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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 667 records · Page 37
All sourcesNASA NTRSDOE OSTI
DOE OSTI2012

KLF10, transforming growth factor-{beta}-inducible early gene 1, acts as a tumor suppressor

Highlights: Black-Right-Pointing-Pointer KLF10{sup -/-} mice exhibited accelerated papilloma development after DMBA/TPA treatment. Black-Right-Pointing-Pointer KLF10{sup -/-} keratinocytes showed increased proliferation and apoptosis. Black-Right-Pointing-Pointer KLF10{sup -/-} MEFs yielded more colonies than wild-type one with H-Ras transfection. Black-Right-Pointing-Pointer KLF10 dose-dependently activated p21{sup WAF1/CIP1} transcription. Black-Right-Pointing-Pointer KLF10 is a tumor suppressor and that it targets p21{sup WAF1/CIP1} transcription. -- Abstract: Krueppel-like factor 10 (KLF10) has been suggested to be a putative tumor suppressor. In the present study, we generated KLF10 deficient mice to explore this hypothesis in vivo. KLF10 deficient mice exhibited increased predisposition to skin tumorigenesis and markedly accelerated papilloma development after DMBA/TPA treatment. On the other hand, KLF10 deficient keratinocytes showed increased proliferation and apoptosis. In colony formation assays after oncogenic H-Ras transfection, KLF10 deficient mouse embryonic fibroblasts (MEFs) yielded more colonies than wild-type MEFs. Furthermore, KLF10 dose-dependently activated p21{sup WAF1/CIP1} transcription, which was independent of p53 and Sp1 binding sites in p21{sup WAF1/CIP1} promoter. This study demonstrates that KLF10 is a tumor suppressor and that it targets p21{sup WAF1/CIP1} transcription.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2013

Myostatin acts as an autocrine/paracrine negative regulator in myoblast differentiation from human induced pluripotent stem cells

Highlights: ► iPS-derived cells express myostatin and its receptor upon myoblast differentiation. ► Myostatin inhibits myoblast differentiation by inhibiting MyoD and Myo5a induction. ► Silencing of myostatin promotes differentiation of human iPS cells into myoblasts. -- Abstract: Myostatin, also known as growth differentiation factor (GDF-8), regulates proliferation of muscle satellite cells, and suppresses differentiation of myoblasts into myotubes via down-regulation of key myogenic differentiation factors including MyoD. Recent advances in stem cell biology have enabled generation of myoblasts from pluripotent stem cells, but it remains to be clarified whether myostatin is also involved in regulation of artificial differentiation of myoblasts from pluripotent stem cells. Here we show that the human induced pluripotent stem (iPS) cell-derived cells that were induced to differentiate into myoblasts expressed myostatin and its receptor during the differentiation. An addition of recombinant human myostatin (rhMyostatin) suppressed induction of MyoD and Myo5a, resulting in significant suppression of myoblast differentiation. The rhMyostatin treatment also inhibited proliferation of the cells at a later phase of differentiation. RNAi-mediated silencing of myostatin promoted differentiation of human iPS-derived embryoid body (EB) cells into myoblasts. These results strongly suggest that myostatin plays an important role in regulation of myoblast differentiation from iPS cells of human origin. The present findings also have significant implications for potential regenerative medicine for muscular diseases.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

MiR-361-5p acts as a tumor suppressor in prostate cancer by targeting signal transducer and activator of transcription-6(STAT6)

