Linc00152 promotes malignant progression of glioma stem cells by regulating miR-103a-3p/FEZF1/CDC25A pathway

Author(s): Mingjun Yu ¹ ^, ² ^, ³ , Yixue Xue ⁴ ^, ⁵ ^, ⁶ , Jian Zheng ¹ ^, ² ^, ³ , Xiaobai Liu ¹ ^, ² ^, ³ , Hai Yu ¹ ^, ² ^, ³ , Libo Liu ⁴ ^, ⁵ ^, ⁶ , Zhen Li ¹ ^, ² ^, ³ , Yunhui Liu ¹ ^, ² ^, ³ ^,

Publication date (Electronic): 26 June 2017

Journal: Molecular Cancer

Publisher: BioMed Central

Keywords: Long non-coding RNA, linc00152, miR-103a-3p, Glioma stem cells, FEZF1, CDC25A

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Abstract

Background

Glioma is one of the most frequent intracranial malignant tumors. LncRNAs have been identified as new modulators in the origination and progression of glioma.

Methods

Quantitative real-time PCR were conducted to evaluate the expression of linc00152 and miRNA-103a-3p in glioma tissues and cells. Western blot were used to determine the expression of FEZF1 and CDC25A in glioma tissues and cells. Stable knockdown of linc00152 or over-expression of miR-103a-3p in glioma stem cells (GSCs) were established to explore the function of linc00152 and miR-103a-3p in GSCs. Further, luciferase reports were used to investigate the correlation between linc00152 and miR-103a-3p. Cell Counting Kit-8, transwell assays, and flow cytometry were used to investigate the function of linc00152 and miR-103a-3p in GSC malignant biological behaviors. ChIP assays were employed to ascertain the correlations between FEZF1 and CDC25A.

Results

Linc00152 was up-regulated in glioma tissues as well as in GSCs. Knockdown of linc00152 inhibited cell proliferation, migration and invasion, while promoted GSC apoptosis. Linc00152 regulated the malignant behavior of GSCs by binding to miR-103a-3p, which functions as a tumor suppressor. In addition, knockdown of linc00152 down-regulated forebrain embryonic zinc finger protein 1 (FEZF1), a direct target of miR-103a-3p which played an oncogenic role in GSCs. FEZF1 elevated promoter activities and up-regulated expression of the oncogenic gene cell division cycle 25A (CDC25A). CDC25A over-expression activated the PI3K/AKT pathways, which regulated the malignant behavior of GSCs.

Conclusions

Linc00152/miR-103a-3p/FEZF1/CDC25A axis plays a novel role in regulating the malignant behavior of GSCs, which may be a new potential therapeutic strategy for glioma therapy.

Electronic supplementary material

The online version of this article (doi:10.1186/s12943-017-0677-9) contains supplementary material, which is available to authorized users.

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Most cited references 46

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CDC25 phosphatases in cancer cells: key players? Good targets?

Rose Boutros, Valérie Lobjois, Bernard Ducommun (2007)

Cell division cycle 25 (CDC25) phosphatases regulate key transitions between cell cycle phases during normal cell division, and in the event of DNA damage they are key targets of the checkpoint machinery that ensures genetic stability. Taking only this into consideration, it is not surprising that CDC25 overexpression has been reported in a significant number of human cancers. However, in light of the significant body of evidence detailing the stringent complexity with which CDC25 activities are regulated, the significance of CDC25 overexpression in a subset of cancers and its association with poor prognosis are proving difficult to assess. We will focus on the roles of CDC25 phosphatases in both normal and abnormal cell proliferation, provide a critical assessment of the current data on CDC25 overexpression in cancer, and discuss both current and future therapeutic strategies for targeting CDC25 activity in cancer treatment.

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Long non-coding RNA Linc00152 is involved in cell cycle arrest, apoptosis, epithelial to mesenchymal transition, cell migration and invasion in gastric cancer.

Jing-jing Zhao, Yongchao Liu, Wenhong Zhang … (2015)

Gastric cancer remains a serious threat to public health with high incidence and mortality worldwide. Accumulating evidence demonstrates that long non-coding RNAs (lncRNAs) play important roles in regulating gene expression and are involved in various pathological processes, including gastric cancer. To investigate the possible role of dysregulated lncRNAs in gastric cancer development, we performed lncRNA microarray and identified 3141 significantly differentially expressed lncRNAs in gastric cancer tissues. Next, some of deregulated lncRNAs were validated among about 60 paired gastric cancer specimens such as Linc00261, DKFZP434K028, RPL34-AS1, H19, HOTAIR and Linc00152. Our results found that the decline of DKFZP434K028 and RPL34-AS1, and the increased expression of Linc00152 positively correlated with larger tumor size. The high expression levels of HOTAIR were associated with lymphatic metastasis and poor differentiation. Since the biological roles of Linc00152 are largely unknown in gastric cancer pathogenesis, we assessed its functions by silencing its up-regulation in gastric cancer cells. We found that Linc00152 knockdown could inhibit cell proliferation and colony formation, promote cell cycle arrest at G1 phase, trigger late apoptosis, reduce the epithelial to mesenchymal transition (EMT) program, and suppress cell migration and invasion. Taken together, we delineate the gastric cancer lncRNA signature and demonstrate the oncogenic functions of Linc00152. These findings may have implications for developing lncRNA-based biomarkers for diagnosis and therapeutics for gastric cancer.

