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lncRNA LINC01494 Promotes Proliferation, Migration And Invasion In Glioma Through miR-122-5p/CCNG1 Axis

lncRNA LINC01494 Promotes Proliferation, Migration And Invasion In Glioma Through... OncoTargets and Therapy Dovepress open access to scientific and medical research Open Access Full Text Article ORIGINAL RE SE ARCH lncRNA LINC01494 Promotes Proliferation, Migration And Invasion In Glioma Through miR-122-5p/CCNG1 Axis This article was published in the following Dove Press journal: OncoTargets and Therapy 1, Background: Long noncoding RNAs (lncRNAs) are recognized as key effectors in tumor, Chang Li * 2, including glioma. LINC01494 is an uncharacterized novel lncRNA. In this research, we Guozhang Hu * aimed to investigate the function of LINC01494 in glioma. Bo Wei 4 Methods: Gene relative expression was analyzed by qRT-PCR method. CCK8, colony Le Wang formation and Transwell assay was used to determine cell proliferation, migration and Naijie Liu invasion. Bioinformatics analyses were used to predict the target of LINC01494 and miR- Department of VIP Unit, China-Japan 122-5p. Luciferase reporter assay was utilized to validate the interactions between Union Hospital of Jilin University, LINC01494 and miR-122-5p or CCNG1 and miR-122-5p. Changchun 130031, People’s Republic of China; Department of First-aid Results: LINC01494 was identified as a significantly upregulated lncRNA in glioma Medicine, China-Japan Union Hospital of through bioinformatics analysis. Furthermore, LINC01494 upregulation indicated poor prog- Jilin University, Changchun 130031, nosis. Meanwhile, in vitro investigation indicated that silencing LINC01494 with siRNAs People’s Republic of China; Department of Neurosurgery, China-Japan Union obviously inhibited the proliferation, cell cycle, migration and invasion of glioma cells. Hospital of Jilin University, Changchun Besides, it is found that LINC01494 expression was negatively correlated with miR-122-5p. 130031, People’s Republic of China; We demonstrated that LINC01494 inhibited miR-122-5p to upregulate CCNG1 expression Department of Ophthalmology, The First Hospital of Jilin University, through direct interaction. Rescue assay further demonstrated that LINC01494/miR-122-5p/ Changchun 130021, People’s Republic of CCNG1 signaling cascade plays a critical role in regulating glioma cell proliferation, China migration and invasion. *These authors contributed equally to Conclusion: Taken together, our findings demonstrated the essential function and molecular this work mechanism of LINC01494 in glioma progression. Keywords: LINC01494, miR-122-5p, CCNG1, glioma, proliferation Introduction Glioma is one of the most aggressive cancers in the nervous system and causes a large number of deaths every year worldwide. Currently, surgery combined with adjuvant therapy is the main strategy for glioma treatment. Nevertheless, prognosis 3,4 of glioma patients is quite poor. The effective biomarkers for glioma diagnosis and prognosis and the therapeutic targets for glioma intervention are still lacking. Therefore, defining molecular mechanisms regulating glioma development is very necessary and urgently needed. Long noncoding RNAs (lncRNAs) are characterized with over 200 nucleotides Correspondence: Naijie Liu Department of Neurosurgery, in length and little protein-coding potential. As a novel member of the noncoding China-Japan Union Hospital of Jilin RNA family, lncRNAs have attracted much attention in recent years. Accumulating University, 126 Xiantai Street, Changchun 130031, People’s Republic of China studies have indicated that lncRNAs play critical roles in regulating multiple Tel +86 431186 4310 7700 Email [email protected] biological processes, including division, differentiation and metastasis. Aberrant submit your manuscript | www.dovepress.com OncoTargets and Therapy 2019:12 7655–7662 7655 DovePress © 2019 Li et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work http://doi.org/10.2147/OTT.S213345 you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Li et al Dovepress negative controls were bought from GenePharma. These expression of lncRNAs is associated with tumorigenesis. vectors were transfected into U87 and U251 cells using For example, lncRNA CASC11 is upregulated in osteosar- Lipofectamine 3000 (Invitrogen) according to the manu- coma and promotes tumor metastasis. Overexpression of facturer’s protocol. 