Highlights: • The role of miR-361-5p in prostate cancer (PCa) has not been evaluated until date. • We found that the expression of miR-361-5p in CRPC was lower than in ADPC. • MiR-361-5p suppressed DU145 cell proliferation and triggered apoptosis. • STAT6 is a direct target of miR-361-5p. • STAT6 enhances the expression of Bcl-xL at the transcriptional level. - Abstract: Castration-resistant prostate cancer (CRPC), whose pathogenesis is known to be regulated by microRNAs (miRNAs), has a poor prognosis. In our present study, we found that the expression of miR-361-5p in CRPC was lower than in androgen-dependent prostate cancer (ADPC), indicating that miR-361-5p may play an important role in the progression of ADPC to CRPC. The role of miR-361-5p in prostate cancer (PCa) has not been evaluated until date. Our findings suggest that miR-361-5p is a suppressor in CRPC. Signal transducer and activator of transcription-6 (STAT6), a direct target of miR-361-5p, enhances the expression of B-cell lymphoma-extra large (Bcl-xL), while miR-361-5p inhibits its expression through STAT6. Therefore, miR-361-5p has great clinical significance in preventing the malignant progression of PCa.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

TCP10L acts as a tumor suppressor by inhibiting cell proliferation in hepatocellular carcinoma

Highlights: • TCP10L was down-regulated in clinical hepatocellular carcinoma (HCC). • Expression of TCP10L correlated significantly with tumor size and Milan criteria. • Overexpression of TCP10L attenuated growth of HCC cells both in vitro and in vivo. • Knocking down TCP10L promoted cell proliferation and tumorigenesis of HCC cells. - Abstract: TCP10L (T-complex 10 (mouse)-like) has been identified as a liver and testis-specific gene. Although a potential transcriptional suppression function of TCP10L has been reported previously, biological function of this gene still remains largely elusive. In this study, we reported for the first time that TCP10L was significantly down-regulated in clinical hepatocellular carcinoma (HCC) samples when compared to the corresponding non-tumorous liver tissues. Furthermore, TCP10L expression was highly correlated with advanced cases exceeding the Milan criteria. Overexpression of TCP10L in HCC cells suppressed colony formation, inhibited cell cycle progression through G0/G1 phase, and attenuated cell growth in vivo. Consistently, silencing of TCP10L promoted cell cycle progression and cell growth. Therefore, our study has revealed a novel suppressor role of TCP10L in HCC, by inhibiting proliferation of HCC cells, which may facilitate the diagnosis and molecular therapy in HCC.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Double-stranded RNA transcribed from vector-based oligodeoxynucleotide acts as transcription factor decoy

Highlights: • A shRNA vector based transcription factor decoy, VB-ODN, was designed. • VB-ODN for NF-κB inhibited cell viability in HEK293 cells. • VB-ODN inhibited expression of downstream genes of target transcription factors. • VB-ODN may enhance nuclear entry ratio for its feasibility of virus production. - Abstract: In this study, we designed a short hairpin RNA vector-based oligodeoxynucleotide (VB-ODN) carrying transcription factor (TF) consensus sequence which could function as a decoy to block TF activity. Specifically, VB-ODN for Nuclear factor-κB (NF-κB) could inhibit cell viability and decrease downstream gene expression in HEK293 cells without affecting expression of NF-κB itself. The specific binding between VB-ODN produced double-stranded RNA and NF-κB was evidenced by electrophoretic mobility shift assay. Moreover, similar VB-ODNs designed for three other TFs also inhibit their downstream gene expression but not that of themselves. Our study provides a new design of decoy for blocking TF activity.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

USP22 acts as an oncogene by regulating the stability of cyclooxygenase-2 in non-small cell lung cancer

The histone ubiquitin hydrolase ubiquitin-specific protease 22 (USP22) is an epigenetic modifier and an oncogene that is upregulated in many types of cancer. In non-small cell lung cancer (NSCLC), aberrant expression of USP22 is a predictor of poor survival, as is high expression of cyclooxygenase-2 (COX-2). Despite its oncogenic role, few substrates of USP22 have been identified and its mechanism of action in cancer remains unclear. Here, we identified COX-2 as a direct substrate of USP22 and showed that its levels are modulated by USP22 mediated deubiquitination. Silencing of USP22 downregulated COX-2, decreased its half-life, and inhibited lung carcinoma cell proliferation by directly interacting with and modulating the stability and activity of COX-2 through the regulation of its ubiquitination status. The findings of the present study suggest a potential mechanism underlying the oncogenic role of USP22 mediated by the modulation of the stability and activity of COX-2. - Highlights: • USP22 interacts with COX-2. • USP22 deubiquitinates and stabilizes COX-2. • USP22 is required for COX-2-mediated upregulation of prostaglandin E2.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Long none coding RNA HOTTIP/HOXA13 act as synergistic role by decreasing cell migration and proliferation in Hirschsprung disease

