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At least 1,495 records · Page 83
All sourcesNASA NTRSDOE OSTI
DOE OSTI2016

Long non-coding RNA lnc-MX1-1 is associated with poor clinical features and promotes cellular proliferation and invasiveness in prostate cancer

Long non-coding RNAs (lncRNAs) are emerging as key molecules in human cancer genesis and progression, including prostate cancer. Large amount of lncRNAs have been found that differentially expressed between prostate cancer tissues and normal prostate tissues. Whether these lncRNAs could serve as a novel biomarker for prostate cancer diagnosis or prognosis, and their biological functions in prostate cancer need further investigation. In the present study, we identified that lncRNA lnc-MX1-1 is over-expressed in prostate cancer tissues compared with their adjacent normal prostate tissues by gene expression array profiling. The expression of lnc-MX1-1 in 60 prostate cancer cases was determined by real-time quantitative PCR and the correlations between lnc-MX1-1 expression and patients' clinical features were further analyzed. Next, we impaired lnc-MX1-1 expression using RNAi in LNCaP and 22Rv1 prostate cancer cells to explore the effects of lnc-MX1-1 on proliferation and invasiveness of the cells. Our results showed that there was a significant association between over-expression of lnc-MX1-1 and patients' clinical features such as PSA, Gleason score, metastasis, and recurrence free survival. Moreover, knockdown of lnc-MX1-1 reduced both proliferation and invasiveness of LNCaP and 22Rv1 cells. In conclusion, the results suggest that lnc-MX1-1 may serve as a potential biomarker and therapeutic target for prostate cancer. - Highlights: • LncRNA lnc-MX1-1 is up-regulated in prostate cancer. • Overexpression of lnc-MX1-1 is correlated with poor prostate cancer clinical features. • Knockdown of lnc-MX1-1 reduces proliferation and invasiveness of prostate cancer cells.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Downregulated long non-coding RNA MEG3 in breast cancer regulates proliferation, migration and invasion by depending on p53’s transcriptional activity

Long non-coding RNAs (lncRNAs) was found to play critical roles in tumorigenesis, hence, screen of tumor-related lncRNAs, identification of their biological roles is important for understanding the processes of tumorigenesis. In this study, we identified the expressing difference of several tumor-related lncRNAs in breast cancer samples and found that, MEG3, which is downregulated in non-small cell lung cancer (NSCLC) tumor tissues, is also downregulated in breast cancer samples compared with adjacent tissues. For figuring out the effect of MEG3 in breast cancer cells MCF7 and MB231, we overexpressed MEG3 in these cells, and found that it resulted the inhibition of proliferation, colony formation, migration and invasion capacities by enhancing p53’s transcriptional activity on its target genes, including p21, Maspin and KAI1. MEG3 presented similar effects in MB157, which is a p53-null breast cancer cell line, when functional p53 but not p53R273H mutant, which lacks transcriptional activity, was introduced. Surprisingly, overexpression of MEG3 activates p53’s transcriptional activity by decreasing MDM2’s transcription level, and thus stabilizes and accumulates P53. Taken together, our findings indicate that MEG3 is downregulated in breast cancer tissues and affects breast cancer cells’ malignant behaviors, which indicate MEG3 a potential therapeutic target for breast cancer. - Highlights: • MEG3 RNA is widely downregulated in breast tumor tissue. • MEG3 regulates P53 indirectly through transcriptional regulation of MDM2. • Under unstressed condition, MEG3-related P53 accumulation transcriptionally activates p53’s target genes. • MEG3 expression level tightly regulates proliferation, colony formation, migration and invasion in breast tumor cells.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Long non-coding RNA linc-cdh4-2 inhibits the migration and invasion of HCC cells by targeting R-cadherin pathway

