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| ORIGINAL ARTICLE |
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| Year : 2014 | Volume
: 51
| Issue : 7 | Page : 77-81 |
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MicroRNA-449a inhibits cell growth in lung cancer and regulates long noncoding RNA nuclear enriched abundant transcript 1
J You, Y Zhang, B Liu, Y Li, N Fang, L Zu, X Li, Q Zhou
Tianjin Key Labotatory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin 300052, China
| Date of Web Publication | 27-Mar-2015 |
Correspondence Address:
J You
Tianjin Key Labotatory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin 300052
China
Y Zhang
Tianjin Key Labotatory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin 300052
China
 Source of Support: This study was partly supported by the grants from the Key Project from National Natural Science Foundation of China (No.81000950), National 863 Program (No.2012AA02A502, 2012AA02A201), National 973 Program (No.2010CB529405), Conflict of Interest: None  | Check |
DOI: 10.4103/0019-509X.154055
Objective: Lung cancer has become the primary cause of cancer-related death now. New therapies targeting the molecular regulatory machinery were required imperatively. MicroRNAs and long noncoding RNAs can respectively or cooperatively function as oncogenes or tumor suppressor genes in human cancers. The present study identified that miR-449a was down-regulated in tissue of human lung cancer. In this study, we aimed to investigate the function of miR-449a in NL9980 and L9981 lung carcinoma cells lines and the relationship with lncRNA nuclear enriched abundant transcript 1 (NEAT1). Materials and Methods: miR-449a was profiled in several lung carcinoma cell lines by quantitative reverse transcription-polymerase chain reaction RT-PCR. We analyzed the effects of miR-449a overexpression on proliferation, apoptosis and cell cycle in L9981 cells. The regulatory relationship between miR-449a and NEAT1 was predicted in silico and further studied by miR-449a inhibitor and mimics assay. Results: miR-449a was expressed in four cell lines, which we selected, however miR-449a was in high level in NL9980 and in low level in L9981 (P < 0.05). When the miR-449a was the overexpression in L9981 cells, the cell growth was suppressed, and the apoptosis cells were promoted compared with the control group (P < 0.05). The G1/G0 became longer and S, G2/M became shorter (P < 0.05) by miR-449a overexpression. Further study of the interaction between miR-449a and NEAT1 show that NEAT1 was up-regulated when cells were transfected with miR-449a inhibitor, and NEAT1 was down-regulated when cells transfected with miR-449a mimics. Conclusions: Our data indicate that miR-449a may function as a suppressor of lung cancer, and affects the expression of NEAT1 in lung cancer cells.
Keywords: Lung cancer, miR-449a, nuclear enriched abundant transcript 1
How to cite this article:
You J, Zhang Y, Liu B, Li Y, Fang N, Zu L, Li X, Zhou Q. MicroRNA-449a inhibits cell growth in lung cancer and regulates long noncoding RNA nuclear enriched abundant transcript 1. Indian J Cancer 2014;51, Suppl S3:77-81 |
How to cite this URL:
You J, Zhang Y, Liu B, Li Y, Fang N, Zu L, Li X, Zhou Q. MicroRNA-449a inhibits cell growth in lung cancer and regulates long noncoding RNA nuclear enriched abundant transcript 1. Indian J Cancer [serial online] 2014 [cited 2022 Nov 29];51, Suppl S3:77-81. Available from: https://www.indianjcancer.com/text.asp?2014/51/7/77/154055 |
You J and Zhang Y contributed equally to this work
| » Introduction | |  |
Lung cancer remains to be the leading reason of cancer death worldwide in both developing country and developed country. It has been the second leading cause of cancer-related deaths among females, next to breast cancer. [1] Approximately, 50% of lung cancer patients are already at an advanced stage, [2] and most of lung cancer already metastasizes to the liver, brain, [3] which make poor prognosis. The air pollution and smoking have been proved to be the main causative factors of lung cancer. Even great progress has been made in early diagnosis and treatment strategies in recent decades, patients with lung cancer are related to poor prognosis, with an estimated 5-year survival rate of no >20%. [2],[4] Therefore, it is imminently to further our investigation on the underlying molecular and cellular mechanisms of lung cancer to find out new treatment methods.
