Long non-coding RNA XIST regulates gastric cancer progression by acting as a molecular sponge of miR-101 to modulate EZH2 expression

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Abstract

Background

Long non-coding RNAs (lncRNAs) have emerged as critical regulators of tumor progression. However, the role and molecular mechanism of lncRNA XIST in gastric cancer is still unknown.

Methods

Real-time PCR analysis was performed to measure the expression levels of lncRNA XIST in gastric cancer tissues and cell lines, the correlation between lncRNA XIST expression and clinicopathological characteristics and prognosis was analyzed in gastric cancer patients. The biological function of lncRNA XIST on gastric cancer cells were determined both in vitro and in vivo. The regulating relationship between lncRNA XIST and miR-101 was investigated in gastric cancer cells.

Results

lncRNA XIST was significantly up-regulated in gastric cancer tissues and cell lines. Overexpression of lncRNA XIST was markedly associated with larger tumor size, lymph node invasion, distant metastasis and TNM stage in gastric cancer patients. Functionally, knockdown of lncRNA XIST exerted tumor-suppressive effects by inhibiting cell proliferation, migration and invasion in vitro and tumor growth and metastasis in vivo. Furthermore, an inverse relationship between lncRNA XIST and miR-101 was found. Polycomb group protein enhancer of zeste homolog 2 (EZH2), a direct target of miR-101, could mediated the biological effects that lncRNA XIST exerted.

Conclusions

lncRNA XIST is up-regulated and is associated with aggressive tumor phenotypes and patient survival in gastric cancer, and the newly identified lncRNA XIST/miR-101/EZH2 axis could be a potential biomarkers or therapeutic targets for gastric cancer patients.

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Most cited references 30

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Long noncoding RNA as modular scaffold of histone modification complexes.

Miao-Chih Tsai, Ohad Manor, Yue Wan … (2010)

Long intergenic noncoding RNAs (lincRNAs) regulate chromatin states and epigenetic inheritance. Here, we show that the lincRNA HOTAIR serves as a scaffold for at least two distinct histone modification complexes. A 5' domain of HOTAIR binds polycomb repressive complex 2 (PRC2), whereas a 3' domain of HOTAIR binds the LSD1/CoREST/REST complex. The ability to tether two distinct complexes enables RNA-mediated assembly of PRC2 and LSD1 and coordinates targeting of PRC2 and LSD1 to chromatin for coupled histone H3 lysine 27 methylation and lysine 4 demethylation. Our results suggest that lincRNAs may serve as scaffolds by providing binding surfaces to assemble select histone modification enzymes, thereby specifying the pattern of histone modifications on target genes.

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Large intergenic non-coding RNA-RoR modulates reprogramming of human induced pluripotent stem cells.

Sabine Loewer, Moran Cabili, Mitchell Guttman … (2010)

The conversion of lineage-committed cells to induced pluripotent stem cells (iPSCs) by reprogramming is accompanied by a global remodeling of the epigenome, resulting in altered patterns of gene expression. Here we characterize the transcriptional reorganization of large intergenic non-coding RNAs (lincRNAs) that occurs upon derivation of human iPSCs and identify numerous lincRNAs whose expression is linked to pluripotency. Among these, we defined ten lincRNAs whose expression was elevated in iPSCs compared with embryonic stem cells, suggesting that their activation may promote the emergence of iPSCs. Supporting this, our results indicate that these lincRNAs are direct targets of key pluripotency transcription factors. Using loss-of-function and gain-of-function approaches, we found that one such lincRNA (lincRNA-RoR) modulates reprogramming, thus providing a first demonstration for critical functions of lincRNAs in the derivation of pluripotent stem cells.

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The melanoma-upregulated long noncoding RNA SPRY4-IT1 modulates apoptosis and invasion.