Long non-coding RNAs (LncRNAs) have played very important roles in the malignancy behaviors of hepatocellular carcinoma (HCC). Linc-cdh4-2 (TCONS-00027978) is a novel LncRNA that has been identified in HCC tissues from our previous study. Overexpression of linc-cdh4-2 in HCC cell lines (SK-Hep-1 and Huh7) significantly decreases the migration and invasion abilities of these cells, while knockdown the expression of linc-cdh4-2 significantly increases the migration and invasion abilities. Interestingly, neither the over expression nor the knock down of linc-cdh4-2 could affect the viability and proliferation of HCC cells. Mechanistically, the linc-cdh4-2 could up-regulate the protein level of R-cadherin through direct binding that might improve the protein stability. Over expression of linc-cdh4-2 could significantly increase the protein levels of R-cadherin and decrease the protein levels of small GTPase RAC1, and vice-versa. Further knockdown R-cadherin in linc-cdh4-2 stably overexpressed cells, could significantly upregulate the protein levels of RAC1 and improve the cell migration and invasion abilities. Taken together, the novel linc-cdh4-2 may negatively regulate the motility of the HCC cells through targeting R-cadherin-RAC1 signaling pathway. - Highlights: • Linc-cdh4-2 negatively related with the invasion and metastasis ability of HCC cells. • Linc-cdh4-2 could up-regulate the protein level of R-cadherin through direct binding. • Knockdown of R-cadherin increases the migration and invasion abilities of HCC cell. • Knockdown of R-cadherin could significantly upregulate the protein levels of RAC1.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Long non-coding RNA NEAT1 facilitates pancreatic cancer progression through negative modulation of miR-506-3p

Recently, long non-coding RNAs (lncRNAs) have been shown to have critical regulatory roles in tumourigenesis. Increasing evidence has suggested that lncRNA NEAT1 has been implicated in various types of human cancer. However, the potential biological roles and regulatory mechanisms of NEAT1 in pancreatic cancer (PC) remains unclear. Here, we found that the expression level of NEAT1 was higher in PC tissues compared to the corresponding non-tumor tissues. Besides, our findings indicate that high NEAT1 expression level is closely correlated with tumor progression and poor survival in PC patients. Furthermore, we also found that knockdown of NEAT1 remarkably suppressed cell proliferation by inducing cell cycle arrest and apoptosis promotion in PC cells. Moreover, bioinformatics analysis and luciferase reporter assay revealed that NEAT1 directly bound to the miR-506-3p, which has been reported to act as a tumor suppressor in diverse cancers. Additionally, our results confirmed that the tumor-promoting effects of NEAT1 in PC cells is at least partly through negative modulation of miR-506-3p. Overall, our results suggested that NEAT1 functions as an oncogenic lncRNA in PC, which could be a novel diagnostic and therapeutic target for PC. - Highlights: • Upregulation of NEAT1 expression was significantly associated with the poor survival in PC patients. • Knockdown of NEAT1 can suppress PC cells growth by inducing cell cycle arrest and apoptosis promotion in vitro study. • NEAT1 functions as an oncogene in pancreatic cancer by acting as a competing endogenous RNA for miR-506-3p. • The tumor-suppressive effects of NEAT1 knockdown in PC cells was partially reversed by miR-506-3p inhibitor.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Bimodal expression of yeast GAL genes is controlled by a long non-coding RNA and a bifunctional galactokinase

Bimodality in gene expression can generate phenotypic heterogeneity facilitating fitness and growth of isogenic cell populations in suboptimal environments. We investigated the mechanism by which, in conditions of limiting galactose, yeast cell populations activate GAL genes in a bimodal fashion with a cell fraction expressing GAL genes (ON), while the rest subpopulation is kept at the non-expressing (OFF) state. We show that a long non-coding RNA (GAL10-ncRNA) crossing the bidirectional GAL1-10 promoter, decreases the rate by which single cells commit transition to the ON state without affecting the rate of GAL transcription per se in ON cells. This is accomplished by repressing stochastic expression of the bifunctional Gal1p galactokinase, which besides its enzymatic activity acts as an essential inducer of the system under those conditions. We show that once single cells switch to the ON state, the GAL10-ncRNA effect is overridden by accumulating Gal1p levels sufficient to feedback positively on Gal4p, and not by the active transcription of GAL10 that occurs in opposite direction relative to that of GAL10-ncRNA. Conversely, GAL10-ncRNA does not influence transition of ON cells, where Gal4p is active, back to the OFF state. Our model suggests that the functional interplay between GAL10-ncRNA transcription, stochastic Gal1p expression and Gal1p positive feedback on Gal4p constitutes a novel molecular switch mechanism dictating the commitment of individual cells for either metabolic state. - Highlights: • Stochastic transcription of the Gal1p galactokinase creates bimodality in GAL expression. • GAL10-ncRNA controls GAL bimodality by repressing Gal1p. • GAL10-ncRNA repression is overridden by the inducing activity of Gal1p itself.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Long non-coding RNA FBXL19-AS1 plays oncogenic role in colorectal cancer by sponging miR-203