MicroRNAs (miRNAs) are the classical oncogenes and tumor suppressors that have been expanded, with the length of 19-22 nucleotides, which regulate posttranscriptional gene expression. By binding with messenger RNA, miRNA can inhibit translation, thereby decreases the expression of proteins. [5] miRNA can act on both tumor oncogenes and tumor-suppressing genes in a wide range of regulations of tumorigenesis, [6] cancer development [7] and cancer cell apoptosis. [8] It has been demonstrated that miRNA genes are frequently located in cancer-associated genomic regions or fragile sites. [9] Previous studies have identified miR-449a expressed in numerous type of cancer, including gastric carcinoma, [10] endometrial cancer, [11] colorectal carcinoma, [12] and lung cancer. [13] miR-449a can induce cancer cell apoptosis in gastric adenocarcinoma, [14] and ovarian cancer. [15] These facts indicate that the miR-449a may be played a critical role in lung cancer as well.
Noncoding RNAs (ncRNAs) are collectively divided into housekeeping RNAs, small noncoding RNAs, and long noncoding RNAs (lncRNAs). [16] lncRNAs are RNA molecules that are longer than 200 nucleotides and are not translated into a protein. [17] With the rapid development of molecular biology, lncRNAs have emerged as novel master regulators of initiation, response and progression to therapy in a wide variety of solid tumors. [18] Numbers of lncRNAs have been proved to be associated with lung cancer through gene expression microarrays. [19],[20],[21] Nuclear enriched abundant transcript 1 (NEAT1), as an lncRNA, was consistently overexpressed in lung cancer metastasis compared to the matched primary tumors. [22] Increasing evidence has demonstrated the interplay between miRNAs and lncRNA. [23] Previous studies showed that Mir-449a was involved in cisplatin resistance and the overexpression of miR-449a of miR-449a increased cisplatin sensitivity mainly through the direct down-regulation of NOTCH1. Therefore, we explored the interaction between miR-449a and NEAT1 in silico, and try to find the approach of miR-449a impacting lung cancer cell growth.
| » Materials and Methods | | |
Materials
Lipofectamine 2000 and TRIzol were purchased from Invitrogen (Shanghai, China). All the primers in this study were purchased from BGI Tech (Shenzhen, China). miR-449a mimics, inhibitor, and control were purchased from Genepharma (Shanghai, China). Reverse Transcriptase M-MLV and SYBR Premix Ex Taq were purchased from TaKaRa Biotechnology (Dalian, China). Rnase was purchased from Sigma (USA).
Cell lines and cell culture
Human lung cancer cell line A549 was purchased from American Type Culture Collection (Manassas, VA). Human lung cancer cell lines NL9980, L9981 and NCI-H1299 were established in our institute. All the cells were grown and maintained in Dulbecco's Modified Eagle Media (DMEM) medium at 37°C, 5% CO 2 . Medium was supplemented with 10% fetal bovine serum, 100 U/mL penicillin and 100 U/mL streptomycin. DMEM medium and fetal bovine serum were purchased from GIBCO BRL (Grand Island, NY).
Transfection of miR-449a inhibitor/mimics
For transfection, the cells were plated on an antibiotic-free growth medium at 30-50% confluence approximately 24 h before transfection. RNA oligonucleotides were transfected at a final concentration of 100 nM, using Lipofectamine 2000 according to the manufacturer's protocol. Further treatment proceeded at 48 h posttransfection.
Cell cycle and apoptosis
L9981 was transfected as described previously. After 48 h, the cells were collected and washed twice with phosphate buffered saline (PBS), resuspended in 300 μl of PBS, and fixed by adding 700 μl of 100% ethanol at 4°C for 24-48 h. The fixed cells were rinsed 3 times with PBS and stained with a propidium iodide (PI) solution containing 100 μg/ml PI and 50 μg/ml RNase in PBS at 37°C for 30 min in the dark. Stained cells were passed through a nylon mesh sieve to remove cell lumps and then were analyzed by cytometry (BD).