Divya Khaitan, Marcel E Dinger, Joseph Mazar … (2011)

The identification of cancer-associated long noncoding RNAs (lncRNAs) and the investigation of their molecular and biological functions are important to understand the molecular biology of cancer and its progression. Although the functions of lncRNAs and the mechanisms regulating their expression are largely unknown, recent studies are beginning to unravel their importance in human health and disease. Here, we report that a number of lncRNAs are differentially expressed in melanoma cell lines in comparison to melanocytes and keratinocyte controls. One of these lncRNAs, SPRY4-IT1 (GenBank accession ID AK024556), is derived from an intron of the SPRY4 gene and is predicted to contain several long hairpins in its secondary structure. RNA-FISH analysis showed that SPRY4-IT1 is predominantly localized in the cytoplasm of melanoma cells, and SPRY4-IT1 RNAi knockdown results in defects in cell growth, differentiation, and higher rates of apoptosis in melanoma cell lines. Differential expression of both SPRY4 and SPRY4-IT1 was also detected in vivo, in 30 distinct patient samples, classified as primary in situ, regional metastatic, distant metastatic, and nodal metastatic melanoma. The elevated expression of SPRY4-IT1 in melanoma cells compared to melanocytes, its accumulation in cell cytoplasm, and effects on cell dynamics, including increased rate of wound closure on SPRY4-IT1 overexpression, suggest that the higher expression of SPRY4-IT1 may have an important role in the molecular etiology of human melanoma.

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Author and article information

Contributors

Dong-liang Chen: chendl@sysucc.org.cn

Huai-qiang Ju: juhq@sysucc.org.cn

Yun-xin Lu: luyx@sysucc.org.cn

Le-zong Chen: chenlz@sysucc.org.cn

Zhao-lei Zeng: zengzl@sysucc.org.cn

Dong-sheng Zhang: zhangdsh@sysucc.org.cn

Hui-yan Luo: luohy@sysucc.org.cn

Feng Wang: wangfeng@sysucc.org.cn

Miao-zhen Qiu: qiumzh@sysucc.org.cn

De-shen Wang: wangdsh@sysucc.org.cn

Da-zhi Xu: xudzh@sysucc.org.cn

Zhi-wei Zhou: zhouzhw@sysucc.org.cn

Helene Pelicano: hpelican@mdanderson.org

Peng Huang: pheng@mdanderson.org

Dan Xie: xiedan@sysucc.org.cn

Feng-hua Wang: wangfh@sysucc.org.cn

Yu-hong Li: liyh@sysucc.org.cn

Rui-hua Xu: +86-20-87343333 , xurh@sysucc.org.cn

Journal

Journal ID (nlm-ta): J Exp Clin Cancer Res

Journal ID (iso-abbrev): J. Exp. Clin. Cancer Res

Title: Journal of Experimental & Clinical Cancer Research : CR

Publisher: BioMed Central (London )

ISSN (Print): 0392-9078

ISSN (Electronic): 1756-9966

Publication date (Electronic): 13 September 2016

Publication date PMC-release: 13 September 2016

Publication date Collection: 2016

Volume: 35

Issue: 1

Electronic Location Identifier: 142

Affiliations

[1 ]State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Medical Oncology, Sun Yat-sen University Cancer Center, No. 651 Dong Feng East Road, Guangzhou, 510060 China

[2 ]University of Texas M.D. Anderson Cancer Center, Houston, TX USA

Article

Publisher ID: 420

DOI: 10.1186/s13046-016-0420-1

PMC ID: 5020507

PubMed ID: 27620004

SO-VID: 226f9816-3ad3-495b-a38e-4bc97bf02069

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 : 15 June 2016

Date accepted : 7 September 2016

Funding

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

Award ID: No.81372570

Award Recipient : Rui-hua Xu

Funded by: Natural Science Foundation of Guangdong Province

Award ID: No.2014A030312015

Award Recipient : Rui-hua Xu

Funded by: Natural Science Foundation of Guangdong Province

Award ID: No.2016A030310195

Award Recipient : Dong-liang Chen

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: long non-coding rna,lncrna xist,mir-101,ezh2,gastric cancer

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: long non-coding rna, lncrna xist, mir-101, ezh2, gastric cancer

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Long non-coding RNA XIST regulates gastric cancer progression by acting as a molecular sponge of miR-101 to modulate EZH2 expression

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Karger: Oncology

Most cited references 30

Long noncoding RNA as modular scaffold of histone modification complexes.

Large intergenic non-coding RNA-RoR modulates reprogramming of human induced pluripotent stem cells.

The melanoma-upregulated long noncoding RNA SPRY4-IT1 modulates apoptosis and invasion.

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