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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 271 records · Page 15
All sourcesNASA NTRSDOE OSTI
DOE OSTI2018

The circular RNA circ-ITCH suppresses ovarian carcinoma progression through targeting miR-145/RASA1 signaling

Highlights: • A broad down-regulation of circ-ITCH and a worse prognosis were found in OC patients. • Circ-ITCH inhibits the cell viability and motility by CCK8, cell cycle, wound healing and invasion assay. • Circ-ITCH inhibits the tumorigenesis ability in xenograft NOD mice in vivo. • Circ-TCH acts as a ceRNA role of circ-ITCH through sponging miR-145 and up-regulation of RASA1 expression. As the leading cause of death for gynecological cancers, ovarian cancer (OC) ranks fifth overall for cancer-related death among women. Emerging evidence has indicated that circular RNA (circRNA), recognized as functional non-coding transcripts in eukaryotic cells, may be involved in many physiological or pathological processes. It was reported that circ-ITCH is downregulated in multi cancers and serves as a powerful tumor suppressor among through a competing endogenous RNA (ceRNA) pathway. However, the existence and the role of circ-ITCH in OC was not reported. Here, we found a broad down-regulation of circ-ITCH in OC tissues and cells, which correlates with a worse prognosis in OC patients. Functional studies suggest that circ-ITCH overexpression inhibits the cell viability and motility by CCK8, cell cycle, wound healing assay and invasion assay. It also inhibits the tumorigenesis ability in xenograft NOD mice in vivo. Mechanically, we demonstrated that circ-TCH acts as a ceRNA to sponge miR-145, increases the level of RASA1, and inhibits the malignant progression of OC cells via the circ-ITCH-miR-145-RASA1 axis in vitro and in vivo. Taken together, our findings provide a novel tumor suppressive role regarding circ-ITCH function in the malignant progression of OC.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Long non-coding RNA OGFRP1 regulates LYPD3 expression by sponging miR-124-3p and promotes non-small cell lung cancer progression

Highlights: • The expression levels of lncRNA OGFRP1 was up-regulated in NSCLC tissues and cell lines. • Overexpression of lncRNA OGFRP1 was associated with advanced clinical features and poor prognosis in NSCLC patients. • LncRNA OGFRP1 promoted NSCLC cells proliferation, migration and invasion by regulation of miR-124-3p-LYPD3 pathway. Long noncoding RNA (OGFRP1) has been reported to be involved in the progression of non-small cell lung cancer (NSCLC). However, the expression pattern, functions and molecular mechanisms of OGFRP1 in NSCLC remains unclear. In the present study, we found that OGFRP1 expression was significantly up-regulated in both NSCLC tissues and cell lines, and the upregulation of OGFRP1 expression is a powerful predictor of advanced clinical stage, lymph nodes metastasis and poor prognosis for NSCLC patients. Loss-of-function assay indicated that knockdown of OGFRP1 inhibited proliferation, migration and invasion, and induced apoptosis in vitro. Mechanistically, OGFRP1 could directly bind to miR-124-3p and effectively act as a competing endogenous RNA (ceRNA) for miR-124-3p to promote the expression of the target gene LYPD3. Taken together, OGFRP1 contributed to progression of NSCLC at least partly through upregulating LYPD3 expression by sponging miR-124-3p, indicating that OGFRP1 may be a novel prognostic biomarker and therapeutic target in NSCLC.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Upregulation of circ-UBAP2 predicts poor prognosis and promotes triple-negative breast cancer progression through the miR-661/MTA1 pathway

