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At least 703 records · Page 39
All sourcesNASA NTRSDOE OSTI
NASA NTRSDate not supplied

Optimal Sensor Mobility Design for Target Tracking with Distributed Sensing, Communication and Computing Infrastructure

The paper presents an airborne target tracking approach with data fusion from distributed stationary and mobile sensor network transmitted through a wireless/wired communication network and using a distributed computing infrastructure. To obtain high quality measurements, sensor flight platforms' positions and orientations are optimized with respect to the available target's position and velocity estimates, and a formation control strategy is applied to derive desired trajectories for the flight platforms. As sensors move, the communication network topology switching is determined using the worst-case approach to handle uncertainties in the target's and sensors' positions, which alters communication delays for sensors' data transmission to computing centers. An optimal data migration algorithm is periodically applied to determine these communication delays for each sensor and the optimal location with minimum end-to-end latency for the target tracking algorithm execution, which is based on adaptive information fusion from multi-modal mobile and stationary sensors inside an Extended Kalman Filter framework. The approach is validated in a desktop simulation environment using synthetic sensor data generated for a simulated target's flight.

Distributed sensing↗
NASA NTRSDate not supplied

Generalized Linear Targeting For Cislunar Flight

An important element of Artemis and NASA’s campaign to explore the Moon is the autonomous onboard two-level targeter (TLT) used during all cislunar flight phases. The function of the TLT is to autonomously recompute the burn targets for the upcoming burn (or multiple burns) in response to navigation and vehicle dispersion providing a solution that meets all of the trajectory constraints. Although the TLT has been utilized previously as a ground-based planning tool, and flown onboard during the Artemis I mission, it’s complexity and iterative nature make is difficult to incorporate into and support rapid analyses such as robust optimal trajectory design applications where speed is essential. In this paper, a set of generalized linear targeting algorithms that mimics many of the properties of the TLT is derived. The generalized algorithms can handle single or multiple impulsive maneuvers, with multiple constraints at multiple fixed or variable times. A linear targeting algorithm for finite burn maneuvers is also derived. The generalized linear targeting algorithms are exceptionally fast and easy to implement in Monte Carlo analysis, linear covariance (LinCov) analysis, and robust optimal trajectory design. Several cislunar flight examples are provided.

Linear Covariance Analysis↗
DOE OSTI2014

Pre-plasma effect on energy transfer from laser beam to shock wave generated in solid target

Efficiency of the laser radiation energy transport into the shock wave generated in layered planar targets (consisting of massive Cu over coated by thin CH layer) was investigated. The targets were irradiated using two laser pulses. The 1ω pulse with the energy of ∼50 J produced a pre-plasma, imitating the corona of the pre-compressed inertial confinement fusion target. The second main pulse used the 1ω or 3ω laser harmonics with the energy of ∼200 J. The influence of the pre-plasma on parameters of the shock wave was determined from the crater volume measurements and from the electron density distribution measured by 3-frame interferometry. The experimental results show that the energy transport by fast electrons provides a definite contribution to the dynamics of the ablative process, to the shock wave generation, and to the ablation pressure in dependence on the target irradiation conditions. The strong influence of the pre-plasma on the investigated process was observed in the 1ω case. Theoretical analysis supports the explanation of experimental results.

70 PLASMA PHYSICS AND FUSION TECHNOLOGY↗
DOE OSTI2023

Shortwave‐Infrared‐Emitting Nanoprobes for CD8 Targeting and In Vivo Imaging of Cytotoxic T Cells in Breast Cancer