48 h later, the transfection efficiency lncRNA DANCR initiates progression of lung cancer. was confirmed by qRT-PCR. LncRNA miR155HG upregulation in glioblastoma regu- lates proliferation, migration and invasion by miR-185/ ANXA2 signaling. Additionally, lncRNA NEAT1 as an Real-Time Quantitative PCR oncogene in breast cancer is significantly upregulated in Total RNAs were obtained from tissues and cell lines using tumor tissues. Therefore, understanding the function of Trizol reagent (Invitrogen). RNAs were transcribed into cDNA novel lncRNAs will be benefit for elucidating the mechan- using Prime-Script RT Reagent Kit (Takara, Dalian, China). ism of glioma development. qPCR was carried out using SYBR Prime Script RT-PCR kits LINC01494 is a novel lncRNA. To date, the function (Takara) on ABI 7300 Fast Real-Time PCR system m (Applied of LINC01494 in tumor is unknown. In the present Biosystems, Foster City, CA) following the manufacturer’s research, we found that LINC01494 expression was upre- protocols. U6 was as a normalized control for miRNA and gulated in glioma. Overexpression of LINC01494 is asso- GAPDH was used as normalized control for other genes. −ΔΔCt ciated with a low survival rate. Knockdown assays Relative expression was calculated using the 2 method. indicated that LINC01494 silencing suppressed glioma The primer sequences were as follows: LINC01494 (Forward: cell proliferation and cell-cycle. Moreover, the potential 5ʹ-CCCGACCTTAGAGTTCTGCG-3ʹ, reverse: 5ʹ-CCCCCA of tumor cell metastasis were also impaired after GGAGAGGGTAAGAT-3ʹ), CCNG1 (Forward: 5ʹ-GTTACC LINC01494 knockdown. We identified that LINC01494 GCTGAGGAGCTGCAGTC-3ʹ, reverse: 5ʹ-GCAGCCATC sponged miR-122-5p to upregulate expression of oncogene CTGGATGGATTCAG-3ʹ) and miR-122-5p (Forward: 5ʹ- CCNG1. In conclusion, our findings elucidated critical GTGACAATGGTGGAATGTGG-3ʹ,reverse:5ʹ-AAAGCAA roles of LINC01494 in glioma progression and revealed ACGATGCCAAGAC-3ʹ), U6 (Forward: 5ʹ-CTCGCTTCGG a novel mechanism. CAGCACA-3ʹ,reverse:5ʹ-AACGCTTCACGAATTTGCGT- 3ʹ) and GAPDH (Forward: 5ʹ-AGCCACATCGCTCAGACA- 3ʹ, reverse: 5ʹTGGACTCCACGACGTACT-3ʹ). Materials And Methods Human Tissue Specimens Cell Proliferation Assay All 39 glioma tissues and responding normal controls were Cellular proliferation was detected using the cell counting obtained from China-Japan Union Hospital of Jilin kit-8 (CCK8; Beyotime, Beijing) assay and colony forma- University. None of them were treated with antitumor tion assay. For CCK8 assay, cells (2000 cells/well) were treatment prior to surgery. All tissues were stored in liquid seeded into 96-well plates and cultured for described days. nitrogen until use. Our study was approved by the Ethics Then CCK8 solution was added and incubated for 2 h. Committee of China-Japan Union Hospital of Jilin Absorbance at 450 nm was determined using a microplate University and written informed consent was got from reader (ELx800; BioTek Instruments, Inc, Winooski, VT). patients. Experiments involving human tissues were con- For colony formation assay, 500 cells were plated in the 6- ducted in accordance with the Declaration of Helsinki. well plates and cultured for 2 weeks. Then clones were fixed and stained. Colony numbers were counted. Cell Culture Glioma cell lines, including U87, U251, LN229 and A172 Luciferase Assay cells, and Human astrocyte cell line (NHA) were from the The binding sites between LINC01494 and miR-122-5p were American Type Culture Collection (ATCC) and cultured predicted by using miRDB. Binding sites between miR-122- using DMEM medium (Gibco, CA) containing 10% FBS 5p and CCNG1 were analyzed by using TargetScan. For (Gibco). luciferase reporter assay, the sequence of LINC01494 or CCNG1 containing the wild-type (WT) or mutant (Mut) bind- Cell Transfection ing site for miR-122-5p was constructed into pmirGLO dual- All siRNAs were bought from GenePharma (Shanghai, luciferase vector (Promega, Madison, WI). Then reporter vec- China). MiR-122-5p mimics, miR-122-5p inhibitors, and tors were transfected into cells together with miR-122-5p submit your manuscript | www.dovepress.com OncoTargets and Therapy 2019:12 DovePress Dovepress Li et al Consistently, LINC01494 level was elevated in tumor cell mimics or controls. 48 h later, the luciferase activity was determined by using a Dual-luciferase Reporter Assay lines in contrast to NHA cells (Figure 1D). Then glioma System (Promega) based on the manufacturer’s instructions. tissues were divided into LINC01494 high expression and low expression groups and analyzed whether LINC01494 could be a prognostic biomarker. Notably, LINC01494 upre- Transwell Assay gulation was correlated with a low survival rate in glioma For cell migration and invasion analysis, the Transwell patients (Figure 1E). assay was performed according to a previous research. Statistical Analysis Effects Of LINC01494 Knockdown On Graphpad Prism software was used for statistical analy- Glioma Proliferation, Migration And sis. Results were expressed as the mean ± SD. All Invasion experiments were independently repeated at least three To analyze the role of LINC01494 in glioma, two indepen- times. The Student’s t-test or ANOVA test was used for dent siRNAs targeting LINC01494 were obtained. As analysis of statistical differences. P < 0.05 was consid- shown, LINC01494 expression was effectively reduced in ered statistically significant. U87 and U251 cells by siRNAs (Figure 2A). Through CCK8 assay, we found that LINC01494 knockdown suppressed the Results proliferation of U87 and U251 cells markedly (Figure 2B). The Expression Of LINC01494 In Glioma We obtained a similar result by using colony formation assay (Figure 2C). Interestingly, LINC01494 knockdown