Highlights: • circ-UBAP2 is significantly up-regulated in TNBC and predicts poor prognosis. • Knockdown of circ-UBAP2 remarkably inhibits TNBC progression both in vitro and in vivo. • circ-UBAP2 exerts its oncogenic effect via miR-661/MTA1 axis in TNBC. Recently, a large number of studies have shown that circular RNA (circRNA) is involved in the development and progression of human cancer. However, its role in triple-negative breast cancer (TNBC) remains largely unknown. In this study, a novel circRNA, circ-UBAP2 (hsa{sub c}irc{sub 0}001846), was shown to be markedly upregulated in TNBC. Moreover, high circ-UBAP2 expression was closely associated with larger tumour size (p = 0.003), advanced TNM stage (p = 0.005), lymph node metastasis (p = 0.002), and unfavourable prognosis (p = 0.0256). Functionally, lentivirus-mediated stable knockdown of circ-UBAP2 dramatically weakened the ability of TNBC cells to proliferate and migrate and induced apoptosis in vitro and in vivo. Regarding the mechanism, we found that circ-UBAP2 was mainly observed in the cytoplasm and was capable of sponging miRNA-661 to increase the expression of the oncogene MTA1. Additionally, silencing of miRNA-661 or overexpression of MTA1 could partially rescue the attenuated malignant phenotype caused by circ-UBAP2 knockdown. Taken together, our data reveal that circ-UBAP2 plays a vital regulatory role in TNBC via the miR-661/MTA1 axis and may serve as a promising therapeutic target for TNBC patients.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

AURKA contributes to the progression of oral squamous cell carcinoma (OSCC) through modulating epithelial-to-mesenchymal transition (EMT) and apoptosis via the regulation of ROS

Highlights: • AURKA knockdown inhibited the proliferation and ETM in OSCC cell lines. • Silencing AURKA induced apoptosis and ROS in OSCC cell lines. • AURKA knockdown inhibited tumor growth in vivo. Oral squamous cell carcinoma (OSCC) is known as one of the most common cancer influencing the head and neck region. However, the molecular mechanisms revealing OSCC progression is largely unclear. Aurora kinase A (AURKA) is a serine-threonine kinase that functions in mitotic spindle formation and chromosome segregation, and is associated with the progression of human cancers. But its role in regulating OSCC development has not yet been investigated. In the study, we found that AURKA expression was up-regulated in OSCC cell lines and tumor specimens from patients. OSCC patients with high expression of AURKA exhibited a significant decreased overall survival rate. In vitro, AURKA knockdown markedly reduced the proliferation, migration and invasion of OSCC cells using cell counting kit-8 (CCK-8), EdU, colony formation and transwell analysis. EMT was suppressed by AURKA silence, as evidenced by the up-regulated expression of E-cadherin and down-regulated Vimentin in OSCC cells. In addition, apoptosis was markedly induced by AURKA inhibition through promoting the expression of cleaved Caspase-3 and poly (ADP)-ribose polymerase (PARP). Reactive oxygen species (ROS) production was also markedly enhanced in AURKA-knockdown OSCC cells. Importantly, we found that repressing ROS generation using its scavenger of n-acetylcysteine (NAC) significantly abolished AURKA silence-induced apoptosis, accompanied with restored proliferation and EMT. In vivo, AURKA knockdown notably inhibited tumor growth. Therefore, knockdown of AURKA suppressed cell proliferation, migration and invasion, and also induced apoptosis and ROS generation in OSCC possibly via the production of ROS, demonstrating that AURKA inhibition might represent a novel therapeutic target for the prevention of OSCC.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Long noncoding RNA MAGI2-AS3 regulates CCDC19 expression by sponging miR-15b-5p and suppresses bladder cancer progression