Long non-coding RNAs (lncRNAs) have emerged as critical regulators of the progression of human cancers, including colorectal cancer (CRC). The study of genome-wide lncRNA expression patterns in metastatic CRC could provide novel mechanism underlying CRC carcinogenesis. In here, we determined the lncRNA expression profiles correlating to CRC with or without lymph node metastasis (LNM) based on microarray analysis. We found that 2439 lncRNAs and 1654 mRNAs were differentially expressed in metastatic CRC relative to primary CRC. Among these dysregulated lncRNAs, FBXL19-AS1 was the most significantly upregulated lncRNA in metastatic tumors. Functionally, knockdown of FBXL19-AS1 played tumor-suppressive effects by inhibiting cell proliferation, migration and invasion in vitro and tumor growth and metastasis in vivo. Overexpression of FBXL19-AS1 was markedly correlated with TNM stage and LNM in CRC. Bioinformatics analysis predicted that miR-203 was potentially targeted by FBXL19-AS1, which was confirmed by dual-luciferase reporter assay. Pearson's correlation analysis showed that miR-203 expression was negatively related to FBXL19-AS1 in tumor tissues. Finally, miR-203 inhibition abrogated the effect of FBXL19-AS1 knockdown on the proliferation and invasion of LoVo cells. Our results reveal the cancer-promoting effect of FBXL19-AS1, acting as a molecular sponge in negatively modulating miR-203, which might provide a new insight for understanding of CRC development. - Highlights: • LncRNA expression signature was different between metastatic and primary tumors. • Knockdown of FBXL19-AS1 inhibits proliferation, migration and invasion in vitro. • Knockdown of FBXL19-AS1 inhibits tumorigenesis and metastasis in vivo. • FBXL19-AS1 was upregulated in CRC tissues and related with lymph node metastasis. • FBXL19-AS1, acting as a molecular sponge in negatively regulating miR-203.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Long intergenic non-coding RNA 668 regulates VEGFA signaling through inhibition of miR-297 in oral squamous cell carcinoma

Recently, long noncoding RNAs (lncRNAs) have been reported to have crucial regulatory efficiency in human cancer biology. Long intergenic non-coding RNA 668 (LINC00668) was regarded as an oncogene in multiple cancers. However, the underlying molecular mechanism of LINC00668 in oral squamous cell carcinoma (OSCC) has not been studied. In this study, we first demonstrated that LINC00668 expression was up-regulated, which was correlated with tumor progression, and miR-297 down-regulated in OSCC tissues and cells. Importantly, LINC00668 expression was negatively correlated with miR-297 expression in OSCC tissues. Loss-of-function of LINC00668 revealed that LINC00668 functioned as a ceRNA for miR-297 to facilitate VEGFA expression, promoting OSCC progression. Furthermore, LINC00668 knockdown suppressed tumor growth and reduced the expression of proliferation antigen ki-67 in vivo. Finally, we confirmed that LINC00668 promoted OSCC activity through VEGFA signaling. In conclusion, these results suggest that LINC00668 promotes OSCC tumorigenesis via miR-297/VEGFA axis, which may provide a new target for the diagnosis and therapy of OSCC disease. - Highlights: • LINC00668 is up-regulated in human primary OSCC tissues. • Expression of VEGFA is up-regulated in primary human OSCC and negatively expressed related to miR-297. • miR-297 inhibits the tumorigenic potential of OSCC cells by down-regulating oncogenic VEGFA gene. • LINC00668's oncogenic functions are partially through reverse regulation of miRNA-297, and then activation of VEGFA.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Upregulated long non-coding RNA LOC90784 promotes cell proliferation and invasion and is associated with poor clinical features in HCC