Checkpoint immunotherapy has made great strides in the treatment of solid tumors, but many patients do not respond to immune checkpoint inhibitors. Identification of tumor‐infiltrating cytotoxic T cells (CTLs) has the potential to stratify patients and monitor immunotherapy responses. In this study, the design of cluster of differentiation (CD8 + ) T cell‐targeted nanoprobes that emit shortwave infrared (SWIR) light in the second tissue‐transparent window for noninvasive, real‐time imaging of CTLs in murine models of breast cancer is presented. SWIR‐emitting rare‐earth nanoparticles encapsulated in human serum albumin are conjugated with anti‐CD8α to target CTLs with high specificity. CTL targeting is validated in vitro through binding of nanoprobes to primary mouse CTLs. The potential for the use of SWIR fluorescence intensity to determine CTL presence is validated in two syngeneic mammary fat pad tumor models, EMT6 and 4T1, which differ in immune infiltration. SWIR imaging using CD8‐targeted nanoprobes successfully identifies the presence of CTLs in the more immunogenic EMT6 model, while imaging confirms the lack of substantial immune infiltration in the nonimmunogenic 4T1 model. In this work, the opportunity for SWIR imaging using CD8‐targeted nanoprobes to assess CTL infiltration in tumors for the stratification and monitoring of responders to checkpoint immunotherapy is highlighted.

Shah, Jay V.↗
DOE OSTI2024

“Off‐Label Use” of the Siderophore Enterobactin Enables Targeted Imaging of Cancer with Radioactive Ti (IV)

Abstract The development of inert, biocompatible chelation methods is required to harness the emerging positron emitting radionuclide 45 Ti for radiopharmaceutical applications. Herein, we evaluate the Ti (IV) ‐coordination chemistry of four catechol‐based, hexacoordinate chelators using synthetic, structural, computational, and radiochemical approaches. The siderophore enterobactin (Ent) and its synthetic mimic TREN‐CAM readily form mononuclear Ti (IV) species in aqueous solution at neutral pH. Radiolabeling studies reveal that Ent and TREN‐CAM form mononuclear complexes with the short‐lived, positron‐emitting radionuclide 45 Ti (IV) , and do not transchelate to plasma proteins in vitro and exhibit rapid renal clearance in naïve mice. These features guide efforts to target the 45 Ti isotope to prostate cancer tissue through the design, synthesis, and evaluation of Ent‐DUPA, a small molecule conjugate composed of a prostate specific membrane antigen (PSMA) targeting peptide and a monofunctionalized Ent scaffold. The [ 45 Ti][Ti(Ent‐DUPA)] 2− complex forms readily at room temperature. In a tumor xenograft model in mice, selective tumor tissue accumulation (8±5 %, n =5), and low off‐target uptake in other organs is observed. Overall, this work demonstrates targeted imaging with 45 Ti (IV) , provides a foundation for advancing the application of 45 Ti in nuclear medicine, and reveals that Ent can be repurposed as a 45 Ti‐complexing cargo for targeted nuclear imaging applications.

Koller, Angus J.↗
DOE OSTI2024

“Off‐Label Use” of the Siderophore Enterobactin Enables Targeted Imaging of Cancer with Radioactive Ti (IV)

The development of inert, biocompatible chelation methods is required to harness the emerging positron emitting radionuclide 45 Ti for radiopharmaceutical applications. Herein, we evaluate the Ti (IV) -coordination chemistry of four catechol-based, hexacoordinate chelators using synthetic, structural, computational, and radiochemical approaches. The siderophore enterobactin (Ent) and its synthetic mimic TREN-CAM readily form mononuclear Ti (IV) species in aqueous solution at neutral pH. Radiolabeling studies reveal that Ent and TREN-CAM form mononuclear complexes with the short-lived, positron-emitting radionuclide 45 Ti (IV) , and do not transchelate to plasma proteins in vitro and exhibit rapid renal clearance in naïve mice. These features guide efforts to target the 45 Ti isotope to prostate cancer tissue through the design, synthesis, and evaluation of Ent-DUPA, a small molecule conjugate composed of a prostate specific membrane antigen (PSMA) targeting peptide and a monofunctionalized Ent scaffold. Additionally, the [ 45 Ti][Ti(Ent-DUPA)] 2− complex forms readily at room temperature. In a tumor xenograft model in mice, selective tumor tissue accumulation (8±5 %, n=5), and low off-target uptake in other organs is observed. Overall, this work demonstrates targeted imaging with 45 Ti (IV) , provides a foundation for advancing the application of 45 Ti in nuclear medicine, and reveals that Ent can be repurposed as a 45 Ti-complexing cargo for targeted nuclear imaging applications.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2013

A new anti-angiogenic small molecule, G0811, inhibits angiogenesis via targeting hypoxia inducible factor (HIF)-1α signal transduction