Highlights: • Expression of MAGI2-AS3, miR-15b-5p and CCDC19 in BCa. • MAGI2-AS3 regulates miR-15b-5p/CCDC19 cascade expression in BCa. • CCDC19 knockdown partly reverses the effects caused by MAGI2-AS3 overexpression in vitro. • MAGI2-AS3 suppresses BCa growth in vivo. Bladder cancer (BCa) belongs to a popular urological malignancy and leads to large numbers of deaths worldwide. Recently, emerging evidences indicate that long noncoding RNAs (lncRNAs) are closely related with BC occurrence and progression. However, the function of lncRNA MAGI2-AS3 remains poorly understood in BC. In this present study, we screened out a novel lncRNA MAGI2-AS3 whose expression was downregulated in BCa tissues. We showed that MAGI2-AS3 downregulation in BCa patients indicated a poor prognosis. Functionally, we showed that MAGI2-AS3 overexpression inhibits proliferation, migration and invasion of BCa cells. Moreover, ectopic expression of MAGI2-AS3 suppresses BCa growth in vivo. Bioinformatics analysis revealed that MAGI2-AS3 could serve as a competing endogenous RNA (ceRNA) for miR-15b-5p. In the meantime, miR-15b-5p directly targeted CCDC19, a tumor suppressor in BCa. Rescue assays demonstrated that knockdown of CCDC19 restored the proliferation, migration and invasion of BCa cells suppressed by MAGI2-AS3 overexpression. In conclusion, this study identified a novel mechanism that MAGI2-AS3/miR-15b-5p/CCDC19 signaling pathway regulates BCa progression.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Propensity Score–Matched Analysis of Comprehensive Local Therapy for Oligometastatic Non-Small Cell Lung Cancer That Did Not Progress After Front-Line Chemotherapy

Purpose: To retrospectively analyze factors influencing survival in patients with non-small cell lung cancer presenting with ≤3 synchronous metastatic lesions. Methods and Materials: We identified 90 patients presenting between 1998 and 2012 with non-small cell lung cancer and ≤3 metastatic lesions who had received at least 2 cycles of chemotherapy followed by surgery or radiation therapy before disease progression. The median number of chemotherapy cycles before comprehensive local therapy (CLT) (including concurrent chemoradiation as first-line therapy) was 6. Factors potentially affecting overall (OS) or progression-free survival (PFS) were evaluated with Cox proportional hazards regression. Propensity score matching was used to assess the efficacy of CLT. Results: Median follow-up time was 46.6 months. Benefits in OS (27.1 vs 13.1 months) and PFS (11.3 months vs 8.0 months) were found with CLT, and the differences were statistically significant when propensity score matching was used (P ≤ .01). On adjusted analysis, CLT had a statistically significant benefit in terms of OS (hazard ratio, 0.37; 95% confidence interval, 0.20-0.70; P ≤ .01) but not PFS (P=.10). In an adjusted subgroup analysis of patients receiving CLT, favorable performance status (hazard ratio, 0.43; 95% confidence interval, 0.22-0.84; P=.01) was found to predict improved OS. Conclusions: Comprehensive local therapy was associated with improved OS in an adjusted analysis and seemed to favorably influence OS and PFS when factors such as N status, number of metastatic lesions, and disease sites were controlled for with propensity score–matched analysis. Patients with favorable performance status had improved outcomes with CLT. Ultimately, prospective, randomized trials are needed to provide definitive evidence as to the optimal treatment approach for this patient population.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2016

Site-Specific Phosphorylation of Ikaros Induced by Low-Dose Ionizing Radiation Regulates Cell Cycle Progression of B Lymphoblast Through CK2 and AKT Activation

Purpose: To determine how low-dose ionizing radiation (LDIR) regulates B lympho-proliferation and its molecular mechanism related with Ikaros, transcription factor. Methods and Materials: Splenocytes and IM-9 cells were uniformly irradiated with various doses of a {sup 137}Cs γ-source, and cell proliferation was analyzed. To determine the LDIR-specific phosphorylation of Ikaros, immunoprecipitation and Western blot analysis were performed. To investigate the physiologic function of LDIR-mediatied Ikaros phosphorylation, Ikaros mutants at phosphorylation sites were generated, and cell cycle analysis was performed. Results: First, we found that LDIR enhances B lymphoblast proliferation in an Ikaros-dependent manner. Moreover, we found that LDIR elevates the phosphorylation level of Ikaros protein. Interestingly, we showed that CK2 and AKT are involved in LDIR-induced Ikaros phosphorylation and capable of regulating DNA binding activity of Ikaros via specific phosphorylation. Finally, we identified LDIR-specific Ikaros phosphorylation sites at S391/S393 and showed that the Ikaros phosphorylations at these sites control Ikaros's ability to regulate G1/S cell cycle progression. Conclusion: Low-dose ionizing radiation specifically phosphorylates Ikaros protein at Ser 391/393 residues to regulate cell cycle progression in B lymphoblast.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Neutron imaging the spatial progression of chemical oxidation of lithium-ion cathode material in a packed bed reactor