caused Tissues increased cells arrested in G0/G1 phase and decreased cells We analyzed a GEO dataset and identified a novel lncRNA LINC01494 that was upregulated in glioma tissues compared in S and G2/M phase (Figure 2D), suggesting that to normal tissues (Figure 1A). To further validate it, we LINC01494 knockdown suppressed cell cycle. Then trans- collected 39 pairs of tumor and nontumor tissues. Northern well assay was performed. We found that depletion of blotting and qRT-PCR results showed LINC01494 expres- LINC01494 impaired the migration and invasion of glioma sion was higher in glioma samples (Figure 1B and C). cells (Figure 2E and F). Figure 1 The expression of LINC01494 in glioma tissues. (A) Expression levels of LINC01494 in glioma tissues and normal tissues based on the GEO database (GSE51146). (B) Northern blotting assay was used to detect LINC01494 expression in three pairs of tissues. (C) Relative expression of LINC01494 in 39 glioma tissues and their adjacent normal controls by qRT-PCR. (D) Relative expression of LINC01494 in glioma cell lines. (E) Kaplan-Meier survival curve according to LINC01494 expression in glioma patients. *P<0.05, **P<0.01 and ***P<0.001. submit your manuscript | www.dovepress.com OncoTargets and Therapy 2019:12 7657 DovePress Li et al Dovepress Figure 2 Effects of LINC01494 knockdown on glioma proliferation, migration and invasion. (A) Two independent siRNAs against LINC01494 were transfected into U87 and U251 cells and the efficiency of LINC01494 knockdown was confirmed. (B) CCK8 assay was performed to test cellular proliferation. (C) LINC01494 knockdown led to reduced colony numbers. (D) The effect of LINC01494 knockdown on cell cycle was analyzed by FACS. (E and F) LINC01494 knockdown suppressed the migration and invasion of U87 and U251 cells. *P<0.05, **P<0.01 and ***P<0.001. AccordingtoCCK8andcolonyformationassays,we LINC01494 Overexpression Promotes found that LINC01494 overexpression promoted the prolifera- Glioma Progression tion, migration and invasion of U87 and U251 cells (Figure To further confirm the roles of LINC01494 on glioma, weo- verexpressedLINC01494inU87andU251cells (Figure 3A). 3B–D). Thus, LINC01494 promotes glioma progression. submit your manuscript | www.dovepress.com OncoTargets and Therapy 2019:12 DovePress Dovepress Li et al Figure 3 LINC01494 overexpression promotes glioma progression. (A) Upregulation of LINC01494 was confirmed by qRT-PCR after transfection with pcDNA3- LINC01494. (B) CCK8 assay was performed to evaluate proliferation. (C and D) Transwell assay for analysis of migration and invasion. *P<0.05. 122-5p inhibited the expression of CCNG1 (Figure 4D). LINC01494 Regulates miR-122-5p/ Importantly, LINC01494 knockdown suppressed expression CCNG1 Axis In Glioma whereas addition of miR-122-5p inhibitors reversed it To research the molecular mechanism, we analyzed the (Figure 4E), suggesting that LINC01494 promoted CCNG1 potential targets of LINC01494 by bioinformatics approach. expression by sponging miR-122-5p. We also found that We identified miR-122-5p which has the highest score. miR-122-5p expression was downregulated in glioma tissues Furthermore, we also analyzed the potential mRNA targets (Figure 4F), whereas CCNG1 levels were remarkably upre- of miR-122-5p and identified CCNG1, which is an important gulated in glioma tissues (Figure 4G and H), implying poten- regulator of cell cycle. Interestingly, we observed an inverse tial functions of miR-122-5p and CCNG1 in glioma. expression correlation between LINC01494 and miR-122-5p or between miR-122-5p and CCNG1 in glioma tissues Effects Of The LINC01494/miR-122-5p/ (Figure 4A). Thus, we further investigated whether there were direct interactions among them through luciferase CCNG1 Axis On Glioma Cells reporter assays. We found that miR-122-5p mimic transfec- To analyze the function of the LINC01494/miR-122-5p/ tion significantly suppressed the activity of WT-LINC01494 CCNG1 signaling, we performed rescued assays. We con- or WT-CCNG1 reporter in U87 and U251 cells (Figure 4B). firmed the transfection efficiency by measure CCNG1 However, mutation of the predicted binding sites for miR- levels (Figure 5A). As shown, CCK8, colony formation 122-5p in the reporter abrogated this trend (Figure 4B). and Transwell assays indicated that addition of miR-122- Thus, LINC01494 directly bound to miR-122-5p while 5p inhibitors abrogated the suppressive functions of miR-122-5p targeted CCNG1. Furthermore, we found that LINC01494 knockdown on proliferation, migration and LINC01494 knockdown significantly increased the expres- invasion (Figure 5B–E). However, together transfection sion of miR-122-5p and vice versa (Figure 4C). And miR- with CCNG1 siRNAs further suppressed the proliferation, submit your manuscript | www.dovepress.com OncoTargets and Therapy 2019:12 7659 DovePress Li et al Dovepress Figure 4 LINC01494 regulates miR-122-5p/CCNG1 axis in glioma. (A) Expression correlation between LINC01494 and miR-122-5p or between miR-122-5p and CCNG1 was analyzed in glioma tissues. (B) Luciferase reporter