A growing amount of literature has indicated that long non-coding RNAs (lncRNAs) are important factors in hepatocellular carcinoma (HCC) progression. However, the significance of lncRNAs in the progression and prognosis of liver cancer is largely unknown. In the present study, upregulated lncRNA LOC90784 was identified through integrative analysis of (GSE58043) and (GSE55191). Furthermore, associations between LOC90784 expression and the clinicopathological characteristics of patients were analyzed with a validated cohort 1 and the Cancer Genome Atlas (TCGA) cohort 2. We investigated the mechanisms by which this highly expressed lncRNA promotes HCC proliferation, invasion and migration via qRT-PCR, fluorescence in situ hybridization (FISH) staining, siRNA transfection, cell proliferation assays, Transwell and colony formation assays, flow cytometry analysis and Western blot. The results showed that LOC90784 expression levels were significantly higher in HCC cell lines and tissues and mainly localized in the cytoplasm. Knockdown of lncRNA LOC90784 expression inhibited proliferation and induced apoptosis and cell cycle arrest by promoting Bax and repressing CDK4 and Cyclin D1 protein expression; it also inhibited invasion and migration by repressing MMP2 and MMP9 expression in HCC cells. LOC90784 overexpression was associated with poor clinical features in the two cohorts and poor overall survival rates in HCC patients with clear resection margins (R0) in cohort 2. These results indicated that LOC90784 upregulation may be a critical oncogene and potential new biomarker in HCC. - Highlights: • LncRNA LOC90784 was overexpressed in HCC tissues and cell lines. • Highly expressed lncRNA LOC90784 was associated with poor clinical features in HCC. • Knockdown of lncRNA LOC90784 expression inhibited proliferation and induced apoptosis and cell cycle arrest. • Knockdown of lncRNA LOC90784 expression inhibited invasion and migration.

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 OSTI2018

C/EBPβ contributes to transcriptional activation of long non-coding RNA NEAT1 during APL cell differentiation

Emerging evidences have shown that long non-coding RNAs (lncRNAs) play critical roles in cancer development and cancer therapy. LncRNA Nuclear Enriched Abundant Transcript 1 (NEAT1) is indispensable during acute promyelocytic leukemia (APL) cell differentiation induced by all-trans retinoic acid (ATRA). However, the precise mechanism of NEAT1 upregulation has not been fully understood. In this study, we performed chromatin immunoprecipitation and luciferase reporter assays to demonstrate that C/EBP family transcription factor C/EBPβ bind to and transactivate the promoter of lncRNA NEAT1 through the C/EBPβ binding sites both around −54 bp and −1453 bp upstream of the transcription start site. Moreover, the expression of C/EBPβ was increased after ATRA treatment, and the binding of C/EBPβ in the NEAT1 promoter was also dramatically increased. Finally, knockdown of C/EBPβ significantly reduced the ATRA-induced upregulation of NEAT1. In conclusion, C/EBPβ directly activates the expression of NEAT1 through binding to the promoter of NEAT1. Knockdown of C/EBPβ impairs ATRA-induced transcriptional activation of NEAT1. Our data indicate that C/EBPβ contributes to ATRA-induced activation of NEAT1 during APL cell differentiation. Our results enrich our knowledge on the regulation of lncRNAs and the regulatory role of C/EBPβ in APL cell differentiation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Long non-coding RNA LUCAT1 modulates methotrexate resistance in osteosarcoma via miR-200c/ABCB1 axis