Emerging electrochemical systems relevant to energy applications including redox targeted flow batteries rely on chemical redox of solid electroactive materials using dissolved redox couples. One configuration to facilitate contact between the redox shuttles and solid material which is volume efficient is a packed bed reactor. While methods have been reported to assess the overall progression by analysis of the packed bed reactor effluent, herein analysis of the spatial progression of the chemical redox will be reported. Combination of neutron and x-ray tomography enabled assessing the pore and particle structure in the packed bed reactor and the spatial homogeneity of the reaction at different overall extents of conversion of the reactor bed. Finally, these characterization tools provide methods to probe the chemical redox processes occurring within the reactor environment.

25 ENERGY STORAGE↗
DOE OSTI2018

Coated particle fuel: Historical perspectives and current progress

We report that coated particle fuel concepts date back some 60 years, and have evolved significantly from the relatively primitive pyrocarbon-coated kernels envisioned by the first pioneers. Improvements in particle design, coating layer properties, and kernel composition have produced the modern tristructural isotropic (TRISO) particle, capable of low statistical coating failure fractions and good fission product retention under extremely severe conditions, including temperatures of 1600 °C for hundreds of hours. The fuel constitutes one of the key enabling technologies for high-temperature gas-cooled reactors, allowing coolant outlet temperatures approaching 1000 °C and contributing to enhanced reactor safety due to the hardiness of the particles. TRISO fuel development has taken place in a number of countries worldwide, and several fuel qualification programs are currently in progress. Here, we discuss the unique history of particle fuel development and some key technology advances, concluding with some of the latest progress in UO 2 and UCO TRISO fuel qualification.

11 NUCLEAR FUEL CYCLE AND FUEL MATERIALS↗
DOE OSTI2017

Temporal expression profiling of plasma proteins reveals oxidative stress in early stages of Type 1 Diabetes progression

We report that blood markers other than islet autoantibodies are greatly needed to indicate the pancreatic beta cell destruction process as early as possible, and more accurately reflect the progression of Type 1 Diabetes Mellitus (T1D). To this end, a longitudinal proteomic profiling of human plasma using TMT-10plex-based LC-MS/MS analysis was performed to track temporal proteomic changes of T1D patients (n = 11) across 9 serial time points, spanning the period of T1D natural progression, in comparison with those of the matching healthy controls (n = 10). To our knowledge, the current study represents the largest (> 2000 proteins measured) longitudinal expression profiles of human plasma proteome in T1D research. By applying statistical trend analysis on the temporal expression patterns between T1D and controls, and Benjamini-Hochberg procedure for multiple-testing correction, 13 protein groups were regarded as having statistically significant differences during the entire follow-up period. Moreover, 16 protein groups, which play pivotal roles in response to oxidative stress, have consistently abnormal expression trend before seroconversion to islet autoimmunity. Importantly, the expression trends of two key reactive oxygen species-decomposing enzymes, Catalase and Superoxide dismutase were verified independently by ELISA.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Longitudinal proteomics analysis in the immediate microenvironment of islet allografts during progression of rejection

