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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 1,153 records · Page 64
All sourcesNASA NTRSDOE OSTI
DOE OSTI2017

Long noncoding RNA linc00346 promotes the malignant phenotypes of bladder cancer

Background: More and more reports have demonstrated that long noncoding RNAs (lncRNAs) play an important role in the development of a variety of carcinomas, including bladder cancer. However, only a small fraction of them have been characterized. Linc00346 have been found to be upregulated in bladder cancer tissues compared to normal tissues in a microarray-based lncRNA profiling study. In this study, we would like to explore the expression pattern and functional role of linc00346 in bladder cancer. Methods: We determined the expression of linc00346 in a cohort of bladder cancer tissues with matched normal tissues as well as human bladder cancer cell lines. We investigated the biological function of linc00346 with CCK-8 assay, colony formation assay, flow cytometry analysis, transwell assay and tumor xenografts mice model. Results: We found that linc00346 was upregulated in bladder cancer tissues compared to normal tissues. Knockdown of linc00346 inhibited bladder cancer cell proliferation and migration, induced cell cycle arrest and cell apoptosis. Conclusion: Our study demonstrates that linc00346 could be a potential oncogene and a therapeutic target in bladder cancer. - Highlights: • linc00346 was upregulated in bladder cancer tissues compared to normal tissues. • linc00346 promoted bladder cancer cell proliferation and migration. • Knockdown of linc00346 induced cell cycle arrest and cell apoptosis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

NRF2 overexpression in mesenchymal stem cells induces stem-cell marker expression and enhances osteoblastic differentiation

Hypoxic environment has been suggested in stem cell culturing as their physiologic niche requires oxygen tension to maintain stemness. The administration of cobalt chloride (CoCl{sub 2}) was widely applied in mimicking hypoxia for its economic advantages and convenience. We confirmed that CoCl{sub 2} could maintain stemness and promote the osteogenesis capacity of MSCs. However, CoCl{sub 2} could induce the apoptosis and hinder the proliferation of MSCs. To find out a potential method maintaining their stemness without threatening their survival, we analyzed the database of Gene Expression Omnibus (GEO) and proposed that NRF2 (nuclear factor erythroid-derived 2-like 2) might be the potential target. We found that knocking down NRF2 expression in MSCs impaired the expression of stem cell markers and the osteogenesis process even under hypoxic environment, but with NRF2 overexpression, the proliferation of MSCs was increased with significantly reduced rate of apoptosis. Therefore, our findings suggested that overexpressing NRF2 could be a potential method for maintaining stemness and preventing apoptosis in MSCs under oxidative stress. - Highlights: • Hypoxia promoted Stemness maintenance and osteogenesis. • NRF2 maybe the bridge that connects stemness and apoptosis under oxidative stress. • NRF2 deficiency impaired the effect of hypoxia on stemness and osteogenesis. • NRF2 promoted the maintenance of stem cell characteristics and prevented apoptosis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Long non-coding RNA PCAT7 regulates ELF2 signaling through inhibition of miR-134-5p in nasopharyngeal carcinoma

While some long noncoding RNAs (lncRNAs) might promote nasopharyngeal carcinoma (NPC) initiation and progression, the involved molecular mechanisms remain largely unclear. Here, we discovered the novel LncRNA, prostate cancer associated transcript 7 (PCAT7), which was overexpressed and associated with worse prognosis in NPC. Decreased PCAT7 expression was found to significantly suppress tumor cell proliferation in vitro, and inhibited tumor growth and reduced the expression of proliferation antigen Ki-67 in vivo. Rescue assay was performed to further confirm that PCAT7 contributed to the progression of NPC through regulating miR-134-5p/ELF2 signal pathway. These results indicated that PCAT7 might contribute to the tumor progression in NPC by functioning as a ceRNA to sponge miR-134-5p. - Highlights: • PCAT7 is up-regulated in human primary NPC tissues. • Expression of ELF2 is up-regulated in primary human NPC and negatively expressed related to miR-134-5p. • MiR-134-5p inhibits the tumorigenic potential of NPC cells by down-regulating oncogenic ELF2 gene. • PCAT7's oncogenic functions are partially through reverse regulation of miRNA-134-5p, and then activation of ELF2.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Expression and prognostic role of orphan receptor GPR110 in glioma