Long noncoding RNAs (lncRNAs) have been confirmed to be associated with various human diseases. However, whether they are associated with Hirschsprung disease (HSCR) progression remains unclear. In this study, we designed the experiment to explore the relationship between lncRNA HOTTIP and HOXA13, and their pathogenicity to HSCR. Quantitative real-time PCR and Western blot were performed to detect the levels of lncRNA, mRNAs, and proteins in colon tissues from 79 patients with HSCR and 79 controls. Small RNA interference transfection was used to study the function experiments in human 293T and SK-N-BE cell lines. The cell viability and activities were detected by the transwell assays, CCK8 assay, and flow cytometry, respectively. LncRNA HOTTIP and HOXA13 were significantly down-regulated in HSCR compared to the controls. Meanwhile, the declined extent of their expression levels makes sense between two main phenotype of HSCR. SiRNA-mediated knock-down of HOTTIP or HOXA13 correlated with decreased levels of each other and both reduced the cell migration and proliferation without affecting cell apoptosis or cell cycle. Our study demonstrates that aberrant reduction of HOTTIP and HOXA13, which have a bidirectional regulatory loop, may play an important role in the pathogenesis of HSCR. - Highlights: • LncRNA HOTTIP and HOXA13 are both down-regulated in HSCR. • HOTTIP and HOXA13 can regulate each other in 293T and SK-N-BE(2) cell lines. • Both HOTTIP and HOXA13 can decrease cell migration and proliferation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

MicroRNA-139-5p acts as a tumor suppressor by targeting ELTD1 and regulating cell cycle in glioblastoma multiforme

MicroRNA-139-5p was identified to be significantly down-regulated in glioblastoma multiform (GBM) by miRNA array. In this report we aimed to clarify its biological function, molecular mechanisms and direct target gene in GBM. Twelve patients with GBM were analyzed for the expression of miR-139-5p by quantitative RT-PCR. miR-139-5p overexpression was established by transfecting miR-139-5p-mimic into U87MG and T98G cells, and its effects on cell proliferation were studied using MTT assay and colony formation assays. We concluded that ectopic expression of miR-139-5p in GBM cell lines significantly suppressed cell proliferation and inducing apoptosis. Bioinformatics coupled with luciferase and western blot assays also revealed that miR-139-5p suppresses glioma cell proliferation by targeting ELTD1 and regulating cell cycle. - Highlights: • miR-139-5p is downregulated in GBM. • miR-139-5p regulates cell proliferation through inducing apoptosis. • miR-139-5p regulates glioblastoma tumorigenesis by targeting 3′UTR of ELTD1. • miR-139-5p is involved in cell cycle regulation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Sam68 promotes Schwann cell proliferation by enhancing the PI3K/Akt pathway and acts on regeneration after sciatic nerve crush