The applicability and benefits of pancreatic islet transplantation are limited due to various issues including the need to avoid immune-mediated rejection. In the present study, we used our experimental platform of allogeneic islet transplant in the anterior chamber of the eye (ACE-platform) to longitudinally monitor the progress of rejection in mice and obtain aqueous humor samples representative of the microenvironment of the graft for accurately-timed proteomic analyses. LC-MS/MS-based proteomics performed on such mass-limited samples (~5 μL) identified a total of 1296 proteins. Various analyses revealed distinct protein patterns associated with the mounting of the inflammatory and immune responses and their evolution with the progression of the rejection. Pathway analyses indicated predominant changes in cytotoxic functions, cell movement, and innate and adaptive immune responses. Furthermore, network prediction analyses revealed transition from humoral to cellular immune response and exacerbation of pro-inflammatory signaling. One of the proteins identified by this localized proteomics as a candidate biomarker of islet rejection, Cystatin 3, was further validated by ELISA in the aqueous humor. This study provides (1) experimental evidence demonstrating the feasibility of longitudinal localized proteomics using small aqueous humor samples and (2) proof-of-concept for the discovery of biomarkers of impending immune attack from the immediate local microenvironment of ACE-transplanted islets.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2016

Recent progress in half-Heusler thermoelectric materials

Highlights: • Summarize the recent progress and advances in HH thermoelectric materials. • Preparing nanocomposites could reduce thermal conductivity. • Introducing enhance phonon scattering could further reduce the thermal conductivity. • Forming ternary systems to reducing the cost effectively. • The new class of HHs presents another opportunity to further optimize the HH system. - Abstract: Half-Heusler (HH) thermoelectric (TE) materials have been attracting extensive research interest over the last two decades, owing to their thermal stability, mechanical strength, and moderate ZT. This material system are potential candidates for medium to high temperature applications, which is close to the temperature range of most industrial waste heat sources. In this mini-review article, we briefly summarize the recent progress and advances in HH thermoelectric materials. Some effectively available approaches, such as HH nanocomposites to reduce thermal conductivity, using larger atomic mass and size differences to enhance phonon scattering to further reduce the thermal conductivity, forming ternary systems following the cost effective approach. In addition, new thermoelectric HH members are also discussed in this article, which points out that many new HH compounds may be possible for TE applications.

36 MATERIALS SCIENCE↗
DOE OSTI2018

A progressive electrochemical sensor for food quality control: Reliable determination of theobromine in chocolate products using a miniaturized boron-doped diamond electrode

In the present paper, a miniaturized boron-doped diamond electrode (BDDE) is proposed as a progressive electrochemical sensor for simple, fast and reliable quantification of dimethylxanthine alkaloid, theobromine (TB). Using cyclic voltammetry, the studied xanthine provided one well-shaped, irreversible and diffusion-controlled oxidation peak at relatively high potentials (+1.2 V vs. Ag/AgCl/3 M KCl reference electrode) in the presence of 0.1 M H2SO4. After selection of suitable experimental conditions, the linear calibration curves for TB were obtained in the concentration range from 0.99 up to 54.5 μM with the sensitivity of 0.07 μA/μM providing both differential pulse (DPV) and square-wave voltammetric (SWV) techniques, respectively. The elaborated voltammetric protocol yielded low detection limits of 0.42 and 0.51 μM accompanied by adequate intra-day repeatability (relative standard deviation of 2.5 and 1.7%) using DPV and SWV procedure, respectively. The interference study revealed the reasonable selectivity when taking the target food samples into account. The practical applicability of the voltammetric protocol using a miniaturized BDDE was verified in the analysis of six commercially available brands of chocolate products with the determined mass percentages of TB ranging from 0.75 to 2.24% and from 0.69 to 2.15% using DPV and SWV procedure, respectively. The obtained results were also in a good agreement with those achieved by reference titration method with potentiometric indication. The progressive electrochemical sensor based on a miniaturized BDDE has appeared to be an attractive candidate for practical applications in food quality control. Besides, the proposed voltammetric protocol presents advantages when compared to others techniques (e.g. chromatography), concerning simplicity, cost, speed of analysis, waste generation (environmentally friendly) and samples pretreatment (only dilution in electrolyte solution prior to analysis). © 2018 Elsevier B.V.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2013