Highlights: •G0811 suppresses HIF-1α expression without cell toxicity. •G0811 exhibits anti-angiogenic activity both in vitro and in vivo. •G0811 provides a new molecular scaffold for the development of therapeutics targeting angiogenesis. -- Abstract: Regulation of hypoxia inducible factor (HIF)-1α stabilization, which in turn contributes to adaptation of tumor cells to hypoxia has been highlighted as a promising therapeutic target in angiogenesis-related diseases. We have identified a new small molecule, G0811, as a potent angiogenesis inhibitor that targets HIF-1α signal transduction. G0811 suppressed HIF-1α stability in cancer cells and inhibited in vitro and in vivo angiogenesis, as validated by tube formation, chemoinvasion, and chorioallantoic membrane (CAM) assays. In addition, G0811 effectively decreased the expression of vascular endothelial growth factor (VEGF), which is one of target genes of HIF-1α. However, G0811 did not exhibit anti-proliferative activities or toxicity in human umbilical vein endothelial cells (HUVECs) at effective doses. These results demonstrate that G0811 could be a new angiogenesis inhibitor that acts by targeting HIF-1α signal transduction pathway.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Eph receptor A10 has a potential as a target for a prostate cancer therapy

Highlights: • EphA10 mRNA is overexpressed in breast, prostate and colon cancer cell lines. • EphA10 is overexpressed in clinical prostate tumors at mRNA and protein levels. • Anti-EphA10 antibodies were cytotoxic on EphA10-positive prostate cancer cells. - Abstract: We recently identified Eph receptor A10 (EphA10) as a novel breast cancer-specific protein. Moreover, we also showed that an in-house developed anti-EphA10 monoclonal antibody (mAb) significantly inhibited proliferation of breast cancer cells, suggesting EphA10 as a promising target for breast cancer therapy. However, the only other known report for EphA10 was its expression in the testis at the mRNA level. Therefore, the potency of EphA10 as a drug target against cancers other than the breast is not known. The expression of EphA10 in a wide variety of cancer cells was studied and the potential of EphA10 as a drug target was evaluated. Screening of EphA10 mRNA expression showed that EphA10 was overexpressed in breast cancer cell lines as well as in prostate and colon cancer cell lines. Thus, we focused on prostate cancers in which EphA10 expression was equivalent to that in breast cancers. As a result, EphA10 expression was clearly shown in clinical prostate tumor tissues as well as in cell lines at the mRNA and protein levels. In order to evaluate the potential of EphA10 as a drug target, we analyzed complement-dependent cytotoxicity effects of anti-EphA10 mAb and found that significant cytotoxicity was mediated by the expression of EphA10. Therefore, the idea was conceived that the overexpression of EphA10 in prostate cancers might have a potential as a target for prostate cancer therapy, and formed the basis for the studies reported here.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

miR-1271 promotes non-small-cell lung cancer cell proliferation and invasion via targeting HOXA5

MicroRNAs (miRNAs) are short, non-coding RNAs (∼22 nt) that play important roles in the pathogenesis of human diseases by negatively regulating numerous target genes at posttranscriptional level. However, the role of microRNAs in lung cancer, particularly non-small-cell lung cancer (NSCLC), has remained elusive. In this study, two microRNAs, miR-1271 and miR-628, and their predicted target genes were identified differentially expressed in NSCLC by analyzing the miRNA and mRNA expression data from NSCLC tissues and their matching normal controls. miR-1271 and its target gene HOXA5 were selected for further investigation. CCK-8 proliferation assay showed that the cell proliferation was promoted by miR-1271 in NSCLC cells, while miR-1271 inhibitor could significantly inhibited the proliferation of NSCLC cells. Interestingly, migration and invasion assay indicated that overexpression of miR-1271 could significantly promoted the migration and invasion of NSCLC cells, whereas miR-1271 inhibitor could inhibited both cell migration and invasion of NSCLC cells. Western blot showed that miR-1271 suppressed the protein level of HOXA5, and luciferase assays confirmed that miR-1271 directly bound to the 3'untranslated region of HOXA5. This study indicated indicate that miR-1271 regulates NSCLC cell proliferation and invasion, via the down-regulation of HOXA5. Thus, miR-1271 may represent a potential therapeutic target for NSCLC intervention. - Highlights: • Overexpression of miR-1271 promoted proliferation and invasion of NSCLC cells. • miR-1271 inhibitor inhibited the proliferation and invasion of NSCLC cells. • miR-1271 targets 3′ UTR of HOXA5 in NSCLC cells. • miR-1271 negatively regulates HOXA5 in NSCLC cells.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