assay indicated that miR-122-5p directly interacted with LINC01494 and CCNG1 in U87 and U251 cells. (C) LINC01494 knockdown promoted miR-122-5p expression and vice versa. (D) miR-122-5p overexpression inhibited CCNG1 expression in glioma cells and vice versa. (E) LINC01494 knockdown suppressed CCNG1 expression via stimulating miR-122-5p. (F) Decreased expression of miR-122-5p was observed in glioma tissues. (G) CCNG1 expression was upregulated in glioma tissues by qRT-PCR. (H) According to TCGA data, CCNG1 expression was increased in glioma tissues compared to normal controls. ***P<0.001. migration and invasion of glioma cells (Figure 5B–E). In CCNG1 expression. Through upregulating CCNG1, conclusion, these data demonstrated that LINC01494 pro- LINC01494 contributes to glioma development. motes glioma progression through modulating miR-122- LncRNA has been acknowledged as competitive endo- 5p/CCNG1 axis. genous RNA (ceRNA) to regulate expression post- transcriptionally. A lot of lncRNAs have been proven to 14,15 Discussion sponge miRNAs to regulate tumorigenesis. For instance, As the most malignant tumor in nervous system, glioma lncRNATUG1 increases migration and invasion of osteosar- displays a poor prognosis and threats human health. coma cells through sponging miR-143-5p and modulating Currently, the mechanism regulating glioma development HIF-1α expression. LncRNA MALAT1 as ceRNA inhibits is still poorly elucidated. In the recent years, lncRNAs has miR-140-5p to promote development of tongue squamous 9 17 been reported to participate in glioma progression. Thus, cell carcinoma. Additionally, LncRNA SNHG3 modulates it is important to further explore the correlation between miRNA-151a-3p/RAB22A signaling and contributes to lncRNA and glioma. In this study, we identified a novel osteosarcoma metastasis. In our study, we also identified lncRNA LINC01494 with high expression level in glioma LINC01494 as a sponge for miR-122-5p. We demonstrated tissues and cell lines. We found that LINC01494 high their direct interaction through luciferase reporter assay. expression predicted a poor prognosis. Functional experi- Several studies have suggested a suppressive role of miR- ments indicated that loss of LINC01494 significantly 122-5p in tumor. For example, miR-122-5p suppresses repressed the proliferation, migration and invasion of growth and metastasis of bile duct carcinoma. MiR-122- glioma cells. Moreover, the cell cycle was arrested after 5p attenuates gastric cancer metastasis in vitro. However, LINC01494 knockdown. We also demonstrated that the role of miR-122-5p in glioma remains unclear. Our data LINC01494 could interact with miR-122-5p and promote indicated that miR-122-5p expression was downregulated in submit your manuscript | www.dovepress.com OncoTargets and Therapy 2019:12 DovePress Dovepress Li et al Figure 5 Effects of the LINC01494/miR-122-5p/CCNG1 axis on glioma cells. (A) Analysis of CCNG1 in U87 and U251 cells transfected with indicated vectors. (B and C) Analysis of cell proliferation by CCK8 and colony formation assays after transfection with indicated vectors. (D and E) Cell migration and invasion was determined by Transwell assay in U87 and U251 cells. **P<0.01 and ***P<0.001. glioma tissues, implying miR-122-5p as a tumor suppressor uncovered. In our study, we also demonstrated that in glioma. CCNG1 expression was regulated by LINC01494/miR- Afterwards, we investigated the targets of miR-122-5p 122-5p axis. Moreover, we found that CCNG1 expression through bioinformatics analysis. We found that CCNG1 was significantly upregulated in glioma tissues, suggesting may be a target. Luciferase reporter assay demonstrated its oncogenic roles. Thus, we then performed rescue their association. Moreover, we showed that CCNG1 assays. We demonstrated that CCNG1 is a pivot effector expression was inhibited by miR-122-5p in glioma. in LINC01494/miR-122-5p/CCNG1 axis and found that CCNG1 is a pivot regulator of cell cycle. Researches silencing of CCNG1 really suppressed proliferation, have revealed an important correlation between CCNG1 migration and invasion of glioma cells. However, mouse and tumorigenesis. For example, CCNG1 upregulation experiments are required in the further to further demon- promotes esophageal squamous cell carcinoma growth. strate the important roles of LINC01494/miR-122-5p/ In pancreatic ductal adenocarcinoma, CCNG1 overexpres- CCNG1 axis in glioma. sion also promotes tumor cell proliferation. Additionally, In summary, our findings demonstrated the novel a critical oncogenic role of CCNG1 is still reported in lncRNA LINC01494 is an oncogenic gene in glioma. 24–26 ovarian cancer, gastric cancer and lung carcinoma. LINC01494 promotes glioma proliferation, migration and invasion through modulating miR-122-5p/CCNG1 axis. Nevertheless, the role of CCNG1 in glioma has not been submit your manuscript | www.dovepress.com OncoTargets and Therapy 2019:12 7661 DovePress Li et al Dovepress 13. Ala U, Karreth FA, Bosia C, et al. 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lncRNA LINC01494 Promotes Proliferation, Migration And Invasion In Glioma Through miR-122-5p/CCNG1 Axis