Glioma is the most common type of malignancy in the central nervous system, which has a poor prognosis due to its rapid progression and diffuse invasion. Identification of novel biomarkers for glioma would be invaluable for studying disease mechanism and improving prognosis. Orphan G protein-coupled receptor 110 (GPR110) belongs to the subfamily VI of adhesion GPCR. The knowledge of the ligand, signaling pathway or physiology function of GPR110 is poorly elucidated. The potential role of GPR110 as an oncogene in mouse has been recently reported by mutagenesis screen. However, its expression and role in human glioma hasn't been identified. Here in the current study, we initially explored the RNA and protein expression of GPR110 in patients with glioma. Statistical analysis proved that GPR110 was highly expressed in some patients, which was correlated with advanced disease stages. Furthermore, univariate and multivariate analyses revealed its role as an independent prognostic biomarker for the overall survival of glioma patients. Interestingly, cellular studies showed that overexpression or knockdown of GPR110 in U87 cells didn't affect cell proliferation and migration. However, the invasion of U87 cells was significantly enhanced by GPR110-overepxression, while inhibited by GPR110-knockdown. The detailed mechanisms remain further investigation although our results suggested the possible participation of STAT3 instead of ERK in the GPR110 signaling pathways. - Highlights: • GPR110 was highly expressed in glioma than normal brain tissues. • High GPR110 indicates poor overall survival of glioma patients. • GPR110 enhance cell invasion without affecting cell proliferation and migration. • GPR110 inhibit the activation of STAT3, but not ERK protein.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Folate receptor alpha is associated with cervical carcinogenesis and regulates cervical cancer cells growth by activating ERK1/2/c-Fos/c-Jun

Folate receptor alpha (FRα) is over-expressed in numerous epithelial malignancies, however, the association between FRα and cervical cancer remains unclear. The purpose of this study was to explore the effects of FRα on cervical cancer and its regulation of the ERK signaling pathway. In this case-control study, moderate/strong expression of FRα, phosphorylated ERK1/2 (p-ERK1/2), p-c-Fos, and p-c-Jun proteins was increased with the progressive severity of cervix lesions (P < 0.05). Moreover, the expression levels of p-ERK1/2, p-c-Fos, and p-c-Jun proteins was positively correlated with those of FRα protein in cervical squamous cell carcinoma (SCC) group (P < 0.05). In vitro experiment indicated down-regulation of FRα by siRNA suppressed cell proliferation, promoted cell apoptosis, induced cell cycle arrest at G0/G1 phase, and reduced expression of p-ERK1/2, p-c-Fos, and p-c-Jun proteins. The results suggest that FRα is associated with the progression of cervical cancer and regulates cervical cancer cells growth through phosphorylating ERK1/2, c-Fos, and c-Jun, which are key factors of the ERK signaling pathway. Therefore, FRα may be an effective target for early detection and therapy of cervical cancer. - Highlights: • FRα expression was increased with the progressive severity of cervix lesions. • FRα expression was positively correlated with that of p-ERK1/2, p-c-Fos, and p-c-Jun in cervical cancer. • Down-regulation of FRα expression suppressed cell proliferation and promoted apoptosis and cell cycle arrest. • Down-regulation of FRα expression reduced the expression of p-ERK1/2, p-c-Fos, and p-c-Jun.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Synergistic suppression of a disintegrin acurhagin-C in combination with AZD4547 and reparixin on terminating development for human osteosarcoma MG-63 cell