MicroRNA-373 functions as an oncogene and targets YOD1 gene in cervical cancer

miR-373 was reported to be elevated in several tumors; however, the role of miR-373 in cervical cancer has not been investigated. In this study we aimed to investigate the role of miR-373 in tumorigenicity of cervical cancer cells in vivo and in vitro. The expression of miR-373 was investigated using real-time reverse transcription-polymerase chain reaction assay in 45 cervical specimens and cervical cancer cell lines. The role of miR-373 in tumorigenicity of cervical cancer cells was assessed by cell proliferation, colony formation in vitro as well as tumor growth assays in vivo with the overexpression of miR-373 or gene silencing. The functional target gene of miR-373 in cervical cancer cells was identified using integrated bioinformatics analysis, gene expression arrays, and luciferase assay. We founded that the expression of miR-373 is upregulated in human cervical cancer tissues and cervical carcinoma cell lines when compared to the corresponding noncancerous tissues. Ectopic overexpression of miR-373 in human cervical cancer cells promoted cell growth in vitro and tumorigenicity in vivo, whereas silencing the expression of miR-373 decreased the rate of cell growth. YOD1 was identified as a direct and functional target of miR-373 in cervical cancer cells. Expression levels of miR-373 were inversely correlated with YOD1 levels in human cervical cancer tissues. RNAi-mediated knockdown of YOD1 phenocopied the proliferation-promoting effect of miR-373. Moreover, overexpression of YOD1 abrogated miR-373-induced proliferation of cervical cancer cells. These results demonstrate that miR-373 increases proliferation by directly targeting YOD1, a new potential therapeutic target in cervical cancer. - Highlights: • The expression of miR-373 is upregulated in human cervical cancer tissues. • miR-373 effects as oncogenic miRNA in cervical cancer in vitro and in vivo. • miR-373 increases proliferation of cervical cancer cells by directly targeting YOD1.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

MiR-520b suppresses proliferation of hepatoma cells through targeting ten-eleven translocation 1 (TET1) mRNA

Accumulating evidence indicates that microRNAs are able to act as oncogenes or tumor suppressor genes in human cancer. We previously reported that miR-520b was down-regulated in hepatocellular carcinoma (HCC) and its deregulation was involved in hepatocarcinogenesis. In the present study, we report that miR-520b suppresses cell proliferation in HCC through targeting the ten-eleven translocation 1 (TET1) mRNA. Notably, we identified that miR-520b was able to target 3′-untranslated region (3′UTR) of TET1 mRNA by luciferase reporter gene assays. Then, we revealed that miR-520b was able to reduce the expression of TET1 at the levels of mRNA and protein using reverse transcription-polymerase chain reaction and Western blotting analysis. In terms of function, 5-ethynyl-2-deoxyuridine (EdU) incorporation and colony formation assays demonstrated that the forced miR-520b expression remarkably inhibited proliferation of hepatoma cells, but TET1 overexpression could rescue the inhibition of cell proliferation mediated by miR-520b. Furthermore, anti-miR-520b enhanced proliferation of hepatoma cells, whereas silencing of TET1 abolished anti-miR-520b-induced acceleration of cell proliferation. Then, we validated that the expression levels of miR-520b were negatively related to those of TET1 mRNA in clinical HCC tissues. Thus, we conclude that miR-520b depresses proliferation of liver cancer cells through targeting 3′UTR of TET1 mRNA. Our finding provides new insights into the mechanism of hepatocarcinogenesis. - Highlights: • TET1 is a novel target gene of miR-520b. • TET1 is upregulated in clinical HCC tissues. • MiR-520b is negatively correlated with TET1 in clinical HCC tissues. • MiR-520b depresses the proliferation of HCC cells through targeting TET1 mRNA.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