RNA extraction and quantitative reverse transcription-polymerase chain reaction
Total RNA was extracted from the cell lines using TRIzol reagent. Then RNA was synthesized into cDNA using M-MLV in a 10-μl volume. Real-time polymerase chain reaction (PCR) was conducted using an SYBR Green mix in a 10 μl reaction volume on an ABI Prism 7500 Sequence Detector System (ABI, Foster City, CA). The expression of each miRNA was normalized to GAPDH and calculated using the 2 -ΔΔCt method. Primer sequences as follow, GAPDH: Forward 5'- TGCACCACCAACTGCTTAGC-3', reverse 5'-GGCATGCACTGTGGTCATGAG-3', miR-449a: Forward 5'- TGCGGTGGCAGTGTATTGTTAGC-3', reverse 5'- CCAGTGCAGGGTCCGAGGT-3', NEAT1: Forward 5'- GUCUGUGUGGAAGGAGGAATT-3', reverse 5'- UUCCUCCUUCCACACAGACTT-3'.
Statistical analysis
All statistical analyses were performed with the Statistical Package for the Social Science (SPSS) 17.0 software (SPSS Inc., Chicago, IL.). The data were presented as mean ± standard deviation. Statistical significance was determined by paired or unpaired Student's t-test. The differences with P < 0.05 were considered as statistically significant.
| » Results | | |
miR-449a was in different level in lung cancer cells
To investigate the expression of miR-449a in lung cancers cells, we detected the miR-449a expression profiles by quantitative reverse transcription (qRT)-PCR in low-metastatic NL9980, high-metastatic L9981, NCI-H1299, and A549. We found that miR-449a levels exhibited a varying pattern in these cell lines. Notably, the expression of miR-449a in NL9980 and L9981 was dramatically different and may be related to its metastatic in cancer [[Figure 1], P < 0.05]. | Figure 1: MiR-449a is differently expressed in metastatic cells. The relative messenger RNA level of miR-449a were detected by quantitative reverse transcription-polymerase chain reaction and normalized against an endogenous control (GAPDH RNA) in several lung cancer cell lines with distinct metastatic ability. Data are reported as mean ± standard deviation (*P < 0.05, Student's t-test)
Click here to view |
miR-449a prompted apoptosis of lung cancer cells
The effect of miR-449a on apoptosis of lung cancer cells was examined by Flow cytometry (FCM). High-metastasis L9981 cells were transfected with 100 nM of miR-449a, and cell apoptosis was detected after 48 h. As shown in [Figure 2]a and b, the percent of apoptosis cells was dramatically up-regulated by the transfection of miR-449a compared to the control group (*P < 0.05). | Figure 2: Overexpression of miR-449a promoted L9981 cell apoptosis. (a) The figure of flow cytometry shows the different apoptosis of cells. (b) L9981 cells transfected with miR-449a mimics show up-regulation of apoptosis compared to the control group (*P < 0.05, Student's t-test)
Click here to view |
miR-449a affected lung cancer cells growth
Transfection of L9981 with miR-449a caused cell cycle arrest at the G1 phase. The percentage of cells in G1 phase increased in response to miR-449a overexpression compared with that of the control group [Table 1] and [Figure 3]. | Figure 3: Overexpression of mir-449a induced cell cycle arrest. Transfection of miR-449a mimics in L9981 cells showed cycle arrest compared to the control group (*P < 0.05, Student's t-test)
Click here to view |
 | Table 1: Percentage of cells in phase G1/G1, S, G2/M in L9981 cell lines examined by flow cytometry
Click here to view |
Nuclear enriched abundant transcript 1 was negatively regulated by miR-449a
First we tested whether miR-449a can interact with NEAT1. We compared the sequence of miR-449a with that of NEAT1 using the bioinformatics program star Base v2.0 (Sun Yat-sen University, Guangzhou, China.) and noticed that miR-449a contains a target site of miR-449a [Figure 4]a. Then we detected the expression of NEAT1 in NL9980, L9981, NCI-H1299, which were transfected with miR-449a inhibitor/mimics, by qRT-PCR. Transfection efficiency was detected by qRT-PCR as well [Figure 4]b. Our result showed that, the level of NEAT1 was up-regulated when the knockdown of miR-449a; on the contrary, the expression of NEAT1 was down-regulated when miR-449a was the overexpression [Figure 4]c. | Figure 4: Interaction between miR-449a and nuclear enriched abundant transcript 1 (NEAT1). (a) miR-449a RNA sequence contains a site complementary to NEAT1. (b) To detected cells that were transfected with miR-449a inhibitor/mimics by quantitative reverse transcription-polymerase chain reaction. It is significant different in miR-449a inhibitor/mimics group
