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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 1,027 records · Page 57
All sourcesNASA NTRSDOE OSTI
DOE OSTI2017

Expansion of CD26 positive fibroblast population promotes keloid progression

Background: Keloid is a skin fibrosis disease that characterised by invasive growth of fibroblasts and aberrant deposition of extracellular matrix. Studies indicated that keloid fibroblasts (KFs) is a class of ‘activated’ fibroblasts, which show accelerated proliferation and excessive extracellular matrix formation as compared with normal fibroblasts (NFs). However, the mechanism underlying keloid fibroblasts dysfunction is still unknown. Objective: To verify CD26 expression difference between KFs and NFs, and investigate the function of CD26 positive fibroblasts in keloid progression. Methods: KFs and NFs were isolated from Keloid tissues and normal skin tissues respectively. Flow cytometry was performed to isolate CD26+/CD26- fibroblasts from KFs and NFs. Proliferation of different fibroblasts were analyzed by CCK8 assay and Ki 67 straining. Profibrotic phenotype difference was detected by qRT-PCR, western blot, ELISA and immunofluorescence. Scratching experiment and transwell assay were used to assess invasion ability of CD26+/CD26- fibroblasts. Diprotin A was used as a CD26 inhibitor to further investigated the function of CD26 fibroblasts in keloid disease. Result: CD26 expression was increased in KFs, and the proportion of CD26+ fibroblasts was significantly increased in KFs. Cell viability analysis showed that CD26+ fibroblasts was more active in proliferation. Furthermore, the expression of profibrotic genes were increased in CD26+ fibroblasts, including TGF-β1, IGF-1, IL6, collagen 1, collagen 3 and fibronectin. And meanwhile, CD26+ fibroblasts showed stronger invasion ability as compared to CD26- fibroblasts. Moreover, Diprotin A significantly suppressed proliferation and extracellular matrix secretion of CD26+ fibroblasts isolated from keloid tissues. Conclusion: Our findings suggest that CD26+ fibroblasts possess proliferation advantage in compare to CD26- fibroblasts, and the advantage caused expansion of CD26 positive fibroblast population promotes keloid progression.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Inhibition of glycolysis by a novel EGFR/HER2 inhibitor KU004 suppresses the growth of HER2+ cancer

Upregulation of glycolysis was often observed in human HER2-overexpressing cancers. In this study, we demonstrated that KU004, a dual novel EGFR/HER2 inhibitor, disrupted cancer cell proliferation via modulation of glycolysis. KU004, inhibited the Warburg effect by suppressing hexokinase II (HK2) expression at the transcriptional and post-translational levels. Further study demonstrated that the downregulation of HKII by KU004 was mainly mediated by the PI3K/Akt signaling pathway. Furthermore, the role of HKII downregulation in KU004-mediated antitumor effect was also confirmed in our in vivo xenograft model. Collectively, these data suggest that multifaceted targeting the aberrant glucose metabolism along with the upstream HER2 may be an effective approach for clinical treatment against HER2+ cancer. - Highlights: • KU004suppressed the glucose metabolism in HER2-overexpressing cancer cells. • KU004 inhibited HKII expression both transcriptionally and post-translationally. • The downregulation of HKII is mediated by the PI3K/Akt signaling pathway. • KU004 inhibited HKII expression and the growth of HER2-overexpressing cells both in vitro and in vivo.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Downregulation of USP18 inhibits growth and induces apoptosis in hepatitis B virus-related hepatocellular carcinoma cells by suppressing BCL2L1