MiR-145 functions as a tumor suppressor targeting NUAK1 in human intrahepatic cholangiocarcinoma

The dysregulation of micro (mi)RNAs is associated with cancer development. The miRNA miR-145 is downregulated in intrahepatic cholangiocarcinoma (ICC); however, its precise role in tumor progression has not yet been elucidated. Novel (nua) kinase family (NUAK)1 functions as an oncogene in various cancers and is a putative target of miR-145 regulation. In this study, we investigated the regulation of NUAK1 by miR-145 in ICC. We found that miR-145 level was significantly decreased in ICC tissue and cell lines, which corresponded with an increase in NUAK1 expression. NUAK1 was found to be a direct target of miR-145 regulation. The overexpression of miR-145 in ICC cell lines inhibited proliferation, growth, and invasion by suppressing NUAK1 expression, which was associated with a decrease in Akt signaling and matrix metalloproteinase protein expression. Similar results were observed by inhibiting NUAK1 expression. These results demonstrate that miR-145 can prevent ICC progression by targeting NUAK1 and its downstream effectors, and can therefore be useful for clinical diagnosis and targeted therapy of ICC. - Highlights: • MiR-145 suppresses ICC proliferation and invasion abilities. • We demonstrated that miR-145 directly targets NUAK1 in ICC. • MiR-145 expression in ICC was associated with Akt signaling and MMPs expression.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

MiR-661 inhibits glioma cell proliferation, migration and invasion by targeting hTERT

In this study, we analyzed the functional role of miR-661 in glioma cell proliferation, migration and invasion. We found that overexpression of miR-661 obviously suppressed the proliferation, migration and invasion of glioma cells. MiRNA target prediction algorithms implied that hTERT is a candidate target gene for miR-661. A fluorescent reporter assay confirmed that miR-661 could lead to hTERT gene silencing by recognizing and specifically binding to the predicted site of the hTERT mRNA 3′ untranslated region (3′UTR) specifically. Furthermore, hTERT knockdown significantly decreased the growth and viability of glioma cells. These results indicate that miR-661 can inhibit glioma cell proliferation, migration and invasion by targeting hTERT. - Highlights: • MiR-661 was downregulated in glioma tissues and functional as a tumor suppressor. • MiR-661 modulates cell proliferation, invasion and migration of glioma cells. • MiR-661 directly target hTERT in glioma cells. • MiR-661 inhibits glioma cell tumorgenesis by targeting hTERT.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

MiR-30e suppresses proliferation of hepatoma cells via targeting prolyl 4-hydroxylase subunit alpha-1 (P4HA1) mRNA

Aberrant microRNA expression has been shown to be characteristic of many cancers. It has been reported that the expression levels of miR-30e are decreased in liver cancer tissues. However, the role of miR-30e in hepatocellular carcinoma remains poorly understood. In the present study, we investigated the significance of miR-30e in hepatocarcinogenesis. Bioinformatics analysis reveals a putative target site of miR-30e in the 3′-untranslated region (3′UTR) of prolyl 4-hydroxylase subunit alpha-1 (P4HA1) mRNA. Moreover, luciferase reporter gene assays verified that miR-30e directly targeted 3′UTR of P4HA1 mRNA. Then, we demonstrated that miR-30e was able to reduce the expression of P4HA1 at the levels of mRNA and protein using reverse transcription-polymerase chain reaction and Western blot analysis. Enforced expression of miR-30e suppressed proliferation of HepG2 cells by 5-ethynyl-2-deoxyuridine (EdU) assay and reduced colony formation of these cells by colony formation analysis. Conversely, anti-miR-30e enhanced the proliferation of hepatoma cells in vitro. Interestingly, the ectopic expression of P4HA1 could efficiently rescue the inhibition of cell proliferation mediated by miR-30e in HepG2 cells. Meanwhile, silencing of P4HA1 abolished the anti-miR-30e-induced proliferation of cells. Clinically, quantitative real-time PCR showed that miR-30e was down-regulated in liver tumor tissues relative to their peritumor tissues. The expression levels of miR-30e were negatively correlated to those of P4HA1 mRNA in clinical liver tumor tissues. Thus, we conclude that miR-30e suppresses proliferation of hepatoma cells through targeting P4HA1 mRNA. Our finding provides new insights into the mechanism of hepatocarcinogenesis. - Highlights: • P4HA1 is a novel target gene of miR-30e. • P4HA1 is increased in clinical HCC tissues. • MiR-30e is negatively correlated with P4HA1 in clinical HCC tissues. • MiR-30e suppresses the proliferation of HCC cells through targeting P4HA1 mRNA.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