Li, Chang; Hu, Guozhang; Wei, Bo; Wang, Le; Liu, Naijie
OncoTargets and therapy , Volume 12 – Sep 18, 2019
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Abstract

OncoTargets and Therapy Dovepress open access to scientific and medical research Open Access Full Text Article ORIGINAL RE SE ARCH lncRNA LINC01494 Promotes Proliferation, Migration And Invasion In Glioma Through miR-122-5p/CCNG1 Axis This article was published in the following Dove Press journal: OncoTargets and Therapy 1, Background: Long noncoding RNAs (lncRNAs) are recognized as key effectors in tumor, Chang Li * 2, including glioma. LINC01494 is an uncharacterized novel lncRNA. In this research, we Guozhang Hu * aimed to investigate the function of LINC01494 in glioma. Bo Wei 4 Methods: Gene relative expression was analyzed by qRT-PCR method. CCK8, colony Le Wang formation and Transwell assay was used to determine cell proliferation, migration and Naijie Liu invasion. Bioinformatics analyses were used to predict the target of LINC01494 and miR- Department of VIP Unit, China-Japan 122-5p. Luciferase reporter assay was utilized to validate the interactions between Union Hospital of Jilin University, LINC01494 and miR-122-5p or CCNG1 and miR-122-5p. Changchun 130031, People’s Republic of China; Department of First-aid Results: LINC01494 was identified as a significantly upregulated lncRNA in glioma Medicine, China-Japan Union Hospital of through bioinformatics analysis. Furthermore, LINC01494 upregulation indicated poor prog- Jilin University, Changchun 130031, nosis. Meanwhile, in vitro investigation indicated that silencing LINC01494 with siRNAs People’s Republic of China; Department of Neurosurgery, China-Japan Union obviously inhibited the proliferation, cell cycle, migration and invasion of glioma cells. Hospital of Jilin University, Changchun Besides, it is found that LINC01494 expression was negatively correlated with miR-122-5p. 130031, People’s Republic of China; We demonstrated that LINC01494 inhibited miR-122-5p to upregulate CCNG1 expression Department of Ophthalmology, The First Hospital of Jilin University, through direct interaction. Rescue assay further demonstrated that LINC01494/miR-122-5p/ Changchun 130021, People’s Republic of CCNG1 signaling cascade plays a critical role in regulating glioma cell proliferation, China migration and invasion. *These authors contributed equally to Conclusion: Taken together, our findings demonstrated the essential function and molecular this work mechanism of LINC01494 in glioma progression. Keywords: LINC01494, miR-122-5p, CCNG1, glioma, proliferation Introduction Glioma is one of the most aggressive cancers in the nervous system and causes a large number of deaths every year worldwide. Currently, surgery combined with adjuvant therapy is the main strategy for glioma treatment. Nevertheless, prognosis 3,4 of glioma patients is quite poor. The effective biomarkers for glioma diagnosis and prognosis and the therapeutic targets for glioma intervention are still lacking. Therefore, defining molecular mechanisms regulating glioma development is very necessary and urgently needed. Long noncoding RNAs (lncRNAs) are characterized with over 200 nucleotides Correspondence: Naijie Liu Department of Neurosurgery, in length and little protein-coding potential. As a novel member of the noncoding China-Japan Union Hospital of Jilin RNA family, lncRNAs have attracted much attention in recent years. Accumulating University, 126 Xiantai Street, Changchun 130031, People’s Republic of China studies have indicated that lncRNAs play critical roles in regulating multiple Tel +86 431186 4310 7700 Email [email protected] biological processes, including division, differentiation and metastasis. Aberrant submit your manuscript | www.dovepress.com OncoTargets and Therapy 2019:12 7655–7662 7655 DovePress © 2019 Li et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work http://doi.org/10.2147/OTT.S213345 you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Li et al Dovepress negative controls were bought from GenePharma. These expression of lncRNAs is associated with tumorigenesis. vectors were transfected into U87 and U251 cells using For example, lncRNA CASC11 is upregulated in osteosar- Lipofectamine 3000 (Invitrogen) according to the manu- coma and promotes tumor metastasis. Overexpression of facturer’s protocol. 