Ubiquitin-specific peptidase 18 (USP18) is closely related with hepatitis B virus (HBV), which has been involved in tumourigenesis. However, there has been little research into the role of USP18 on the progression of hepatocellular carcinoma (HCC), especially in HBV-related HCC. In present study, we found that USP18 expression was aberrantly elevated in HCC tissues than adjacent non-tumour tissues. Importantly, USP18 expression was higher in HBV-related HCC cell lines (HepG2.2.15 and Hep3B) than HBV-unrelated HCC cell lines. Furthermore, knockdown of USP18 significantly suppressed tumour cell proliferation in vitro and tumour growth in vivo, whereas overexpression of USP18 promoted HCC cells growth. Moreover, our experimental data revealed that USP18 silencing obviously blocked cell cycle at G1 phase and increased cell apoptosis. Finally, BCL2L1, a member of BCL2 family protein, was identified as a downstream gene of USP18. Mechanistically, we found that USP18 directly bind to BCL2L1 and positively regulated its expression in HCC cells. Overall, our results suggested that USP18 has a crucial role in regulating diverse aspects of the pathogenesis of HCC, indicating that it might be a potential therapeutic target.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Altered O-glycosylation is associated with inherent radioresistance and malignancy of human laryngeal carcinoma

Highlights: • O-glycosylation contributes to laryngeal carcinoma inherent radioresistance. • O-glycosylation regulates laryngeal carcinoma cell migration and invasion. • O-glycosylation is associated with tumor progression and poor prognosis. • C1GALT1 modifies the O-glycans on integrin β1 and regulates its activity. Radioresistance (inherent or acquired) remains a major obstacle affecting the clinical outcome of radiotherapy for laryngeal carcinoma. Results from our laboratory and other groups suggest that aberrant glycosylation contributes to cancer acquired radioresistance. However, the role of glycosylation in inherent radioresistance of laryngeal carcinoma has not been fully uncovered. In this study, we investigated the glycan profiling of the inherent radioresistant (Hep-2max) and radiosensitive (Hep-2 min) cell lines using lectin microarray analysis. The results revealed that the radioresistant cell line Hep-2max presented higher core 1-type O-glycans than the sensitive one. Further analysis of the O-glycan regulation by benzyl-α-GalNAc application in Hep-2max cells showed partial inhibition of the O-glycan biosynthesis and increased radiosensitivity. In addition, core 1 β1, 3-galactosyltransferase (C1GALT1) overexpression in Hep-2 min cells enhanced cell migration, invasion, and radioresistance. Conversely, knockdown of C1GALT1 in Hep-2max cells was able to suppress these malignant phenotypes. Moreover, mechanistic investigations showed that C1GALT1 modified the O-glycans on integrin β1 and regulated its activity. The glycosylation-mediated radioresistance was further inhibited by anti-integrin β1 blocking antibody. Importantly, we also observed that core 1-type O-glycans expression was correlated with advanced tumor stage, metastasis, and poor survival of laryngeal carcinoma patients. These findings suggest that altered O-glycosylation can lead to the inherent radioresistance and progression, and therefore may be important for enhancing the efficacy of radiotherapy in laryngeal carcinoma.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

AF119895 regulates NXF3 expression to promote migration and invasion of hepatocellular carcinoma through an interaction with miR-6508-3p

Highlights: • A new LncRNA, AF119895, was aberrantly upregulated in HCC tissues and HCC cells. • AF119895 promoted HCC cell migration and invasion in vitro and in vivo. • NXF3 was a downstream target of AF119895. • NXF3 depletion could decrease HCC cells migration and invasion. • AF119895 could act as an endogenous sponge by binding to miR-6508-3p and reduce miR-6508-3p expression. • AF119895 modulates the repression of NXF3 by binding to miR-6508-3p to promote migration and invasion of hepatocellular carcinoma. Various studies revealed that numerous long noncoding RNAs (lncRNAs) have been found dysregulated in HCC and played important role in hepatocarcinogenesis, although the underlying mechanism still remains unclear. Herein, we reported AF119895, a new lncRNA which was identified from microarray and amplified in HCC. Functionally, AF119895 promoted migration and invasion of HCC cells both in vitro and in vivo. Furthermore, we identified that NXF3 was a downstream target of AF119895. NXF3 depletion could decrease HCC cells migration and invasion. In addition, AF119895 could act as an endogenous sponge by binding to miR-6508-3p and reduce miR-6508-3p expression. And miR-6508-3p could regulate NXF3 by interacting with its 3′UTR. These observations collectively demonstrate that AF119895 modulates the repression of NXF3 by binding to miR-6508-3p. Our results outline a novel signaling pathway mediated by AF119895 and suggest its candidacy as a new prognostic biomarker and therapeutic target of HCC.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Tiam1 promotes thyroid carcinoma metastasis by modulating EMT via Wnt/β-catenin signaling