Sam68 (Src-associated in mitosis of 68 kD), a KH domain RNA-binding protein, is not only important in signaling transduction cascades, but crucial in a variety of cellular processes. Sam68 is reported to be involved in the phospoinositide3-kinase (PI3K) and nuclear factor-kappa B (NF-κB) signaling pathways, and it is closely associated with cell proliferation, RNA metabolism, and tumor progression. However, we know little about the role of Sam68 during peripheral nervous system injury and regeneration. In this study, we investigated the expression of Sam68 and its biological significances in sciatic nerve crush. Interestingly, we found Sam68 had a co-localization with S100 (Schwann cell marker). Moreover, after crush, Sam68 had a spatiotemporal protein expression, which was in parallel with proliferation cell nuclear antigen (PCNA). In vitro, we also observed increased expression of Sam68 during the process of TNF-α-induced Schwann cell proliferation model. Besides, flow cytometry analyses, CCK-8, and EDU were all performed with the purpose of investigating the role of Sam68 in the regulation of Schwann cell proliferation. Even more importantly, we discovered that Sam68 could enhance the phosphorylation of Akt while LY294002 (a PI3K inhibitor) obviously reversed Sam68-induced cell proliferation. Finally, we detected the variance during regeneration progress through the rat walk footprint test. In summary, all these evidences demonstrated that Sam68 might participate in Schwann cell proliferation partially via PI3K/Akt pathway and also regulate regeneration after sciatic nerve crush. -- Highlights: •The dynamic changes and location of Sam68 after sciatic nerve crush. •Sam68 promoted Schwann cell proliferation via PI3K/Akt pathway. •Sam68 modulated functional recovery after sciatic nerve crush.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

LOX-related collagen crosslink changes act as an initiator of bone fragility in a ZDF rats model

Highlights: • Bone mechanical loss in type 2 diabetes is mainly restricted to the post-yield behavior. • Loss of insoluble collagen in the matrix phase is the initial cause of bone mechanical loss in type 2 diabetes. • The insoluble collagen amount in bone tissue is the positive regressor of bone post-yield behavior. • The expression of Lox and lox-like family are downregulated in bone tissue in type 2 diabetes. Diabetes mellitus type 2 (DM2) results in bone abnormalities that manifest as increased bone fragility. Bone consists of two phases, the mineral phase and the matrix phase, and disorders in both are seen in DM2. However, the phase in which DM2 mediated bone fragility is initiated is still unknown. In this study, a male Zucker diabetic fatty (fa/fa) (ZDF) rat model was used to investigate the underlying mechanism initiating DM2 mediated bone fragility. The fracture surface morphology, pre- and post-yield bone mechanical behavior, insoluble collagen volume, lysyl oxidase family (LOX) enzyme levels and correlation analysis was performed to determine the relationship between insoluble collagen and post-yield behavior. Four weeks after the induction of diabetes, insoluble collagen was decreased in only the matrix phase in diabetic rats. Consistently, mechanical testing of the bone showed changes only in post-yield behavior. Diabetic rats also had decreased levels of enzymes involved in insoluble collagen formation (LOX and LOXL1 families). Correlation analysis demonstrated that insoluble collagen was a positive regressor of post-yield displacement (R = 0.894, P P < 0.001). Together, these findings suggest that bone fragility in DM2 is initiated in the matrix phase and that the LOX family may play a critical part in the pathogenesis of DM2 mediated bone fragility.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Old drug new tricks: Chlorhexidine acts as a potential allosteric inhibitor toward PAK1

This paper describes the identification of chlorhexidine, an agent commonly used in clinical as a novel potential allosteric inhibitor of PAK1. In cellular assays, chlorhexidine showed a good inhibitory profile, and its inhibitory profile was even better than IPA-3, a well-known allosteric inhibitor. In pharmacology experiments, chlorhexidine successfully inhibited the relief of PAK1 dimer and inhibited the activation of PAK1. Our findings offer an insight for the new drug development of PAK1 inhibitor. We also provide a possible explanation for the phenomenon that the application of the chlorhexidine in peritoneal lavage inhibited the development of tumor.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Circular RNA circ{sub 0}001649 acts as a prognostic biomarker and inhibits NSCLC progression via sponging miR-331-3p and miR-338-5p