MiR-107 suppresses proliferation of hepatoma cells through targeting HMGA2 mRNA 3′UTR

Background and aim: Aberrant expression of miR-107 is involved in the development of several human cancers. However, the role of miR-107 in hepatocellular carcinoma (HCC) is not well documented. In the present study, we aim to explore the function of miR-107 in hepatocarcinogenesis. Methods: Bioinformatics analysis was applied to predict the target genes of miR-107. Luciferase reporter gene assay was performed to verify the miR-107 binding sites in 3′-untranslated region (3′UTR) of high mobility group A2 (HMGA2) mRNA. The expression levels of mRNA and protein were examined using qRT-PCR and Western blot analysis. Functionally, MTT and EdU assays were carried out for proliferation analysis. Clinically, thirty HCC samples and their corresponding peritumor liver tissues were collected. Results: Bioinformatics analysis revealed that miR-107 might target HMGA2 mRNA 3′UTR. Luciferase reporter gene assays verified that the miR-107 binding site was located in the 3′UTR of HMGA2 mRNA. Furthermore, miR-107 could down-regulate HMGA2 at the levels of mRNA and protein in a dose-dependent manner. Interestingly, miR-107 inhibited the proliferation of hepatoma cells, while anti-miR-107 could promote the cell proliferation, which was blocked by the interference of HMGA2. Clinically, miR-107 was lower in HCC samples relative to peritumor liver tissues. The expression levels of miR-107 were negatively correlated with those of HMGA2 mRNA in HCC samples. Conclusion: MiR-107 suppresses the proliferation of hepatoma cells by targeting HMGA2 mRNA. Our finding provides new insights into the mechanism of hepatocarcinogenesis. - Highlights: • HMGA2 is a novel target gene of miR-107. • MiR-107 suppresses the proliferation of HCC cells through targeting HMGA2 mRNA. • MiR-107 is decreased in clinical HCC tissues. • MiR-107 is negatively correlated with HMGA2 in clinical HCC tissues.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

MiR-509-5p suppresses the proliferation, migration, and invasion of non-small cell lung cancer by targeting YWHAG

Dysregulation of microRNAs (miRNAs) expression is prevalent in human malignancy development and progression. As previously reported, miR-509-5p has been identified as a tumor suppressor in various cancers, but its role and functional mechanism in non-small lung cancer (NSCLC) remains unknown. In the present study, we found that miR-509-5p was significantly downregulated in NSCLC tissues and cell lines using Quantitative real-time PCR (qRT-PCR). In addition, overexpression of miR-509-5p markedly inhibited the proliferation, migration, invasion and phosphorylation of Akt of NSCLC cells. Moreover, we identified tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein gamma (YWHAG) as a direct target of miR-509-5p. Knockdown of YWHAG mimicked the inhibitory effects of miR-509-5p on NSCLC cells for proliferation and motility. Finally, the negative correlation between miR-509-5p and YWHAG expression in NSCLC specimens was demonstrated. Taken together, our present study revealed the tumor suppressive role of miR-509-5p in NSCLC by targeting YWHAG, suggesting that miR-509-5p/YWHAG axis might be considered as a novel and potential target for clinical diagnosis and therapeutics of NSCLC. - Highlights: • The tumor suppressive role of miRNA-509-5p in non-small cell lung cancer is revealed. • MiR-509-5p exerts its influence on NSCLC cells by targeting YWHAG. • MiR-509-5p inhibits the phosphorylation of Akt in NSCLC cells. • MiR-509-5p can be deemed as a potential diagnostic and therapeutic target for NSCLC.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

microRNA-495 promotes bladder cancer cell growth and invasion by targeting phosphatase and tensin homolog