Aberrant expression of the guanine nucleotide exchange factor Tiam1 is implicated in the invasive phenotype of many cancers. However, its involvement in thyroid carcinoma and downstream molecular events remains largely undefined. Here, we examined the effects of Tiam1 on the invasiveness and metastasis of thyroid carcinoma in vitro and in vivo and explored the underlying mechanisms by investigating the regulation of Tiam1 expression and the downstream pathways affected. Our results showed that Tiam1 knockdown inhibited the migratory and invasive capacity of thyroid cancer cells, suppressed epithelial-mesenchymal transition (EMT), and inhibited Wnt/β-catenin signaling in vitro. Moreover, Tiam1 knockdown suppressed liver metastasis development in vivo. The effects of Tiam1 on metastasis and EMT mediated by the Wnt/β-catenin pathway were reversed by Rac1 silencing, suggesting that the prometastatic effect of Tiam1 is mediated by the activation of Rac1. These results indicate that Tiam1 may be a prognostic factor and potential therapeutic target for the treatment of thyroid cancers.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Mesenchymal stem cell exosomes promote immunosuppression of regulatory T cells in asthma

Highlights: • MSC exosomes promote Tregs proliferation by upregulating IL-10 and TGF-β1 in asthma. • MSC exosomes enhance immunosuppression capacity of Tregs from asthmatic patient. • The effect of MSC exosomes on Tregs may be mediated by APCs. Mesenchymal stem cells (MSCs) and regulatory T cells (Tregs) are both potent immune-modulators. The aberrant proliferation and function of Tregs plays an important role in the development of asthma. Our previous studies have demonstrated the role of MSCs in promoting proliferation and immune-modulating of Tregs, as well as alleviating airway inflammation of asthmatic mice. In the present study, we isolated exosomes secreted by MSCs and investigated their immunomodulation effect on peripheral blood mononuclear cells (PBMCs) of asthmatic patient. We found that MSC exosomes upregulated IL-10 and TGF-β1 from PBMCs, thus promoting proliferation and immune-suppression capacity of Tregs. Furthermore, antigen presenting cells (APCs) but not CD4+ T cells-dependent pathway was shown to be possible mechanism involved in MSC exosome-mediated regulation. Our data elucidated the key role of exosomes in immune-modulation of MSCs, and suggested the therapeutic potential of MSC exosomes for asthma.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

SPARC is down-regulated by DNA methylation and functions as a tumor suppressor in T-cell lymphoma

Highlights: • SPARC is significantly down-regulated in T-NHL tissues and cell lines. • High levels of SPARC demonstrated a favorable clinical outcome. • SPARC inhibits proliferation, invasion and migration, but promotes apoptosis of T-NHL cells. • 5-Aza-Cdr inhibits proliferation, invasion and migration, but promotes apoptosis of T-NHL cells. The aim of this study was to assess the functional role of SPARC in T-cell non-Hodgkin's lymphoma (T-NHL), as well as the underlying molecular mechanisms. Here, we first identified SPARC expression in T-NHL tissues and cell lines through western blot and real-time PCR (RT-PCR). Overall survival of T-NHL patients with different levels of SPARC was assessed by Kaplan-Meier survival curves. Then cell proliferation, apoptosis, migration and invasion of T-NHL cells with either knockdown or overexpression of SPARC were determined by MTT, flow cytometry, transwell migration and invasion assay, respectively. Finally, the molecular mechanism by which SPARC modulated T-NHL cell progression was assessed. We confirmed that SPARC was significantly down-regulated in T-NHL tissues and cell lines. T-NHL patients with high levels of SPARC demonstrated a favorable clinical outcome. SPARC significantly suppressed cell proliferation, migration and invasion, and EMT process, but facilitated cell apoptosis in T-NHL cells. Further, we found that loss of SPARC expression in T-NHL tissues and cell lines, both in mRNA and protein levels, was associated with the aberrant DNA methylation in SPRAC gene, and the disrupted SPARC expression could be rescued after treatment with the demethylating agent 5-Aza-2′-deoxycitydine (5-Aza-Cdr). Additionally, 5-Aza-Cdr reversed SPARC hypermethylation to restore its biological role as a tumor suppressor in T-NHL cells, including inhibiting cell proliferation, invasion and migration, while promoting cell apoptosis. Our data provided evidence that DNA methylation in SPARC gene may play a role in the progression of T-NHL.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