Highlights: • LncRNA LUCAT1 and ABCB1 protein are both up-regulated in osteosarcoma methotrexate-resistant cells. • LncRNA LUCAT1 knockdown suppress the expression levels drug resistance related genes, proliferation, invasion and tumor growth of osteosarcoma cells in vitro and vivo. • Bioinformatics predictive tools and luciferase assay reveal the LUCAT1/miR-200c/ABCB1 pathway. • Rescue experiments confirm the combined role of LUCAT1, miR-200c and ABCB1 on osteosarcoma methotrexate resistance. Long non-coding RNAs (lncRNAs) have been verified to participate in the tumorigenesis of multiple cancers. Nevertheless, the deepgoing role molecular mechanisms of lncRNAs on osteosarcoma chemoresistance remain unclear. In present study, we investigate the function of lncRNA LUCAT1 on osteosarcoma methotrexate (MTX) resistant phenotype and discover the potential regulatory mechanism. Results showed that LUCAT1 was up-regulated in MTX-resistant cells (MG63/MTX, HOS/MTX) compared to that in parental cells. LncRNA LUCAT1 and ABCB1 protein expression levels were both up-regulated when induced by different concentration of methotrexate. In vitro and vivo, LUCAT1 knockdown decreased the expression levels drug resistance related genes (MDR1, MRP5, LRP1), proliferation, invasion and tumor growth of osteosarcoma cells. Bioinformatics tools and luciferase assay reveled that miR-200c both targeted the 3′-UTR of LUCAT1 and ABCB1 mRNA, suggesting the modulation of LUCAT1 on ABCB1 through sponging miR-200c. Rescue experiments confirmed the combined role of LUCAT1, miR-200c and ABCB1 on osteosarcoma proliferation, invasion and methotrexate resistance. Overall, results indicate the vital role of LUCAT1 in the methotrexate resistance regulation through miR-200c/ABCB1 pathway, providing a novel insight and treatment strategy for osteosarcoma drug resistance.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Long non-coding RNA RMST silencing protects against middle cerebral artery occlusion (MCAO)-induced ischemic stroke

Highlights: • RMST expression is significantly up-regulated ischemic brain. • RMST silencing protects hippocampal neurons against OGD-induced stress. • RMST silencing protects against ischemic brain injury in vivo. • RMST silencing improves neurological function. Long non-coding RNAs (lncRNAs) have emerged as major regulators in neurological diseases, and clarifying their roles in cerebral ischemic injury may provide novel targets for treating ischemic stroke. In this study, we mainly studied the role of lncRNA-RMST in middle cerebral artery occlusion (MCAO)-induced mouse brain injury. We showed that RMST expression level was significantly up-regulated in oxygen-glucose deprivation (OGD)-treated primary hippocampal neuron, MCAO-induced injured brain, and the plasma of patients with ischemic stroke. RMST silencing protected against MCAO-induced ischemic brain injury in vivo and OGD-induced primary hippocampal neuron injury in vitro. Intracerebroventricular injection of RMST shRNA significantly decreased brain RMST expression, reduced brain infarct size, and improved neurological function. Collectively, this study provides evidence that lncRNA is involved in the pathogenesis of ischemic brain injury, and suggests a promising approach of RMST inhibition in treating ischemic stroke.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Long non-coding RNA PVT1-5 promotes cell proliferation by regulating miR-126/SLC7A5 axis in lung cancer

Highlights: • LncRNA-PVT1-5 is up-regulated in lung cancer tissues and cell lines. • LncRNA-PVT1-5 acted as a sponge for miR-126 to regulate cells proliferation in lung cancer cells. • LncRNA-PVT1-5 exerts its role via miR-126/SLC7A5 axis in lung cancer cell modes. Dysregulated long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) play key roles in the development of human cancers. The lncRNA plasmacytoma variant translocation 1 (PVT1) is reported to be an oncogene in a variety of cancers. However, the roles of PVT1-5 and its related miRNAs in lung cancer are poorly understood. In this study, we found that PVT1-5 expression was significantly increased in lung cancer tissues and cell lines. By using biotin-labeled lncRNA-PVT1-5 probe for miRNA in vivo precipitation (miRIP) in lung cancer cells and dual-luciferase reporterassays, we identified that miR-126 was associated with lncRNA-PVT1-5. Furthermore, knockdown of lncRNA-PVT1-5 in cells could down-regulate the expression of SLC7A5, the target of oncogenic miR-126, resulting in the cell proliferation. Conversely, inhibiting the expression of miR-126 markedly increased the expression of SLC7A5 and alleviated cell proliferation inhibition. Thus, our results indicated that lncRNA-PVT1-5 may function as a competing endogenous RNA (ceRNA) for miR-126 to promote cell proliferation by regulating the miR-126/SLC7A5 pathway, suggesting that lncRNA-PVT1-5 plays a crucial role in lung cancer progression and lncRNA-PVT1-5/miR-126/SLC7A5 regulatory network may shed light on tumorigenesis in lung cancer.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Long non-coding RNA UCA1 desensitizes breast cancer cells to trastuzumab by impeding miR-18a repression of Yes-associated protein 1