Current therapies available for the treatment of human osteosarcoma, an aggressive bone tumor, are insufficient. To examine an alternative approach of integrin-based anti-osteosacoma strategy, acurhagin-C, a Glu-Cys-Asp (ECD)-disintegrin, was isolated and evaluated for its application in combination with two potent inhibitors of basic fibroblast growth factor (bFGF) and interleukin-8 (IL-8). The investigation of human osteosarcoma MG-63 cells pre-incubated with a FGF receptor-1 (FGFR-1) blocker AZD4547, a CXC-chemokine receptor-1/-2 (CXCR1/2) antagonist reparixin, and acurhagin-C via two given modes of separation and combination was executed. Detected by flow cytometry, integrins-α2/-α5/-αv/-β1, FGFR-1, CXCR1 and CXCR2 constitutively express on the resting membrane. However, bFGF/IL-8-activated MG-63 cells only statistically enhanced the surface exposure of integrins-α5/-β1, FGFR-1 and CXCR2. In activated MG-63 cells, acurhagin-C targeting integrin-α5 not only might potentiate the inhibitory effect of AZD4547 and reparixin on the surface expression of integrin-α5, FGFR-1 and CXCR2, but also acurhagin-C used alone remained effectively to diminish the surface exposure of those targeted receptors. Hence, a complicated crosstalk mechanism should be involved in the membrane interactions. Furthermore, co-administration of acurhagin-C with AZD4547 and reparixin also showed to have the synergistic suppression toward cell proliferation and the gene expression of matrix metalloproteinase-2. Also, the administration of three-in-one mode could nearly abrogate the cellular attachment onto collagen-IV- and fibronectin-coated wells, as well as penetration into Matrigel-barrier. These data supported an ECD-disintegrin acurhagin-C targeting integrin-α5 upon combined used with AZD4547 and reparixin may become a promising therapeutic approach for attenuating osteosarcoma development. - Highlights: • Acurhagin-C against integrins exerts the application in anti-osteosacoma therapy. • Acurhagin-C in combination with AZD4547 and reparixin has synergistic inhibitions. • The 3 in 1 treatment can diminish MG-63 cells proliferation and MMP-2 expression. • The 3 in 1 treatment can effectively disturb MG-63 cells adhesion and invasion.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Luteoloside induces G0/G1 arrest and pro-death autophagy through the ROS-mediated AKT/mTOR/p70S6K signalling pathway in human non-small cell lung cancer cell lines

Highlights: • Luteoloside has the promising anticancer effects on non-small cell lung cancer (NSCLC) cells, which displayed lower cytotoxic activity toward normal lung cells. • Luteoloside contributes to growth inhibition by inducing G{sub 0}/G{sub 1} phase arrest associated with reduced expression of cell cycle proteins in NSCLC cells. • Luteoloside induces autophagy in NSCLC cells. However, luteoloside does not strongly result in apoptotic cell death in NSCLC cells. • Luteoloside induces autophagy through ROS-mediated specifically the inhibition of AKT/mTOR/p70S6K signalling pathway in NSCLC cells. Autophagy has attracted a great deal of interest in tumour therapy research in recent years. However, the anticancer effect of luteoloside, a naturally occurring flavonoid isolated from the medicinal plant Gentiana macrophylla, on autophagy remains poorly understood in human lung cells. In the present study, we have investigated the anticancer effects of luteoloside on non-small cell lung cancer (NSCLC) cells and demonstrated that luteoloside effectively inhibited cancer cell proliferation, inducing G{sub 0}/G{sub 1} phase arrest associated with reduced expression of CyclinE, CyclinD1 and CDK4; we further found that treatment with luteoloside did not strongly result in apoptotic cell death in NSCLC (A549 and H292) cells. Interestingly, luteoloside induced autophagy in lung cancer cells, which was correlated with the formation of autophagic vacuoles, breakdown of p62, and the overexpression of Beclin-1 and LC3-II, but not in a human bronchial epithelial cell line (BEAS-2B). Notably, pretreatment of cancer cells with 3-MA, an autophagy inhibitor, protected against autophagy and promoted cell viability but not apoptosis. To further clarify whether luteoloside-induced autophagy depended on the PI3K/AKT/mTOR/p70S6K signalling pathway, a major autophagy-suppressive cascade, cells were treated with a combination of AKT inhibitor (LY294002) and mTOR inhibitor (Rap). These results demonstrated that luteoloside induced autophagy in lung cancer cell lines by inhibiting the pathway at p-Akt (Ser473), p-mTOR and p-p70S6K (Thr389). Moreover, we observed that luteoloside-induced cell autophagy was correlated with production of reactive oxygen species (ROS). NAC-mediated protection against ROS clearly implicated ROS in the activation of autophagy and cell death. In addition, the results showed that ROS served as an upstream effector of the PI3K/AKT/mTOR/p70S6K pathway. Taken together, the present study provides new insights into the molecular mechanisms underlying luteoloside-mediated cell death in NSCLC cells and supports luteoloside as a potential anti-cancer agent for targeting NSCLC through the induction of autophagy, inhibition of proliferation and PI3K/AKT/mTOR/p70S6K signalling.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