The formation of giant plasma membrane vesicles enable new insights into the regulation of cholesterol efflux

Highlights: • Giant plasma membrane vesicles serve as a means to monitor cell surface cholesterol. • Increase in cholesterol efflux enhances giant plasma membrane vesicle formation. • Microtubule stabilization and acetylation promote cholesterol efflux in NPC disease. • Actin dynamics and Arl4c modulate lipid efflux and giant plasma membrane vesicles. Aberrant cellular cholesterol accumulation contributes to the pathophysiology of many diseases including neurodegenerative disorders such as Niemann-Pick Type C (NPC) and Alzheimer's Disease{sup 1–4}. Many aspects of cholesterol efflux from cells remain elusive. Here we describe the utility of cholesterol-rich giant plasma membrane vesicles (GPMVs) as a means to monitor cholesterol that is translocated to the plasma membrane for secretion. We demonstrate that small molecules known to enhance lipid efflux, including those in clinical trials for lipid storage disorders, enhance this GPMV formation. Conversely, pharmacological inhibition of cholesterol efflux blocks GPMV formation. We show that microtubule stabilization via paclitaxel treatment and increased tubulin acetylation via HDAC6 inhibition promotes the formation of GPMVs with concomitant reduction in cellular cholesterol in a cell model of NPC disease. The pan-deacetylase inhibitor panobinostat, which has been shown to reduce the severity of cholesterol storage in NPC, elicited a similar response. Further, the disruption of actin polymerization inhibits the formation of GPMVs, whereas the small GTP-binding protein Arl4c promotes actin remodeling at sites overlapping with GPMV formation. Thus, monitoring the formation of GPMVs provides a new avenue to better understand diseases whose pathology may be sensitive to alterations in cellular cholesterol.

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

NUSAP1 gene silencing inhibits cell proliferation, migration and invasion through inhibiting DNMT1 gene expression in human colorectal cancer

Highlights: • NUSAP1 was upregulated in human CRC tissues and cell lines. • NUSAP1 regulates CRC cell proliferation and cell apoptosis. • NUSAP1 mediates CRC cell invasion, migration and EMT. • NUSAP1 silencing suppress the DNMT1 gene expression. Colorectal cancer (CRC) is one of the most common cause of cancer-related death in both female and male patients, with a high capacity for tumor migration and invasion. Recently, aberrant nucleolar and spindle-associated protein 1 (NUSAP1) expression has been reported in several cancers. However, the biological function and molecular mechanism of NUSAP1 in CRC have not been reported. Here, we demonstrated that NUSAP1 gene expression was notably upregulated in CRC tissues and cell lines (Caco2, LS174T, SW480, and LoVo). Subsequently, SW480 and LoVo cells were transfected with NUSAP1 siRNA, respectively, and the biological function of NUSAP1 was investigated. Results indicated that NUSAP1 silencing by siRNA inhibited CRC cell proliferation, and induces cell apoptosis. Moreover, NUSAP1 knockdown suppressed cell migration, cell invasion, and epithelial-to-mesenchymal transition (EMT). Furthermore, NUSAP1 silencing notably inhibited the mRNA and protein expression level of DNA methyltransferase 1 (DNMT1). DNMT1 overexpression partly rescued the effect of NUSAP1 silencing on colorectal cancer biological function. Taken together, NUSAP1 gene silencing induced cell apoptosis, and inhibited cell proliferation, cell migration, cell invasion, and EMT in colorectal cancer through inhibiting DNMT1 gene expression. These findings indicat that NUSAP1 is a promising molecular target for CRC treatment.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