Liver proteomics in progressive alcoholic steatosis

Fatty liver is an early stage of alcoholic and nonalcoholic liver disease (ALD and NALD) that progresses to steatohepatitis and other irreversible conditions. In this study, we identified proteins that were differentially expressed in the livers of rats fed 5% ethanol in a Lieber–DeCarli diet daily for 1 and 3 months by discovery proteomics (two-dimensional gel electrophoresis and mass spectrometry) and non-parametric modeling (Multivariate Adaptive Regression Splines). Hepatic fatty infiltration was significantly higher in ethanol-fed animals as compared to controls, and more pronounced at 3 months of ethanol feeding. Discovery proteomics identified changes in the expression of proteins involved in alcohol, lipid, and amino acid metabolism after ethanol feeding. At 1 and 3 months, 12 and 15 different proteins were differentially expressed. Of the identified proteins, down regulation of alcohol dehydrogenase (− 1.6) at 1 month and up regulation of aldehyde dehydrogenase (2.1) at 3 months could be a protective/adaptive mechanism against ethanol toxicity. In addition, betaine-homocysteine S-methyltransferase 2 a protein responsible for methionine metabolism and previously implicated in fatty liver development was significantly up regulated (1.4) at ethanol-induced fatty liver stage (1 month) while peroxiredoxin-1 was down regulated (− 1.5) at late fatty liver stage (3 months). Nonparametric analysis of the protein spots yielded fewer proteins and narrowed the list of possible markers and identified D-dopachrome tautomerase (− 1.7, at 3 months) as a possible marker for ethanol-induced early steatohepatitis. The observed differential regulation of proteins have potential to serve as biomarker signature for the detection of steatosis and its progression to steatohepatitis once validated in plasma/serum. -- Graphical abstract: The figure shows the Hierarchial cluster analysis of differentially expressed protein spots obtained after ethanol feeding for 1 (1–3) and 3 (4–6) months. C and E represent pair-fed control and ethanol-fed rats, respectively. Highlights: ► Proteins related to ethanol-induced steatosis and mild steatohepatitis are identified. ► ADH1C and ALDH2 involved in alcohol metabolism are differentially expressed at 1 and 3 months. ► Discovery proteomics identified a group of proteins to serve as potential biomarkers. ► Using nonparametric analysis DDT is identified as a possible marker for liver damage.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Intake of high-fat diet stimulates the risk of ultraviolet radiation-induced skin tumors and malignant progression of papillomas to carcinoma in SKH-1 hairless mice

Previously, we showed that administration of a high-fat diet (HF-diet) to C57BL/6 mice exacerbates their response to short-term UVB radiation-induced inflammation in the skin. To explore the effects of an HF-diet on UVB-induced tumorigenesis, we have used the SKH-1 hairless mouse model in which the mice are exposed to UVB radiation (180 mJ/cm{sup 2}) three times a week for 24 weeks. The development of UVB-induced skin tumors was rapid and the tumor multiplicity and tumor size were significantly higher (P < 0.01–0.005) in the mice fed an HF-diet than the mice fed a control-diet (C-diet). Moreover, the malignant progression of UVB-induced papillomas to carcinomas was higher in HF-diet-fed mice. On analysis of tumors and tumor-uninvolved skin samples from the tumor-bearing mice, we found that administration of an HF-diet significantly enhanced the levels of UVB-induced expression of cyclooxygenase-2 (COX-2), prostaglandin E{sub 2} (P < 0.01), and PGE{sub 2} receptors, and activation of NF-κB in the UVB-exposed skin as well as in tumors. In addition the HF-diet enhanced the expression of proinflammatory cytokines, including tumor necrosis factor-α (P < 0.01), interleukin (IL)-1β (P < 0.01) and IL-6 (P < 0.05) in the UVB-exposed skin as well as in tumors. Western blot analysis revealed that HF-diet enhanced the levels of epidermal cell proliferation, phosphatidylinositol 3-kinase and phosphorylation of Akt at Ser{sup 473} in UVB-exposed skin and skin tumors. Collectively, these data demonstrate that the regular consumption of an HF-diet increases the risk of photocarcinogenesis in mice and that this is associated with enhanced expression of inflammatory mediators in the UVB-exposed skin and tumors. - Highlights: • Consumption of high-fat diet increases UVB-induced skin tumor development in mice. • Intake of high-fat diet stimulates progression of UV-induced papilloma to carcinoma. • Intake of high-fat diet enhances inflammation in UV-exposed skin • Regular consumption of low-fat diet may inhibit the risk of photocarcinogenesis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Exposure to 9,10-phenanthrenequinone accelerates malignant progression of lung cancer cells through up-regulation of aldo-keto reductase 1B10