48 h later, the transfection efficiency lncRNA DANCR initiates progression of lung cancer. was confirmed by qRT-PCR. LncRNA miR155HG upregulation in glioblastoma regu- lates proliferation, migration and invasion by miR-185/ ANXA2 signaling. Additionally, lncRNA NEAT1 as an Real-Time Quantitative PCR oncogene in breast cancer is significantly upregulated in Total RNAs were obtained from tissues and cell lines using tumor tissues. Therefore, understanding the function of Trizol reagent (Invitrogen). RNAs were transcribed into cDNA novel lncRNAs will be benefit for elucidating the mechan- using Prime-Script RT Reagent Kit (Takara, Dalian, China). ism of glioma development. qPCR was carried out using SYBR Prime Script RT-PCR kits LINC01494 is a novel lncRNA. To date, the function (Takara) on ABI 7300 Fast Real-Time PCR system m (Applied of LINC01494 in tumor is unknown. In the present Biosystems, Foster City, CA) following the manufacturer’s research, we found that LINC01494 expression was upre- protocols. U6 was as a normalized control for miRNA and gulated in glioma. Overexpression of LINC01494 is asso- GAPDH was used as normalized control for other genes. −ΔΔCt ciated with a low survival rate. Knockdown assays Relative expression was calculated using the 2 method. indicated that LINC01494 silencing suppressed glioma The primer sequences were as follows: LINC01494 (Forward: cell proliferation and cell-cycle. Moreover, the potential 5ʹ-CCCGACCTTAGAGTTCTGCG-3ʹ, reverse: 5ʹ-CCCCCA of tumor cell metastasis were also impaired after GGAGAGGGTAAGAT-3ʹ), CCNG1 (Forward: 5ʹ-GTTACC LINC01494 knockdown. We identified that LINC01494 GCTGAGGAGCTGCAGTC-3ʹ, reverse: 5ʹ-GCAGCCATC sponged miR-122-5p to upregulate expression of oncogene CTGGATGGATTCAG-3ʹ) and miR-122-5p (Forward: 5ʹ- CCNG1. In conclusion, our findings elucidated critical GTGACAATGGTGGAATGTGG-3ʹ,reverse:5ʹ-AAAGCAA roles of LINC01494 in glioma progression and revealed ACGATGCCAAGAC-3ʹ), U6 (Forward: 5ʹ-CTCGCTTCGG a novel mechanism. CAGCACA-3ʹ,reverse:5ʹ-AACGCTTCACGAATTTGCGT- 3ʹ) and GAPDH (Forward: 5ʹ-AGCCACATCGCTCAGACA- 3ʹ, reverse: 5ʹTGGACTCCACGACGTACT-3ʹ). Materials And Methods Human Tissue Specimens Cell Proliferation Assay All 39 glioma tissues and responding normal controls were Cellular proliferation was detected using the cell counting obtained from China-Japan Union Hospital of Jilin kit-8 (CCK8; Beyotime, Beijing) assay and colony forma- University. None of them were treated with antitumor tion assay. For CCK8 assay, cells (2000 cells/well) were treatment prior to surgery. All tissues were stored in liquid seeded into 96-well plates and cultured for described days. nitrogen until use. Our study was approved by the Ethics Then CCK8 solution was added and incubated for 2 h. Committee of China-Japan Union Hospital of Jilin Absorbance at 450 nm was determined using a microplate University and written informed consent was got from reader (ELx800; BioTek Instruments, Inc, Winooski, VT). patients. Experiments involving human tissues were con- For colony formation assay, 500 cells were plated in the 6- ducted in accordance with the Declaration of Helsinki. well plates and cultured for 2 weeks. Then clones were fixed and stained. Colony numbers were counted. Cell Culture Glioma cell lines, including U87, U251, LN229 and A172 Luciferase Assay cells, and Human astrocyte cell line (NHA) were from the The binding sites between LINC01494 and miR-122-5p were American Type Culture Collection (ATCC) and cultured predicted by using miRDB. Binding sites between miR-122- using DMEM medium (Gibco, CA) containing 10% FBS 5p and CCNG1 were analyzed by using TargetScan. For (Gibco). luciferase reporter assay, the sequence of LINC01494 or CCNG1 containing the wild-type (WT) or mutant (Mut) bind- Cell Transfection ing site for miR-122-5p was constructed into pmirGLO dual- All siRNAs were bought from GenePharma (Shanghai, luciferase vector (Promega, Madison, WI). Then reporter vec- China). MiR-122-5p mimics, miR-122-5p inhibitors, and tors were transfected into cells together with miR-122-5p submit your manuscript | www.dovepress.com OncoTargets and Therapy 2019:12 DovePress Dovepress Li et al Consistently, LINC01494 level was elevated in tumor cell mimics or controls. 48 h later, the luciferase activity was determined by using a Dual-luciferase Reporter Assay lines in contrast to NHA cells (Figure 1D). Then glioma System (Promega) based on the manufacturer’s instructions. tissues were divided into LINC01494 high expression and low expression groups and analyzed whether LINC01494 could be a prognostic biomarker. Notably, LINC01494 upre- Transwell Assay gulation was correlated with a low survival rate in glioma For cell migration and invasion analysis, the Transwell patients (Figure 1E). assay was performed according to a previous research. Statistical Analysis Effects Of LINC01494 Knockdown On Graphpad Prism software was used for statistical analy- Glioma Proliferation, Migration And sis. Results were expressed as the mean ± SD. All Invasion experiments were independently repeated at least three To analyze the role of LINC01494 in glioma, two indepen- times. The Student’s t-test or ANOVA test was used for dent siRNAs targeting LINC01494 were obtained. As analysis of statistical differences. P < 0.05 was consid- shown, LINC01494 expression was effectively reduced in ered statistically significant. U87 and U251 cells by siRNAs (Figure 2A). Through CCK8 assay, we found that LINC01494 knockdown suppressed the Results proliferation of U87 and U251 cells markedly (Figure 2B). The Expression Of LINC01494 In Glioma We obtained a similar result by using colony formation assay (Figure 2C). Interestingly, LINC01494 