A high-sugar diet affects cellular and humoral immune responses in Drosophila

Highlights: • A high-sugar diet impairs the in vivo phagocytosis. • A high-sugar diet disrupts the F-actin extension and the sessile hemocyte structure. • A high-sugar diet activates JNK and Toll pathways in innate immune system. A high-sugar diet (HSD) induces Type 2 diabetes (T2D) and obesity, which severely threaten human health. The Drosophila T2D model has been constructed to study the mechanisms of insulin resistance, diet-induced cardiovascular diseases and other conditions. Innate immunity is the first line of defense against invading pathogens and parasites. However, few studies have focused on the relationship between a HSD and the innate immune response in Drosophila. In this study, we fed flies a high-sucrose diet and observed defects in the phagocytosis of latex beads and B. bassiana spores. The actin cytoskeleton was also disrupted in hemocytes from HSD-fed larvae. Furthermore, HSD induced the differentiation of lamellocytes in the lymph gland and circulating hemolymph, which rarely occurs in healthy bodies, via JNK signaling. In addition, the Toll and JNK pathways were excessively activated in the fat bodies of HSD-fed larvae, and a large number of dead cells were observed. Finally, HSD induced the aberrant activation of the innate immune system, including inflammation. Our results have established a connection between T2D and the innate immune response.

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↗
DOE OSTI2018

CDK7 activated beta-catenin/TCF signaling in hepatocellular carcinoma

Over-activation of beta-catenin/TCF signaling is very common in the progression of hepatocellular carcinoma (HCC). The molecular mechanisms leading to the aberrant activation of beta-catenin/TCF signaling are not fully understood. In this study, it was found that CDK7 was up-regulated in HCC tissues and its expression inversely correlated with the survival of HCC patients. Functional study showed that CDK7 promoted the growth and migration of HCC cells, and knocking down the expression of CDK7 inhibited the growth of HCC cells in both liquid culture and soft agar. Mechanistically, CDK7 interacted with beta-catenin, enhanced the interaction between beta-catenin and TCF4, and activated beta-catenin/TCF signaling. Taken together, this study demonstrated the oncogenic roles of CDK7 in HCC and suggested that CDK7 might be a promising therapeutic target.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Hippo, Drosophila MST, is a novel modifier of motor neuron degeneration induced by knockdown of Caz, Drosophila FUS

Highlights: • Mutation in Hippo suppressed aberrant eye morphology induced by Cabeza knockdown. • Mutation in Hippo suppressed neuron-specific defects induced by Cabeza knockdown. • Mutation in Hippo restored Cabeza protein in the nucleus. • Hippo mRNA level increased in Cabeza knockdown. • Cabeza may negatively regulate hippo. Mutations in the Fused in Sarcoma (FUS) gene have been identified in familial ALS in human. Drosophila contains a single ortholog of human FUS called Cabeza (Caz). We previously established Drosophila models of ALS targeted to Caz, which developed the locomotive dysfunction and caused anatomical defects in presynaptic terminals of motoneurons. Accumulating evidence suggests that ALS and cancer share defects in many cellular processes. The Hippo pathway was originally discovered in Drosophila and plays a role as a tumor suppressor in mammals. We aimed to determine whether Hippo pathway genes modify the ALS phenotype using Caz knockdown flies. We found a genetic link between Caz and Hippo (hpo), the Drosophila ortholog of human Mammalian sterile 20-like kinase (MST) 1 and 2. Loss-of-function mutations of hpo rescued Caz knockdown-induced eye- and neuron-specific defects. The decreased Caz levels in nuclei induced by Caz knockdown were also rescued by loss of function mutations of hpo. Moreover, hpo mRNA level was dramatically increased in Caz knockdown larvae, indicating that Caz negatively regulated hpo. Our results demonstrate that hpo, Drosophila MST, is a novel modifier of Drosophila FUS. Therapeutic targets that inhibit the function of MST could modify the pathogenic processes of ALS.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