Highlights: • Knockdown of UCA1 expression restored sensitivity of breast cancer cells to trastuzumab. • UCA1 knockdown upregulated miR-18a and downregulated YAP1 in breast cancer cells. • YAP1 is a direct target of miR-18a in breast cancer cells. • The UCA1/miR-18a/YAP1 feedback axis regulated the sensitivity of breast cancer cells to trastuzumab. Breast cancer resistance to the monoclonal erbB2/HER2 antibody trastuzumab (or herceptin) has become a significant obstacle in clinical targeted therapy of HER2-positive breast cancer. Previous research demonstrated that such drug resistance may be related to dysregulation of miRNA expression. Here, we found that knockdown of the long non-coding RNA, urothelial cancer associated 1 (UCA1), can promote the sensitivity of human breast cancer cells to trastuzumab. Mechanistically, UCA1 knockdown upregulated miR-18a and promoted miR-18a repression of Yes-associated protein 1 (YAP1). A luciferase reporter assay confirmed the association of miR-18a with wild-type UCA1 but not with UCA1 mutated at the predicted miR-18a-binding site. The direct targeting of YAP1 by miR-18a was verified by the observation that miR-18a mimic suppressed luciferase expression from a construct containing the YAP1 3′ untranslated region. Meanwhile, reciprocal repression of UCA1 and miR-18a were found to be Argonaute 2-dependent. Knockdown of YAP1 recapitulated the effect of UCA1 silencing by reducing the viability of trastuzumab-treated breast cancer cells, whereas inhibition of miR-18a abrogated UCA1 knockdown-induced improvement of trastuzumab sensitivity in breast cancer cells. These findings demonstrate that the UCA1/miR-18a/YAP1 axis plays an important role in regulating the sensitivity of breast cancer cells to trastuzumab, which has implications for the development of novel approaches to improving breast cancer responses to targeted therapy.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Long non-coding RNA THOR promotes human osteosarcoma cell growth in vitro and in vivo

Highlights: • LncRNA THOR (“Lnc-THOR”) is expressed in human osteosarcoma (OS) cells and tissues. • Lnc-THOR siRNA inhibits human OS cell survival and proliferation. • Lnc-THOR over-expression promotes human OS cell survival and proliferation. • Lnc-THOR knockout inhibits U2OS cell growth in vitro and in vivo Long non-coding RNA (LncRNA) dysregulation is associated with human osteosarcoma (OS) cell progression. Recent studies have characterized a novel but ultra-conserved LncRNA THOR (“Lnc-THOR”) as a cancer-specific LncRNA, mediating cell growth. In the current study, we show that Lnc-THOR is expressed in established and primary human OS cells. It is also detected in human OS tissues, but not in the surrounding normal bone tissues. siRNA-induced knockdown or CRSIPR/Cas9-mediated knockout Lnc-THOR significantly inhibited human OS cell survival and proliferation. Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) target mRNAs, including IGF2, GLI1 and CD44, were downregulated in Lnc-THOR-silenced OS cells as well. Conversely, forced over-expression of Lnc-THOR enhanced IGF2BP1 target mRNA expression, promoting OS cell survival and proliferation. In vivo, xenograft tumors of Lnc-THOR-knockout U2OS cells grew significantly slower than the control U2OS tumors. Together, these results show that Lnc-THOR expression is essential for human OS cell growth. Lnc-THOR could be a novel therapeutic target and/or diagnosis marker for human OS.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Long non-protein coding RNA DANCR functions as a competing endogenous RNA to regulate osteoarthritis progression via miR-577/SphK2 axis