and control group (*P < 0.01, Student's t-test). (c) The overexpression or knockdown of miR-449a contributed to the different level of NEAT1 compared to the control group (*P < 0.01, Student's t-test)
Click here to view |
| » Discussion | | |
Many evidences show that the expression level of miRNA differs in carcinoma and noncarcinoma cells with great molecular and clinical implications. More than 22000 new cases of lung cancer emerge every year around the world, including men and women. [2] As a consequence, many groups have focused on the molecular mechanisms of lung cancer development, especially the miRNA and new popular molecular lncRNA recently. It has been confirmed that miRNAs were associated with the formation and progression of lung cancer. [24] In addition, other studies explained that the miRNAs contributed to cell proliferation, apoptosis, metastasis and development in lung cancer. Ling et al. [25] found that miR-145 can inhibit lung cancer cell metastasis and EMT via targeting the Oct4 mediated Wnt/β-catenin signaling pathway. Jiang et al. [26] showed that miR-212/132 may mediate proliferation and cell cycle arrest through p21 and cyclin D in lung cancer cells.
miR-449a expression has been reported in several types of cancers. Down-regulation of miR-449a has been detected in several cancers. Jeon et al. [27] found that miR-449a was down-regulated in 21 pairs of lung cancer tissues and induced growth arrest by targeting HDAC-1. Ren et al. [13] demonstrated that miR-449a caused cell cycle arrest and cell senescence in A549 and 95D cells. Our present study discovered that miR-449a was in different expression upon the metastasis ability. In low-metastatic NL9980, miR-449a was in high level; on the opposite, miR-449a was in low level in high-metastatic L9981. Thus, we thought that miR-449a may have a possible relation with metastatic of lung cancer cell. However, the growth of cell may be affected by miR-449a, then we explored the apoptosis and cell cycle of L9981, which has a low level of miR-449a, using miR-449a mimics by FCM. As we predicted, the apoptosis rate of L9981 was increased. The cell number addition to G0/G1 suggested that the cell growth also was suppressed. Therefore, miR-449a may function as a tumor suppressor in lung cancer, and miR-449a may be a potential target for treatment of lung cancer.
Not only miRNAs were concerned, but also lncRNA has become a current research topic. LncRNAs have been shown to aberrantly express in human cancers and involved in carcinogenesis. [13] LncRNAs have been defined to have an important function in cells such as chromatin, [28] RNA processing, [29] structural scaffolds [30] and modulation of apoptosis and invasion. [31] Deregulations of noncoding RNAs including lncRNAs and miRNAs have been frequently implicated in cancers. A growing number of evidence has discovered the interplay between miRNAs and lncRNA. [23] Tsang et al. [32] demonstrated that HOTTIP was a novel oncogenic lncRNA, which was negatively regulated by miR-125b. miR-21 has been shown to negatively regulate lncRNA GAS5 in breast cancer. [33] Previously study reported that NEAT1 was highly expressed in lymph node metastasis in lung cancer and promoted cancer cell growth. [22] Therefore, we speculated that whether lncRNAs may be under the regulation of miR-449a. Interestingly, NEAT1 was shown to harbor putative miRNA binding sites of the tumor suppressive miR-449a, based on in silico prediction. Subsequently, we investigated the interaction between miR-449a and NEAT1 by qRT-PCR after transfection of miR-449a inhibitor/mimics. The result showed that knockdown of miR-449a contributed to up-regulation of NEAT1, and overexpression of miR-449a contributed to down-regulation of NEAT1. This finding indicated that the miR-449a may negative regulated the expression of NEAT1. Previous studies demonstrated that miR-449a function as a tumor-suppressor, [14] and NEAT1 may promote cancer cell growth. [22] In theory, our results are in line with previous reports.
| » Conclusion | | |
Further research on the interaction between miRNA and lncRNA is needed to define the progression of lung cancer and expand on the current findings. A new way that miR-449a affected the apoptosis, proliferation, and cell cycle was through its negative regulation of NEAT1. But it is imperative to have further mechanistic investigation on finding any protein was included in the regulatory pathway. However, our result explained that miR-449a may function as a suppressor of lung cancer, which is prospectively associated with the lncRNA NEAT1 than affect lung cancer cell growth. miR-449a, NEAT1, or both may be the new targets of lung cancer treatment.