knockdown caused Tissues increased cells arrested in G0/G1 phase and decreased cells We analyzed a GEO dataset and identified a novel lncRNA LINC01494 that was upregulated in glioma tissues compared in S and G2/M phase (Figure 2D), suggesting that to normal tissues (Figure 1A). To further validate it, we LINC01494 knockdown suppressed cell cycle. Then trans- collected 39 pairs of tumor and nontumor tissues. Northern well assay was performed. We found that depletion of blotting and qRT-PCR results showed LINC01494 expres- LINC01494 impaired the migration and invasion of glioma sion was higher in glioma samples (Figure 1B and C). cells (Figure 2E and F). Figure 1 The expression of LINC01494 in glioma tissues. (A) Expression levels of LINC01494 in glioma tissues and normal tissues based on the GEO database (GSE51146). (B) Northern blotting assay was used to detect LINC01494 expression in three pairs of tissues. (C) Relative expression of LINC01494 in 39 glioma tissues and their adjacent normal controls by qRT-PCR. (D) Relative expression of LINC01494 in glioma cell lines. (E) Kaplan-Meier survival curve according to LINC01494 expression in glioma patients. *P<0.05, **P<0.01 and ***P<0.001. submit your manuscript | www.dovepress.com OncoTargets and Therapy 2019:12 7657 DovePress Li et al Dovepress Figure 2 Effects of LINC01494 knockdown on glioma proliferation, migration and invasion. (A) Two independent siRNAs against LINC01494 were transfected into U87 and U251 cells and the efficiency of LINC01494 knockdown was confirmed. (B) CCK8 assay was performed to test cellular proliferation. (C) LINC01494 knockdown led to reduced colony numbers. (D) The effect of LINC01494 knockdown on cell cycle was analyzed by FACS. (E and F) LINC01494 knockdown suppressed the migration and invasion of U87 and U251 cells. *P<0.05, **P<0.01 and ***P<0.001. AccordingtoCCK8andcolonyformationassays,we LINC01494 Overexpression Promotes found that LINC01494 overexpression promoted the prolifera- Glioma Progression tion, migration and invasion of U87 and U251 cells (Figure To further confirm the roles of LINC01494 on glioma, weo- verexpressedLINC01494inU87andU251cells (Figure 3A). 3B–D). Thus, LINC01494 promotes glioma progression. submit your manuscript | www.dovepress.com OncoTargets and Therapy 2019:12 DovePress Dovepress Li et al Figure 3 LINC01494 overexpression promotes glioma progression. (A) Upregulation of LINC01494 was confirmed by qRT-PCR after transfection with pcDNA3- LINC01494. (B) CCK8 assay was performed to evaluate proliferation. (C and D) Transwell assay for analysis of migration and invasion. *P<0.05. 122-5p inhibited the expression of CCNG1 (Figure 4D). LINC01494 Regulates miR-122-5p/ Importantly, LINC01494 knockdown suppressed expression CCNG1 Axis In Glioma whereas addition of miR-122-5p inhibitors reversed it To research the molecular mechanism, we analyzed the (Figure 4E), suggesting that LINC01494 promoted CCNG1 potential targets of LINC01494 by bioinformatics approach. expression by sponging miR-122-5p. We also found that We identified miR-122-5p which has the highest score. miR-122-5p expression was downregulated in glioma tissues Furthermore, we also analyzed the potential mRNA targets (Figure 4F), whereas CCNG1 levels were remarkably upre- of miR-122-5p and identified CCNG1, which is an important gulated in glioma tissues (Figure 4G and H), implying poten- regulator of cell cycle. Interestingly, we observed an inverse tial functions of miR-122-5p and CCNG1 in glioma. expression correlation between LINC01494 and miR-122-5p or between miR-122-5p and CCNG1 in glioma tissues Effects Of The LINC01494/miR-122-5p/ (Figure 4A). Thus, we further investigated whether there were direct interactions among them through luciferase CCNG1 Axis On Glioma Cells reporter assays. We found that miR-122-5p mimic transfec- To analyze the function of the LINC01494/miR-122-5p/ tion significantly suppressed the activity of WT-LINC01494 CCNG1 signaling, we performed rescued assays. We con- or WT-CCNG1 reporter in U87 and U251 cells (Figure 4B). firmed the transfection efficiency by measure CCNG1 However, mutation of the predicted binding sites for miR- levels (Figure 5A). As shown, CCK8, colony formation 122-5p in the reporter abrogated this trend (Figure 4B). and Transwell assays indicated that addition of miR-122- Thus, LINC01494 directly bound to miR-122-5p while 5p inhibitors abrogated the suppressive functions of miR-122-5p targeted CCNG1. Furthermore, we found that LINC01494 knockdown on proliferation, migration and LINC01494 knockdown significantly increased the expres- invasion (Figure 5B–E). However, together transfection sion of miR-122-5p and vice versa (Figure 4C). And miR- with CCNG1 siRNAs further suppressed the proliferation, submit your manuscript | www.dovepress.com OncoTargets and Therapy 2019:12 7659 DovePress Li et al Dovepress Figure 4 LINC01494 regulates miR-122-5p/CCNG1 axis in glioma. (A) Expression correlation between LINC01494 and miR-122-5p or between miR-122-5p and CCNG1 was analyzed in glioma tissues. (B) Luciferase