Highlights: • DANCR was increased in OA. • DANCR inhibition suppressed OA chondrocytes proliferation and induced cell apoptosis. • DANCR-miR-577/SphK2 axis play important roles in OA. Long noncoding RNAs (lncRNAs) have been known to be involved in multiple diverse diseases, including osteoarthritis (OA). This study aimed to explore the role of differentiation antagonizing non-protein coding RNA (DANCR) in OA and identify the potential molecular mechanisms. The expression of DANCR in cartilage samples from patients with OA was detected using quantitative reverse transcription–polymerase chain reaction. The effects of DANCR on the viability of OA chondrocytes and apoptosis were explored using cell counting kit 8 assay and flow cytometry assay, respectively. Additionally, the interaction among DANCR, miR-577, and SphK2 was explored using dual-luciferase reporter and RIP assays. The present study found that DANCR was significantly upregulated in patients with OA. Functional assays demonstrated that DANCR inhibition suppressed the proliferation of OA chondrocytes and induced cell apoptosis. The study also showed that DANCR acted as a competitive endogenous RNA to sponge miR-577, which targeted the mRNA of SphK2 to regulate the survival of OA chondrocytes. In conclusion, the study revealed that lncRNA DANCR might promote the proliferation of OA chondrocytes and reduce apoptosis through the miR-577/SphK2 axis. Thus, lncRNA DANCR might be considered as a potential therapeutic target for OA treatment.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Long non-coding RNA CASP5 promotes the malignant phenotypes of human glioblastoma multiforme

Highlights: • The expression of lncRNA CASP5 in GBM tissues was significantly higher than that in adjacent tissues. • LncRNA CASP5 promoted the proliferation of GBM cells both in vitro and in vivo. • LncRNA CASP5 facilitated the migration and invasion of GBM cells. Long non-coding RNAs (lncRNAs) have been demonstrated to be intensively involved in the development of various carcinomas, including glioblastoma multiforme (GBM). However, only a few of them have been well characterized. LncRNA CASP5 have been found to be up-regulated in GBM tissues compared with normal tissues in a microarray-based lncRNA profiling study. In the present study, we further explored the biological role of lncRNA CASP5 in GBM.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Effect of long non-coding RNA H19 on oxidative stress and chemotherapy resistance of CD133+ cancer stem cells via the MAPK/ERK signaling pathway in hepatocellular carcinoma

Highlights: • The H19 expression is higher in HCC tissues than in adjacent normal tissues. • CD133-positive Huh7 cells account for (99.4 ± 3.6)% by flow cytometry. • Inhibition of H19 induces OS in CD133 + cancer stem cells. • Inhibition of H19 reverses chemoresistance in CD133 + cancer stem cells. • Inhibition of H19 contributes to inactivation of MAPK/ERK signaling pathway. We explored the ability of a long non-coding RNA H19, to influence oxidative stress (OS) and chemotherapy resistance of CD133 + cancer stem cells via the MAPK/ERK signaling pathway in HCC. HCC tissues with corresponding adjacent normal tissues were collected. CD133 + HuH7 cells were sorted and assigned into five groups. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were performed to determine expression levels mRNAs and proteins. Levels of reactive oxygen species (ROS) and malonaldehyde (MDA), and activity of superoxide dismutase (SOD) were measured. Cell viability was analyzed by MTT assay and cell apoptosis by flow cytometry. Compared with adjacent normal tissues, the H19 expression level was higher and MAPK and ERK protein levels were lower in HCC tissues. Compared with the blank group, in the pcDNA-H19 group, H19 expression level, MAPK and ERK protein levels, MDR1 and GST-π expression levels were increased, ROS and MDA levels were decreased, SOD activity was weakened, cell viability was promoted, and cell apoptosis was inhibited; in the siH19 group, H19 expression level, MAPK and ERK protein levels, MDR1 and GST-π expression levels were reduced, ROS and MDA levels were elevated, SOD activity was enhanced, cell viability was inhibited, and cell apoptosis was promoted. There was no significant difference among blank, NC and pcDNA-H19 + PD98059 groups. The study provides evidence that downregulation of H19 may induce OS and reverse chemotherapy resistance of CD133 + cancer stem cells by blocking the MAPK/ERK signaling pathway in HCC.

60 APPLIED LIFE SCIENCES↗