C6 glioma-conditioned medium induces malignant transformation of mesenchymal stem cells: Possible role of S100B/RAGE pathway

Highlights: • C6 glioma-conditioned medium induces MSCs malignant transformation. • The transformed cells are tumorigenesis and phenotypically distinct from MSCs. • GCM increases MSCs RAGE, Akt1 and STAT3 expression. • S100B increases MSCs RAGE, Akt1, STAT3 and proliferation, migration and invasion. • RAGE inhibitor abolish S100B induced Akt1, STAT3 activation and cellular functions. Mesenchymal stem cells (MSCs) have been widely studied as an attractive therapeutic agent for the treatment of tumors. However, the adverse effects of the tumor paracrine factors who affect MSCs are still unclear. In this study, we report for the first time that C6 glioma-conditioned medium (GCM) induces malignant transformation of MSCs. In contrast to MSCs, the transformed mesenchymal stem cells (TMCs) exhibited tumor cell characterizations in vitro and highly tumorigenic in vivo. Furthermore, GCM and recombinant S100B increased receptor for advanced glycation end products (RAGE) and its downstream Akt1, STAT3 genes expression as well as phosphorylation and transcriptional activation. Finally, blockage of S100B-RAGE interaction by RAGE inhibitor FPS-ZM1 attenuated GCM and S100B-induced Akt1, STAT3 activation, abolished its cell proliferation, migration and invasion actions. Together, these results suggest that the RAGE pathway may play a possible role in malignant transformation procedure of MSCs, and that this process may be mediated through S100B.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Long non-coding RNA-422 acts as a tumor suppressor in colorectal cancer

Highlights: • LncRNA-422 in CRC tissues was significantly lower than that in adjacent tissues. • The expression of lncRNA-422 was correlated with TNM stage of CRC. • LncRNA-422 inhibits the proliferation, migration and invasion of CRC cells. • LncRNA-422 acts as a tumor suppressor by PI3K/AKT/mTOR pathway in CRC. Colorectal cancer (CRC) is one of the most frequent cancer in numerous of countries worldwidely. The initiation and progression of CRC is an extremely complex process, and have been suggested a correlation with Long non-coding RNAs (lncRNAs). Our results showed that lncRNA-422(ENST00000415820) significantly downregulated in the tissues and serum of CRC patients, and is closely associated with the poor prognosis. Then gain or loss of lncRNA-422 models in SW480 and SW620cells were established. The results showed that lncRNA-422 overexpression inhibited cell proliferation, migration, and invasion. Knockdown of lncRNA-422 promoted tumorigensis. Western blot and qRT-PCR were performed to examine the activity of the PI3K/AKT/mTOR pathway in CRC cells after alternation of lncRNA-422. Results showed that lncRNA-422 acts as a tumor suppressor by PI3K/AKT/mTOR pathway in CRC.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

