derived from endothelial progenitor cells ameliorate acute lung injury by transferring miR-126

Highlights: • Administration of EPC-Exos ameliorated LPS-induced ALI and restored the in vivo lung integrity. • The microRNA miR-126 was enriched in EPC-Exos and the abilities of EPC-Exos to protect against LPS were relayed by the horizontal shuttled miR-126. • Transferred miR-126 to target endothelial cells downregulated SPRED1 and implicated RAF/ERK signaling pathways in the reparative process in rat model of lung injury. Endothelial progenitor cell (EPC) has potential to attenuate pulmonary inflammation and injury. As a pivotal paracrine entity of stem cells, whether EPC-derived exosomes (EPC-Exos) contribute to acute lung injury (ALI) remains unknown. Exosomes were purified from conditional medium of EPCs, and then characterized by electron micrograph and immunoblotting. A model of ALI was induced by lipopolysaccharide (LPS) and then rats were transplanted with EPC-Exos. The underlying mechanisms of action of EPC-Exos were examined in vitro endothelial functional assays including the TEER, proliferation (CKK-8), angiogenesis and migration. A possible underlying mechanism was examined by western blotting and further animal studies. Administration of EPC-Exos ameliorated LPS-induced ALI and restored the in vivo pulmonary integrity. EPC-Exos enhanced the proliferation, migration and tube formation of the endothelial cells (ECs). Furthermore, we found that miR-126 was enriched in EPC-Exos and can be delivered onto ECs. Modification of EPCs through miR-126 knockdown can diminish their exosomes function in vitro, indicative of the abilities of EPC-Exos to protect against LPS were inherited by the horizontal shuttled miR-126. Luciferase reporter assays confirmed that miR-126 could target SPRED1. Additionally, the miR-126 transferred to target endothelial cells resulted in subsequent downregulation of SPRED1 and promoted RAF/ERK signaling pathways and subsequent improvement in endothelial cell function. Our study revealed a novel role of exosomal miRNAs in EPC-mediated therapy, suggesting that the clinical application of EPC-Exos might represent a strategy in ALI/ARDS.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Resveratrol promotes oxidative stress to drive DLC1 mediated cellular senescence in cancer cells

Highlights: • Resveratrol stimulates senescence-associated proteins to induce cellular senescence. • Resveratrol causes mitochondrial dysfunction to promote ROS production. • DLC1 is essential for resveratrol induced senescence by promoting ROS production. • DLC1 induces cellular senescence through FoxO3a/NF-κB signaling mediated by SIRT1. • ROS production as the cause of resveratrol to induce DNA damage in cancer cells. Induction of cellular senescence represents a novel strategy to inhibit aberrant proliferation of cancer cells. Resveratrol is gaining attention for its cancer preventive and suppressive properties. Tumor suppressor gene DLC1 is shown to induce apoptosis, suppress migration and invasion in various cancer cells. However, the function of DLC1 in cancer cellular senescence is unclear. This study was designed to investigate the biological role of DLC1 in resveratrol induced cancer cellular senescence. Our results showed that resveratrol inhibited proliferation of cancer cell lines (MCF-7, MDA-MB-231 and H1299) and induced senescence along with increase of SA-β-gal activity and regulation of senescence-associated molecular markers p38MAPK, p-p38MAPK, p27, p21, Rb and p-Rb protein. The underlying mechanism was that resveratrol induced mitochondrial dysfunction with reduction of mitochondrial membrane potential, down-regulation of MT-ND1, MT-ND6 and ATPase8 in transcript level and down-regulation of PGC-1α in protein level to result in ROS production. With ROS elevation, resveratrol decreased DNMT1 and increased DLC1 expression significantly. However, after ROS scavenger NAC was added to the cancer cells treated by resveratrol, DNMT1, DLC1 and senescence-associated molecular markers were reversed. This reveals that resveratrol induced cancer cellular senescence through DLC1 in a ROS-dependent manner. Silencing DLC1 markedly attenuated SA-β-gal activity and p38MAPK, p27 and p21 protein levels, and increased Rb expression, indicating that resveratrol promoted senescence via targeting DLC1. Moreover, DLC1 promoted senescence through FoxO3a/NF-κB signaling mediated by SIRT1 after resveratrol treatment. Finally, resveratrol increased ROS production to induce DNA damage with p-CHK1 up-regulation and result in cancer cellular senescence. This is the first time to investigate resveratrol induced cancer cellular senescence by primarily targeting DLC1. Induction of cellular senescence by resveratrol may represent a novel anticancer mechanism.

60 APPLIED LIFE SCIENCES↗