reporter assay indicated that miR-122-5p directly interacted with LINC01494 and CCNG1 in U87 and U251 cells. (C) LINC01494 knockdown promoted miR-122-5p expression and vice versa. (D) miR-122-5p overexpression inhibited CCNG1 expression in glioma cells and vice versa. (E) LINC01494 knockdown suppressed CCNG1 expression via stimulating miR-122-5p. (F) Decreased expression of miR-122-5p was observed in glioma tissues. (G) CCNG1 expression was upregulated in glioma tissues by qRT-PCR. (H) According to TCGA data, CCNG1 expression was increased in glioma tissues compared to normal controls. ***P<0.001. migration and invasion of glioma cells (Figure 5B–E). In CCNG1 expression. Through upregulating CCNG1, conclusion, these data demonstrated that LINC01494 pro- LINC01494 contributes to glioma development. motes glioma progression through modulating miR-122- LncRNA has been acknowledged as competitive endo- 5p/CCNG1 axis. genous RNA (ceRNA) to regulate expression post- transcriptionally. A lot of lncRNAs have been proven to 14,15 Discussion sponge miRNAs to regulate tumorigenesis. For instance, As the most malignant tumor in nervous system, glioma lncRNATUG1 increases migration and invasion of osteosar- displays a poor prognosis and threats human health. coma cells through sponging miR-143-5p and modulating Currently, the mechanism regulating glioma development HIF-1α expression. LncRNA MALAT1 as ceRNA inhibits is still poorly elucidated. In the recent years, lncRNAs has miR-140-5p to promote development of tongue squamous 9 17 been reported to participate in glioma progression. Thus, cell carcinoma. Additionally, LncRNA SNHG3 modulates it is important to further explore the correlation between miRNA-151a-3p/RAB22A signaling and contributes to lncRNA and glioma. In this study, we identified a novel osteosarcoma metastasis. In our study, we also identified lncRNA LINC01494 with high expression level in glioma LINC01494 as a sponge for miR-122-5p. We demonstrated tissues and cell lines. We found that LINC01494 high their direct interaction through luciferase reporter assay. expression predicted a poor prognosis. Functional experi- Several studies have suggested a suppressive role of miR- ments indicated that loss of LINC01494 significantly 122-5p in tumor. For example, miR-122-5p suppresses repressed the proliferation, migration and invasion of growth and metastasis of bile duct carcinoma. MiR-122- glioma cells. Moreover, the cell cycle was arrested after 5p attenuates gastric cancer metastasis in vitro. However, LINC01494 knockdown. We also demonstrated that the role of miR-122-5p in glioma remains unclear. Our data LINC01494 could interact with miR-122-5p and promote indicated that miR-122-5p expression was downregulated in submit your manuscript | www.dovepress.com OncoTargets and Therapy 2019:12 DovePress Dovepress Li et al Figure 5 Effects of the LINC01494/miR-122-5p/CCNG1 axis on glioma cells. (A) Analysis of CCNG1 in U87 and U251 cells transfected with indicated vectors. (B and C) Analysis of cell proliferation by CCK8 and colony formation assays after transfection with indicated vectors. (D and E) Cell migration and invasion was determined by Transwell assay in U87 and U251 cells. **P<0.01 and ***P<0.001. glioma tissues, implying miR-122-5p as a tumor suppressor uncovered. In our study, we also demonstrated that in glioma. CCNG1 expression was regulated by LINC01494/miR- Afterwards, we investigated the targets of miR-122-5p 122-5p axis. Moreover, we found that CCNG1 expression through bioinformatics analysis. We found that CCNG1 was significantly upregulated in glioma tissues, suggesting may be a target. Luciferase reporter assay demonstrated its oncogenic roles. Thus, we then performed rescue their association. Moreover, we showed that CCNG1 assays. We demonstrated that CCNG1 is a pivot effector expression was inhibited by miR-122-5p in glioma. in LINC01494/miR-122-5p/CCNG1 axis and found that CCNG1 is a pivot regulator of cell cycle. Researches silencing of CCNG1 really suppressed proliferation, have revealed an important correlation between CCNG1 migration and invasion of glioma cells. However, mouse and tumorigenesis. For example, CCNG1 upregulation experiments are required in the further to further demon- promotes esophageal squamous cell carcinoma growth. strate the important roles of LINC01494/miR-122-5p/ In pancreatic ductal adenocarcinoma, CCNG1 overexpres- CCNG1 axis in glioma. sion also promotes tumor cell proliferation. Additionally, In summary, our findings demonstrated the novel a critical oncogenic role of CCNG1 is still reported in lncRNA LINC01494 is an oncogenic gene in glioma. 24–26 ovarian cancer, gastric cancer and lung carcinoma. LINC01494 promotes glioma proliferation, migration and invasion through modulating miR-122-5p/CCNG1 axis. Nevertheless, the role of CCNG1 in glioma has not been submit your manuscript | www.dovepress.com OncoTargets and Therapy 2019:12 7661 DovePress Li et al Dovepress 13. Ala U, Karreth FA, Bosia C, et al. 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