FOXK1 plays an oncogenic role in the development of esophageal cancer

Forkhead box k1 (FOXK1) is a member of the FOX class of transcription factors and it is dysregulated in many solid tumors including hepatocellular carcinoma, gastric cancer, colorectal cancer and prostate cancer. However, the expression status of FOXK1 and its clinical significance in esophageal cancer (EC) is still uncertain. Our study aimed at investigating the significance of FOXK1 expression in human EC and its biological function in the development of EC. We found that FOXK1 was overexpressed in EC tissues compared with corresponding non-tumor tissues using immunohistochemistry. And high FOXK1 expression was related to poor differentiation of EC. The Kaplan-Meier curve indicated that high FOXK1 expression may result in poor prognosis of EC patients. Furthermore, overexpression of FOXK1 in EC9706 cell inhibited cell apoptosis and promoted cell proliferation and migration, and suppression of FOXK1 in EC109 cell obtained reverse results. Our data suggest that FOXK1 plays an oncogenic role in EC pathogenesis and can serve as a therapeutic target for patients with EC. - Highlights: • It's the first time investigating the relationship between FOXK1 and esophageal cancer (EC). • FOXK1 could inhibit cell apoptosis and promote cell proliferation and migration of EC in vitro. • FOXK1 plays an oncogenic role in EC pathogenesis and can serve as a therapeutic target for patients with EC.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Upregulation of PAG1/Cbp contributes to adipose-derived mesenchymal stem cells promoted tumor progression and chemoresistance in breast cancer

C-terminal Src kinase (Csk)-binding protein (Cbp) is a ubiquitously expressed transmembrane adaptor protein which regulating Src family kinase (SFK) activities. Although SFKs are well known for their involvement in breast cancer, the function of Cbp in breast carcinogenesis upon the adipose-tumor microenvironment has not been investigated. Here, we reported that adipose-derived mesenchymal stem cells (ASCs) induced increased expression of Cbp accompanied by enhanced cell proliferation and chemotherapy resistance in breast cancer cell MCF-7/ADR. Depletion of Cbp in breast cancer cell by RNA interference led to remarkable inhibition of cell proliferation, invasion as well as synergy with adriamycin hydrochloride to suppress the tumor growth. Furthermore, silencing of Cbp concomitantly inhibited the expression of phosphoryl of Src, AKT and mTOR signals. Our study highlights the underlying mechanism of cross interaction between ASCs and breast cancer cells, and indicates that PAG1/Cbp in breast cancer cell may modulate tumor progression and acquired chemoresistance in the ASCs-associated breast cancer microenvironment through Src and AKT/mTOR pathways.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Overexpression of DBC1, correlated with poor prognosis, is a potential therapeutic target for hepatocellular carcinoma

Highlights: • DBC1 was upregulated in HCC tissues and cell lines. • Overexpression of DBC1 was correlated with clinicopathological parameters in HCC. • Overexpression of DBC1 predicts poor disease-free survival (DFS) and overall survival (OS) in HCC. • Knockdown of DBC1 inhibits HCC cell lines proliferation. Deleted in Breast Cancer 1 (DBC1) is a regulatory protein involved in cell metabolism and cancer progression. Nevertheless, the expression and prognostic values of DBC1 in hepatocellular carcinoma (HCC) are still not well understood. The following study investigated the clinical significance and biological function of DBC1 in HCC. Briefly, overexpression of DBC1 at transcriptional and translational levels in human HCC tissues compared to adjacent normal tissues was observed using quantitative real-time polymerase chain reaction (qRT-PCR), western blot (WB) and immunohistochemistry (IHC) approach. Furthermore, upregulated DBC1 was significantly correlated with tumor size (p = 0.005), N stage (p = 0.016), M stage (p = 0.011), tumor differentiation (p in vitro. To conclude, these findings demonstrated that DBC1 was essential in tumorigenesis and proliferation. Moreover, it was identified as a potential therapeutic target for HCC.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Galangin enhances TGF-β1-mediated growth inhibition by suppressing phosphorylation of threonine 179 residue in Smad3 linker region