Accumulating evidence documented the key functions of circular RNAs (circRNAs) in various malignancies. However, the study regarding the involvement of circRNAs in non-small cell lung cancer (NSCLC) has just begun. In the present study, qRT-PCR was used to determine the expression of circ{sub 0}001649 in NSCLC tissues and cells. Its clinical significance was further assessed by Fisher's exact test, Kaplan-Meier analysis and Cox regression model. Additionally, loss-of-function and gain-of-function experiments were carried out to detect the functional role of circ{sub 0}001649 in cell proliferation, migration and invasion. Furthermore, animal study was performed to confirm the in vitro results. Importantly, luciferase reporter assay was induced to reveal the underlying mechanism of circ{sub 0}001649. As a result, circ{sub 0}001649 was decreased in NSCLC tissues and cells and this downregulation is correlated with advanced TNM stage, positive lymph node metastasis and unfavorable prognosis. Additionally, circ{sub 0}001649 inhibited cell growth and metastasis both in vitro and in vivo. In mechanism, circ{sub 0}001649 was identified as the sponge of miR-331-3p and miR-338-5p. Moreover, the biological functions of circ{sub 0}001649 is partly dependent on its regulation on miR-331-3p and miR-338-5p. Collectively, this study suggested that circ{sub 0}001649/miR-331-3p/miR-338-5p regulatory signaling might be a potential target for NSCLC therapy.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Hypermethylated KCNQ1 acts as a tumor suppressor in hepatocellular carcinoma

Highlights: • Decreased KCNQ1 expression was associated with a poor prognosis in HCC. • KCNQ1acts as a tumor suppressor in HCC. • KCNQ1 interacts with β-catenin to affect its subcellular distribution. • Activation of β-Catenin restores the inhibitory roles of KCNQ1 in HCC. Potassium (K{sup +}) channels are dysregulated in tumor tissues and functionally these channels contribute significantly to the malignant phenotypes of the cancer cells, including cell apoptosis, chemo- and radio-resistance, proliferation, and migration. However, little is known about the potential implications of K{sup +} channels in hepatocellular carcinoma (HCC). The aim of the current study was to investigate the expression profile of KCNQ1 in HCC and assess its possible cellular implications as well as mechanism to disease progression. Using real-time qPCR and western blotting technique, we found that KCNQ1 was frequently down-regulated in HCC cell lines and tissues, and HCC patients with lower KCNQ1 expression had a poor prognosis. Specifically, DNA hypermethylation of KCNQ1 promoter resulted in its downregulation in HCC. Bioinformatic analysis indicated a regulatory role of KCNQ1 in the epithelial-to-mesenchymal transition process. Gain-of-function study showed that KCNQ1 exhibited remarkable inhibitory roles on tumor metastasis in vitro and in vivo. Mechanistically, KCNQ1 can interact with β-catenin to affect its subcellular distribution and subsequently reduce the activity of Wnt/β-catenin signaling, which further blocks the expression of its downstream targets, including c-Myc, MMP7, and CCND1. Restoration of β-catenin activity largely compromised the tumor-suppressive roles of KCNQ1 in the invasive capacity of HCC cells. In conclusion, KCNQ1 is down-regulated in HCC and may suppress HCC metastasis, which could represent a prognostic marker and promising therapeutic target for HCC.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Long noncoding RNA LSINCT5 acts as an oncogene via increasing EZH2-induced inhibition of APC expression in osteosarcoma

Long noncoding RNAs (lncRNAs) are recognized as a class of critical regulators in various tumors. Recently, lncRNA LSINCT5 has been reported to promote the progression of bladder cancer, ovarian cancer, gastric cancer, and breast cancer. However, the biological function of LSINCT5 remains elusive in osteosarcoma (OS). In our study, we found that LSINCT5 was significantly upregulated in OS tissues than in adjacent normal tissues. Additionally, the expression of LSINCT5 was inversely associated with the prognosis of patients with OS. LSINCT5 knockdown dramatically inhibited OS cell proliferation in vitro and tumor growth in vivo. Mechanistic exploration revealed that LSINCT5 interacted with EZH2 to suppress the expression of APC, a negative regulator of the Wnt/β-catenin pathway. Moreover, rescue assays suggested that LSINCT5 exerted oncogenic roles by partially inhibiting APC expression in OS. In summary, our study demonstrated that LSINCT5 was a promising candidate for OS prognosis and therapy.

60 APPLIED LIFE SCIENCES↗