Inhalation of 9,10-phenanthrenequinone (9,10-PQ), a major quinone in diesel exhaust, exerts fatal damage against a variety of cells involved in respiratory function. Here, we show that treatment with high concentrations of 9,10-PQ evokes apoptosis of lung cancer A549 cells through production of reactive oxygen species (ROS). In contrast, 9,10-PQ at its concentrations of 2 and 5 μM elevated the potentials for proliferation, invasion, metastasis and tumorigenesis, all of which were almost completely inhibited by addition of an antioxidant N-acetyl-L-cysteine, inferring a crucial role of ROS in the overgrowth and malignant progression of lung cancer cells. Comparison of mRNA expression levels of six aldo-keto reductases (AKRs) in the 9,10-PQ-treated cells advocated up-regulation of AKR1B10 as a major cause contributing to the lung cancer malignancy. In support of this, the elevation of invasive, metastatic and tumorigenic activities in the 9,10-PQ-treated cells was significantly abolished by the addition of a selective AKR1B10 inhibitor oleanolic acid. Intriguingly, zymographic and real-time PCR analyses revealed remarkable increases in secretion and expression, respectively, of matrix metalloproteinase 2 during the 9,10-PQ treatment, and suggested that the AKR1B10 up-regulation and resultant activation of mitogen-activated protein kinase cascade are predominant mechanisms underlying the metalloproteinase induction. In addition, HPLC analysis and cytochrome c reduction assay in in vitro 9,10-PQ reduction by AKR1B10 demonstrated that the enzyme catalyzes redox-cycling of this quinone, by which ROS are produced. Collectively, these results suggest that AKR1B10 is a key regulator involved in overgrowth and malignant progression of the lung cancer cells through ROS production due to 9,10-PQ redox-cycling. - Highlights: • 9,10-PQ promotes invasion, metastasis and tumorigenicity in lung cancer cells. • The 9,10-PQ-elicited promotion is possibly due to AKR1B10 up-regulation. • AKR1B10 acts as a key regulator for MMP2 induction via activation of MAPK cascade. • AKR1B10 is a predominant reductase involved in redox-cycling of 9,10-PQ in the cells.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2012

Chemokines in tumor development and progression

Chemokines were originally identified as mediators of the inflammatory process and regulators of leukocyte trafficking. Subsequent studies revealed their essential roles in leukocyte physiology and pathology. Moreover, chemokines have profound effects on other types of cells associated with the inflammatory response, such as endothelial cells and fibroblasts. Thus, chemokines are crucial for cancer-related inflammation, which can promote tumor development and progression. Increasing evidence points to the vital effects of several chemokines on the proliferative and invasive properties of tumor cells. The wide range of activities of chemokines in tumorigenesis highlights their roles in tumor development and progression.

60 APPLIED LIFE SCIENCES↗