Highlights: • Galangin significantly induced apoptosis in the presence of TGF-β1. • Galangin inhibits phosphorylation of the Thr-179 site at the Smad3 linker region. • Galangin suppresses CDK4-mediated Smad3 linker phosphorylation. Smad3 linker phosphorylation is a candidate target for several kinases that play important roles in cancer cell initiation, proliferation and progression. Also, Smad3 is an essential intracellular mediator of TGF-β1-induced transcriptional responses during carcinogenesis. Therefore, it is highly advantageous to identify and develop inhibitors targeting Smad3 linker phosphorylation for the treatment of cancers. Galangin (3,5,7-trihydroxyflavone) has been known to be an active flavonoid showing a cytotoxic effect on several cancer cells. However, the mechanism of action of galangin in various cancers remains unclear, and there has been no report concerning regulation of Smad3 phosphorylation by galangin. In the present study, we show that galangin significantly induced apoptosis and inhibited cell proliferation in the presence of TGF-β1 in both human prostate and pancreatic cancer cell lines. Particularly, galangin effectively inhibits phosphorylation of the Thr-179 site at Smad3 linker region through suppression of CDK4 phosphorylation. Thus, galangin can be a promising candidate as a selective inhibitor to suppress phosphorylation of Smad3 linker region.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

CD1d is a novel cell-surface marker for human monocytic myeloid-derived suppressor cells with T cell suppression activity in peripheral blood after allogeneic hematopoietic stem cell transplantation

Highlights: • High-content screening identified a set of cell-surface marker candidates expressed in HLA-DR{sup -}CD14{sup +} M-MDSCs. • CD1d and CD226 are novel markers for the human M-MDSC subset. • CD1d-expressing M-MDSC showed the suppressive activity of T cell proliferation and could be a valuable marker for of human M-MDSCs. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that regulate immune responses in cancer and various pathological conditions. However, the phenotypic and functional heterogeneity of human MDSCs represents a major hurdle for the development of therapeutic strategies targeting or regulating MDSCs in tumor progression, inflammation, and graft-versus-host disease (GVHD). We previously shown that circulating HLA-DR{sup -}CD14{sup +} monocytic MDSCs are a major contributor to clinical outcomes after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In this study, we identified, using high-throughput screening, a set of surface markers that are strongly expressed in HLA-DR{sup -}CD14{sup +} monocytic MDSCs isolated from the peripheral blood (PB) of patients receiving allo-HSCT. Subsequent experiments showed the consistent dominant expression of CD1d in monocytic MDSCs of allo-HSCT PB in comparison with granulocytic MDSCs. In addition, CD1d-expressing cells isolated from PB of allo-HSCT patients showed the suppressive activity of T cell proliferation and higher expression of MyD88 and IDO compared with CD1d{sup −} cells. Our results suggest that CD1d could be a valuable marker for further therapeutic evaluation of human monocytic MDSCs for immune-related diseases, including GVHD.

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↗
DOE OSTI2018

Elevated O-GlcNAcylation stabilizes FOXM1 by its reduced degradation through GSK-3β inactivation in a human gastric carcinoma cell line, MKN45 cells