Acknowledgments
This study was partly supported by the grants from the Key Project from National Natural Science Foundation of China (No. 81000950), National 863 Program (No. 2012AA02A502, 2012AA02A201), National 973 Program (No. 2010CB529405).
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1]
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A Novel Model for Predicting Associations between Diseases and LncRNA-miRNA Pairs Based on a Newly Constructed Bipartite Network |
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| Shunxian Zhou,Zhanwei Xuan,Lei Wang,Pengyao Ping,Tingrui Pei | | Computational and Mathematical Methods in Medicine. 2018; 2018: 1 | | [Pubmed] | [DOI] | | | 24 |
NEAT1_2 functions as a competing endogenous RNA to regulate ATAD2 expression by sponging microRNA-106b-5p in papillary thyroid cancer |
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| Wei Sun,Xiabin Lan,Hao Zhang,Zhihong Wang,Wenwu Dong,Liang He,Ting Zhang,Ping Zhang,Jinhao Liu,Yuan Qin | | Cell Death & Disease. 2018; 9(3) | | [Pubmed] | [DOI] | | | 25 |
A comprehensive analysis of the predicted targets of miR-642b-3p associated with the long non-coding RNA HOXA11-AS in NSCLC cells |
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| Yu Zhang, Jie Luo, Xiao Wang, Han-Lin Wang, Xiu-Ling Zhang, Ting-Qing Gan, Gang Chen, Dian-Zhong Luo | | Oncology Letters. 2018; | | [Pubmed] | [DOI] | | | 26 |
Silencing of the long non-coding RNA NEAT1 suppresses glioma stem-like properties through modulation of the miR-107/CDK6 pathway |
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| Xiaoli Yang,Zheng Xiao,Xiaowei Du,Lina Huang,Ganqin Du | | Oncology Reports. 2017; 37(1): 555 | | [Pubmed] | [DOI] | | | 27 |
Histological and Pathological Assessment of miR-204 and SOX4 Levels in Gastric Cancer Patients |
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| Xiao Yuan,Shuanhu Wang,Mulin Liu,Zhen Lu,Yanqing Zhan,Wenbin Wang,A-Man Xu | | BioMed Research International. 2017; 2017: 1 | | [Pubmed] | [DOI] | | | 28 |
The Value of lncRNA NEAT1 as a Prognostic Factor for Survival of Cancer Outcome: A Meta-Analysis |
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| Yunyuan Zhang,Limin Lun,Hui Li,Qing Wang,Jieru Lin,Runhua Tian,Huazheng Pan,Haiping Zhang,Xian Chen | | Scientific Reports. 2017; 7(1) | | [Pubmed] | [DOI] | | | 29 |
Development of a pipeline for automated, high-throughput analysis of paraspeckle proteins reveals specific roles for importin a proteins |
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| Andrew T. Major,Yoichi Miyamoto,Camden Y. Lo,David A. Jans,Kate L. Loveland | | Scientific Reports. 2017; 7(1) | | [Pubmed] | [DOI] | | | 30 |
miR-449a |
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| He Yong-Ming,Ji Ai-Jun,Xu Xiao-Yue,Lu Jian-Wei,Yu Chen,Chen Ye | | Anti-Cancer Drugs. 2017; 28(10): 1067 | | [Pubmed] | [DOI] | | | 31 |
High expression of long non-coding RNA NEAT1 indicates poor prognosis of human cancer |
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| Jian Fang, Fuhao Qiao, Jingjing Tu, Jinfeng Xu, Fangfang Ding, Yun Liu, Bufugdi Andreas Akuo, Jianpeng Hu, Shihe Shao | | Oncotarget. 2017; 8(28): 45918 | | [Pubmed] | [DOI] | | | 32 |
Long non-coding RNA NEAT1 regulates permeability of the blood-tumor barrier via miR-181d-5p-mediated expression changes in ZO-1, occludin, and claudin-5 |