Accumulating evidence has linked deregulation of microRNA-495 (miR-495) to tumorigenesis; however, its function in tumor progression is controversial. This work was undertaken to explore the expression and biological roles of miR-495 in bladder cancer. The expression of miR-495 was examined in 67 pairs of bladder cancer and adjacent normal bladder tissues. The roles of miR-495 in bladder cancer cell proliferation and invasion in vitro and tumorigenesis in vivo were determined. Direct target gene(s) mediating the activity of miR-495 in bladder cancer cells was identified. It was found that miR-495 was expressed at greater levels in bladder tissues and cell lines. High expression of miR-495 was significantly associated with larger tumor size, advanced TNM stage, and lymph node metastasis. Overexpression of miR-495 significantly promoted bladder cancer cell proliferation and invasion, whereas inhibition of miR-495 suppressed cell proliferation and invasion. PTEN, a well-defined tumor suppressor was identified to be a target gene of miR-495. A significant inverse correlation between miR-495 and PTEN expression was noted in bladder cancer tissues (r = −0.3094, P = 0.0125). Overexpression of miR-495 led to reduction of PTEN expression in bladder cancer cells. Rescue experiments showed that enforced expression of PTEN impaired miR-495-mediated bladder cancer proliferation and invasion. In vivo mouse studies demonstrated that overexpression of miR-495 accelerated the growth of subcutaneous bladder cancer xenografts, which was associated with downregulation of PTEN. Overall, these findings indicate that miR-495 upregulation contributes to bladder cancer cell growth, invasion, and tumorigenesis by targeting PTEN and offer a potential therapeutic target for bladder cancer. - Highlights: • miR-495 upregulation induces aggressive phenotype in bladder cancer. • miR-495 is inversely correlated with PTEN in bladder cancer. • miR-495 promotes bladder cancer cell proliferation and invasion by targeting PTEN.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Hsa{sub c}irc{sub 0}009910 promotes carcinogenesis by promoting the expression of miR-449a target IL6R in osteosarcoma

Highlights: • Hsa{sub c}irc{sub 0}009910 plays oncogenic role in osteosarcoma cells. • Circ{sub 0}009910 acted as a sponge of miR-449a. • Inhibition of miR-449a impairs the tumor suppressor role of circ{sub 0}009910 silencing. • IL6R was a functional target of miR-449a. • JAK1/STAT3 signaling involves in circ{sub 0}009910/miR-449a/IL6R related tumorigenesis. Circular RNAs (circRNAs) have recently shown capabilities as gene regulators in mammals. Some of them interact with microRNAs (miRNAs) and function as sponges to affect related miRNAs' activities. In this study, the molecular function of circRNA{sub 0}009910 and its potential downstream miRNA targets were explored. The expression levels of hsa{sub c}irc{sub 0}009910 were found to be overexpressed in osteosarcoma (OS) cells. Knockdown of circ{sub 0}009910 induced cell proliferation inhibition, cell cycle arrest, and apoptosis in OS cells. The target miRNA was predicted to be miR-449a, whose expression was downregulated in OS cells. Inhibition of miR-449a abolished the effect of circ{sub 0}009910 knockdown on cell growth and apoptosis. The expression of miR-449a were found to be negatively correlated with that of circ{sub 0}009910 in OS tissues. Direct interaction of circ{sub 0}009910 and miR-449a was confirmed through dual-luciferase assays. Moreover, IL6R was predicted as a potential target of miR-449a. Overexpression of miR-449a decreased the mRNA and protein levels of IL6R. Restoration of IL6R impaired the miR-449a induced inhibition of cell proliferation, cell cycle arrest, and apoptosis. The mRNA expression of IL6R was inversely correlated with miR-449a in OS tissues. In addition, JAK1/STAT3 signaling pathway was regulated by circ{sub 0}009910/miR-449a/IL6R axis. Taken together, we suggested that circ{sub 0}009910 acted as a sponge of miR-449a and upregulated miR-449a functional target IL6R, thereby contributed to carcinogenesis of OS.

60 APPLIED LIFE SCIENCES↗