MicroRNA-23a promotes colorectal cancer cell survival by targeting PDK4

Highlights: • miR-23a is overexpressed in CRC cell lines and tissues compared with that of normal cells. • miR-23a repress both the mRNA and protein expressions of PDK4. • PDK4 negatively regulate CRC proliferation via suppressing PDH activity. • miR-23a facilitates PDH activation and oxidative phosphorylation via targeting PDK4. • miR-23a promotes CRC cells proliferation in vitro and in vivo via targeting PDK4. MicroRNA (miR) is important regulators of gene expression, and aberrant miR expression has been linked to oncogenesis; however, little is understood about their contribution to colorectal cancer (CRC). Here, we determined that miR-23a is overexpressed in human colorectal cancer cell lines and tissues compared with that of normal cells. The stable over-expression of miR-23a in CRC cells was sufficient to promote cell proliferation in vitro and in vivo. Further studies showed that miR-23a can directly bind to the 3′untranslated region (3′UTR) of PDK4 mRNA and subsequently repress both the mRNA and protein expressions of PDK4. PDK4 negatively regulate CRC proliferation via suppressing PDH activity. Ectopic expression of PDK4 by transiently transfected with PDK4 vector encoding the entire coding sequence could reverse the effects of miR-23a on CRC proliferation. By this way, miR-23a promotes PDH activation and oxidative phosphorylation to generate sufficient ATP for cell proliferation. Our results illustrated that the up-regulation of miR-23a played an important role in CRC cell proliferation through direct repressing PDK4, suggesting a potential application of miR-23a in prognosis prediction and therapeutic application in CRC.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Lymphocytic microparticles suppress retinal angiogenesis via targeting Müller cells in the ischemic retinopathy mouse model

Highlights: F0B7 • LMPs possess strong angiogenesis-inhibiting properties. F0B7 • LMPs suppress Müller cell-derived angiogenic/chemoattractant factors. F0B7 • LMPs attenuate pathological retinal NV and the infiltration of macrophages in vivo. F0B7 • LMPs downregulate ERK1/2 and HIF-1α both in vitro and in vivo. Retinopathy of prematurity (ROP) is the primary cause of visual impairment and vision loss in premature infants, which results from the formation of aberrant retinal neovascularization (NV). An emerging body of evidence has shown that Müller cells are the predominant source of vascular endothelial growth factor (VEGF), which also serves as a chemoattractant for monocyte/macrophage lineage. The recruitment of macrophages is increased during retinal NV, and they exert a pro-angiogenic role in ROP. We have shown that lymphocytic microparticles (microvesicles; LMPs) derived from apoptotic human T lymphocytes possess strong angiogenesis-inhibiting properties. Here, we investigated the effect of LMPs on the chemotactic capacity of Müller cells in vitro using rat Müller cell rMC-1 and mouse macrophage RAW 264.7. In addition, the impact of LMPs was determined in vivo using a mouse model of oxygen-induced ischemic retinopathy (OIR). The results revealed that LMPs were internalized by rMC-1 and reduced their cell proliferation dose-dependently without inducing cell apoptosis. LMPs inhibited the chemotactic capacity of rMC-1 on RAW 264.7 via reducing the expression of VEGF. Moreover, LMPs attenuated pathological retinal NV and the infiltration of macrophages in vivo. LMPs downregulated ERK1/2 and HIF-1α both in vitro and in vivo. These findings expand our understanding of the effects of LMPs, providing evidence of LMPs as a promising therapeutic approach for the treatment of retinal NV diseases.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

miRNAs: Critical mediators of breast cancer metastatic programming

Highlights: • This review highlights the crucial role played by miRNAs in the process of metastatic evolution of breast cancer. MicroRNA mediated aberrant gene regulation has been implicated in several diseases including cancer. Recent research has highlighted the role of epigenetic modulation of the complex process of breast cancer metastasis by miRNAs. miRNAs play a crucial role in the process of metastatic evolution by facilitating alterations in the phenotype of tumor cells and the tumor microenvironment that promote this process. They act as critical determinants of the multi-step progression starting from carcinogenesis all the way to organotropism. In this review, we focus on the current understanding of the compelling role of miRNAs in breast cancer metastasis.

60 APPLIED LIFE SCIENCES↗