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| Junqing Guo,Heng Cai,Jian Zheng,Xiaobai Liu,Yunhui Liu,Jun Ma,Zhongyou Que,Wei Gong,Yana Gao,Wei Tao,Yixue Xue | | Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 2017; 1863(9): 2240 | | [Pubmed] | [DOI] | | | 33 |
The lncRNA XIST exhibits oncogenic properties via regulation of miR-449a and Bcl-2 in human non-small cell lung cancer |
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| Ya-long Zhang,Xue-bing Li,Yan-xu Hou,Nian-zhen Fang,Jia-cong You,Qing-hua Zhou | | Acta Pharmacologica Sinica. 2017; | | [Pubmed] | [DOI] | | | 34 |
The lncRNA XIST exhibits oncogenic properties via regulation of miR-449a and Bcl-2 in human non-small cell lung cancer |
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| Ya-long Zhang,Xue-bing Li,Yan-xu Hou,Nian-zhen Fang,Jia-cong You,Qing-hua Zhou | | Acta Pharmacologica Sinica. 2017; 38(3): 371 | | [Pubmed] | [DOI] | | | 35 |
Emerging role of long noncoding RNAs in lung cancer: Current status and future prospects |
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| Hui Tao,Jing-Jing Yang,Xiao Zhou,Zi-Yu Deng,Kai-Hu Shi,Jun Li | | Respiratory Medicine. 2016; 110: 12 | | [Pubmed] | [DOI] | | | 36 |
Professor HUANG Sheng-Kai |
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| Yi-zhong Hu,Ling Gao | | Acta Pharmacologica Sinica. 2016; 37(12): 1645 | | [Pubmed] | [DOI] | | | 37 |
Long noncoding RNA NEAT1 is an unfavorable prognostic factor and regulates migration and invasion in gastric cancer |
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| Jing-wei Fu,Ying Kong,Xu Sun | | Journal of Cancer Research and Clinical Oncology. 2016; 142(7): 1571 | | [Pubmed] | [DOI] | | | 38 |
Cellular, physiological and pathological aspects of the long non-coding RNA NEAT1 |
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| Pang-Kuo Lo,Benjamin Wolfson,Qun Zhou | | Frontiers in Biology. 2016; 11(6): 413 | | [Pubmed] | [DOI] | | | 39 |
NEAT1 upregulates EGCG-induced CTR1 to enhance cisplatin sensitivity in lung cancer cells |
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| Pan Jiang, Xiaoyue Wu, Xuemin Wang, Wenbin Huang, Qing Feng | | Oncotarget. 2016; 7(28): 43337 | | [Pubmed] | [DOI] | | | 40 |
Long noncoding RNA NEAT1 promotes laryngeal squamous cell cancer through regulating miR-107/CDK6 pathway |
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| Peng Wang,Tianyi Wu,Han Zhou,Qianqian Jin,Guoqing He,Haoyang Yu,Lijia Xuan,Xin Wang,Linli Tian,Yanan Sun,Ming Liu,Lingmei Qu | | Journal of Experimental & Clinical Cancer Research. 2016; 35(1) | | [Pubmed] | [DOI] | | | 41 |
Knockdown of NEAT1 restrained the malignant progression of glioma stem cells by activating microRNA let-7e |
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| Wei Gong, Jian Zheng, Xiaobai Liu, Jun Ma, Yunhui Liu, Yixue Xue | | Oncotarget. 2016; 7(38): 62208 | | [Pubmed] | [DOI] | | | 42 |
Aberrant NEAT1 expression is associated with clinical outcome in high grade glioma patients |
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| Chengbiao He,Bing Jiang,Jianrong Ma,Qiaoyu Li | | APMIS. 2016; 124(3): 169 | | [Pubmed] | [DOI] | | | 43 |
Crosstalk between Long Noncoding RNAs and MicroRNAs in Health and Disease |
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| Ahmed Bayoumi,Amer Sayed,Zuzana Broskova,Jian-Peng Teoh,James Wilson,Huabo Su,Yao-Liang Tang,Il-man Kim | | International Journal of Molecular Sciences. 2016; 17(3): 356 | | [Pubmed] | [DOI] | |
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