Highlights: • FOXM1 protein level and the cell proliferation were upregulated in a human gastric cancer cell line, MKN45 cells. • The ubiquitination and degradation of FOXM1 protein were both suppressed by high glucose and TMG treatment. • However, the O-GlcNAcylation was not detected on FOXM1 but not on GSK-3β. • The degradation of FOXM1 protein were suppressed by the treatment of GSK-3β inhibitors. • The higher risk of gastric cancer in diabetic patients could be due to O-GlcNAcylation-mediated FOXM1 stabilization. O-GlcNAcylation is a dynamic post-translational modification of cytonuclear proteins for intracellular signaling. Elevated O-GlcNAcylation is a general feature of cancer and contributes to cancer progression, and recent studies indicate the contribution to increasing incidence of various types of cancer in diabetic patients. However, the role of O-GlcNAcylation in tumor progression is not fully elucidated. Forkhead box M1 (FOXM1), a master mitotic transcription factor, has been implicated in all major hallmarks of cancer, and is wildly expressed in solid tumors. Given that FOXM1 expression was reported to be elevated in gastric cancer, we examined the effect of high glucose or an inhibitor of O-GlcNAc hydrolase, Thiamet G (TMG), on FOXM1 protein expression in a human gastric cancer cell line, MKN45 cells, and confirmed that FOXM1 protein level and the cell proliferation were upregulated. To investigate the molecular mechanisms by which FOXM1 protein expression is regulated by O-GlcNAcylation, the effect of high glucose and TMG on FOXM1 ubiquitination was examined in MKN45 cells. As a result, the ubiquitination and degradation of FOXM1 protein were both suppressed by high glucose and TMG treatment. However, the O-GlcNAcylation was not detected on FOXM1 but not on GSK-3β. High glucose and TMG treatment increased phospho-serine 9 GSK-3β, an inactive form, and the degradation of FOXM1 protein was suppressed by treatment of GSK-3β inhibitors in MKN45 cells. Taken together, we suggest that high glucose and elevated O-GlcNAcylation stabilize FOXM1 protein by its reduced degradation via GSK-3β inactivation in MKN45 cells, suggesting that the higher risk of gastric cancer in diabetic patients could be partially due to O-GlcNAcylation-mediated FOXM1 stabilization.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Harmine promotes molar root development via SMAD1/5/8 phosphorylation

Tooth and bone are major tissues involved in physiological calcification in the body, and they use similar molecular pathways for development, homeostasis, and regeneration. Harmine (HMN) is a natural small compound that stimulates osteoblast differentiation in vitro and in vivo. Here we examined the biological effect of HMN on the postnatal development of molar tooth roots and periodontal tissues. HMN supported the formation of tooth roots and periodontal tissues in developing tooth germs. In tooth germ organ culture, HMN promoted the elongation of Hertwig's epithelial root sheath (HERS) and stimulated cell proliferation in HERS and dental follicle-derived tissues, including dental papillae and dental follicles. HMN stimulated cell proliferation and cell movement of HERS-derived cells without mesenchymal cells in vitro and directly induced the phosphorylation of SMAD1/5/8 protein in HERS-derived cells. Our results indicated that HMN was the first natural small compound to stimulate postnatal development of tooth germs.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

ZEB1 stimulates breast cancer growth by up-regulating hTERT expression

Highlights: • hTERT expression is positively correlated with ZEB1 expression in breast cancer. • ZEB1 promotes hTERT expression and telomerase activity in breast cancer cell lines. • ZEB1 increases the transcriptional activity of the hTERT promoter but does not bind to the E-box. • ZEB1 controls hTERT expression by interacting with the co-activator Yes-associated protein (YAP). Dysfunctional cell proliferation and death are the foundation of the malignant biological characteristics of cancers. In this study, we discovered that ZEB1 was positively correlated with hTERT in breast invasive ductal carcinoma samples at both the mRNA and protein levels. Further, our in vitro study in breast cancer cell lines confirmed that ZEB1 regulates hTERT expression at the mRNA and protein levels; thus, hTERT promotes or inhibits telomerase activity, and telomere length is either protected or reduced. Finally, we verified that ZEB1, which mostly functions as a transcriptional repressor, can recruit the co-activator YAP to enhance the transcriptional activation of hTERT. Fascinatingly, instead of acting on E-boxes, the ZEB1/YAP complex tends to function as a transcriptional activator by binding with sequences potentially located in the hTERT promoter. Consequently, our research revealed a new ZEB1-hTERT signaling pathway involved in cell proliferation regulation that has never before been illuminated in breast cancer.

60 APPLIED LIFE SCIENCES↗