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TTBK2 circular RNA promotes glioma malignancy by regulating miR-217/HNF1β/Derlin-1 pathway

Jian Zheng, Xiaobai Liu, Yixue Xue … (2017)

Background Circular RNAs are a subgroup of non-coding RNAs and generated by a mammalian genome. Herein, the expression and function of circular RNA circ-TTBK2 were investigated in human glioma cells. Methods Fluorescence in situ hybridization and quantitative real-time PCR were conducted to profile the cell distribution and expression of circ-TTBK2 and microRNA-217 (miR-217) in glioma tissues and cells. Immunohistochemical and western blot were used to determine the expression of HNF1β and Derlin-1 in glioma tissues and cells. Stable knockdown of circ-TTBK2 or overexpression of miR-217 glioma cell lines (U87 and U251) were established to explore the function of circ-TTBK2 and miR-217 in glioma cells. Further, luciferase reports and RNA immunoprecipitation were used to investigate the correlation between circ-TTBK2 and miR-217. Cell Counting Kit-8, transwell assays, and flow cytometry were used to investigate circ-TTBK2 and miR-217 function including cell proliferation, migration and invasion, and apoptosis, respectively. ChIP assays were used to ascertain the correlations between HNF1β and Derlin-1. Results We found that circ-TTBK2 was upregulated in glioma tissues and cell lines, while linear TTBK2 was not dysregulated in glioma tissues and cells. Enhanced expression of circ-TTBK2 promoted cell proliferation, migration, and invasion, while inhibited apoptosis. MiR-217 was downregulated in glioma tissues and cell lines. We also found that circ-TTBK2, but not linear TTBK2, acted as miR-217 sponge in a sequence-specific manner. In addition, upregulated circ-TTBK2 decreased miR-217 expression and there was a reciprocal negative feedback between them in an Argonaute2-dependent manner. Moreover, reintroduction of miR-217 significantly reversed circ-TTBK2-mediated promotion of glioma progression. HNF1β was a direct target of miR-217, and played oncogenic role in glioma cells. Remarkably, circ-TTBK2 knockdown combined with miR-217 overexpression led to tumor regression in vivo. Conclusions These results demonstrated a novel role circ-TTBK2 in the glioma progression. Electronic supplementary material The online version of this article (doi:10.1186/s13045-017-0422-2) contains supplementary material, which is available to authorized users.

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Author and article information

Contributors

Yunhui Liu: +86 024 96615-36111 , liuyh_cmuns@163.com

Journal

Journal ID (nlm-ta): Mol Cancer

Journal ID (iso-abbrev): Mol. Cancer

Title: Molecular Cancer

Publisher: BioMed Central (London )

ISSN (Electronic): 1476-4598

Publication date (Electronic): 26 June 2017

Publication date PMC-release: 26 June 2017

Publication date Collection: 2017

Volume: 16

Electronic Location Identifier: 110

Affiliations

[1 ]ISNI 0000 0004 1806 3501, GRID grid.412467.2, Department of Neurosurgery, , Shengjing Hospital of China Medical University, ; Shenyang, 110004 People’s Republic of China

[2 ]Liaoning Clinical Medical Research Center in Nervous System Disease, Shenyang, 110004 People’s Republic of China

[3 ]Key Laboratory of Neuro-oncology in Liaoning Province, Shenyang, 110004 People’s Republic of China

[4 ]ISNI 0000 0000 9678 1884, GRID grid.412449.e, Department of Neurobiology, College of Basic Medicine, , China Medical University, ; Shenyang, 110122 People’s Republic of China

[5 ]ISNI 0000 0000 9678 1884, GRID grid.412449.e, Key Laboratory of Cell Biology, Ministry of Public Health of China, , China Medical University, ; Shenyang, 110122 People’s Republic of China

[6 ]ISNI 0000 0000 9678 1884, GRID grid.412449.e, Key Laboratory of Medical Cell Biology, Ministry of Education of China, , China Medical University, ; Shenyang, 110122 People’s Republic of China

Article

Publisher ID: 677

DOI: 10.1186/s12943-017-0677-9

PMC ID: 5485714

PubMed ID: 28651608

SO-VID: 7c3449be-63ee-4733-97bb-ca875ecc8883

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 4 March 2017

Date accepted : 7 June 2017

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 81672511, 81372484 and 81573010

Award Recipient : Yunhui Liu

Funded by: Liaoning Science and Technology Plan Project

Award ID: 2015225007

Award Recipient : Yunhui Liu

Funded by: Shenyang Science and Technology Plan Projects

Award ID: F15-199-1-30 and F15-199-1-57

Award Recipient : Yunhui Liu

Funded by: outstanding scientific fund of Shengjing hospital

Award ID: 201304

Award Recipient : Yunhui Liu

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: long non-coding rna,linc00152,mir-103a-3p,glioma stem cells,fezf1,cdc25a

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: long non-coding rna, linc00152, mir-103a-3p, glioma stem cells, fezf1, cdc25a

Linc00152 promotes malignant progression of glioma stem cells by regulating miR-103a-3p/FEZF1/CDC25A pathway

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Abstract

Background

Methods

Results

Conclusions

Electronic supplementary material

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Stress signalling in stem cells

Most cited references 46

CDC25 phosphatases in cancer cells: key players? Good targets?

Long non-coding RNA Linc00152 is involved in cell cycle arrest, apoptosis, epithelial to mesenchymal transition, cell migration and invasion in gastric cancer.

TTBK2 circular RNA promotes glioma malignancy by regulating miR-217/HNF1β/Derlin-1 pathway

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