LEIGC long non-coding RNA acts as a tumor suppressor in gastric carcinoma by inhibiting the epithelial-to-mesenchymal transition

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Abstract

Background

Long non-coding RNAs have been shown to have critical regulatory roles in cancer biology. However, the contributions of lncRNAs to gastric cancer remain largely unknown.

Methods

The differential expression of lncRNAs in gastric cancer and paired non-cancerous tissues were identified by microarray and validated using quantitative real-time PCR. Gastric samples from patients with gastric cancer were further analyzed for levels of a specifically downregulated lncRNA (termed as LEIGC).

Results

We found that there were significantly lower levels of LEIGC expression in cancer tissue than in adjacent non-cancerous tissues in human gastric cancers ( P < 0.01). Overexpression of LEIGC suppressed tumor growth and cell proliferation, and enhanced the sensitivity of gastric cancer cells to 5-fluorouracil (5-FU), whereas knockdown of LEIGC showed the opposite effect. We further demonstrated LEIGC functions by inhibiting the epithelial-to-mesenchymal transition (EMT) in gastric cancer.

Conclusions

Our data suggested that LEIGC is a tumor-suppressing lncRNA in gastric cancer, and led us to propose that lncRNAs may play important regulatory roles in cancer development and progression.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2407-14-932) contains supplementary material, which is available to authorized users.

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Most cited references 21

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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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Long non-coding RNA ANRIL is required for the PRC2 recruitment to and silencing of p15(INK4B) tumor suppressor gene.

Y Kotake, T. Nakagawa, K Kitagawa … (2011)

A 42 kb region on human chromosome 9p21 encodes for three distinct tumor suppressors, p16(INK4A), p14(ARF) and p15(INK4B), and is altered in an estimated 30-40% of human tumors. The expression of the INK4A-ARF-INK4B gene cluster is silenced by polycomb during normal cell growth and is activated by oncogenic insults and during aging. How the polycomb is recruited to repress this gene cluster is unclear. Here, we show that expression of oncogenic Ras, which stimulates the expression of p15(INK4B) and p16(INK4A), but not p14(ARF), inhibits the expression of ANRIL (antisense non-coding RNA in the INK4 locus), a 3.8 kb-long non-coding RNA expressed in the opposite direction from INK4A-ARF-INK4B. We show that the p15(INK4B) locus is bound by SUZ12, a component of polycomb repression complex 2 (PRC2), and is H3K27-trimethylated. Notably, depletion of ANRIL disrupts the SUZ12 binding to the p15(INK4B) locus, increases the expression of p15(INK4B), but not p16(INK4A) or p14(ARF), and inhibits cellular proliferation. Finally, RNA immunoprecipitation demonstrates that ANRIL binds to SUZ12 in vivo. Collectively, these results suggest a model in which ANRIL binds to and recruits PRC2 to repress the expression of p15(INK4B) locus.

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LncRNA-Dependent Mechanisms of Androgen Receptor-regulated Gene Activation Programs

Liuqing Yang, Chunru Lin, Chunyu Jin … (2013)

While recent studies indicated roles of long non-coding RNAs (lncRNAs) in physiologic aspects of cell-type determination and tissue homeostasis 1 yet their potential involvement in regulated gene transcription programs remain rather poorly understood. Androgen receptor (AR) regulates a large repertoire of genes central to the identity and behavior of prostate cancer cells 2 , and functions in a ligand-independent fashion in many prostate cancers when they become hormone refractory after initial androgen deprivation therapy 3 . Here, we report that two lncRNAs highly overexpressed in aggressive prostate cancer, PRNCR1 and PCGEM1, bind successively to the AR and strongly enhance both ligand-dependent and ligand-independent AR-mediated gene activation programs and proliferation in prostate cancer cells. Binding of PRNCR1 to the C-terminally acetylated AR on enhancers and its association with DOT1L appear to be required for recruitment of the second lncRNA, PCGEM1, to the DOT1L-mediated methylated AR N-terminus. Unexpectedly, recognition of specific protein marks by PCGEM1-recruited Pygopus2 PHD domain proves to enhance selective looping of AR-bound enhancers to target gene promoters in these cells. In “resistant” prostate cancer cells, these overexpressed lncRNAs can interact with, and are required for, the robust activation of both truncated and full length AR, causing ligand-independent activation of the AR transcriptional program and cell proliferation. Conditionally-expressed short hairpin RNA (shRNA) targeting of these lncRNAs in castration-resistant prostate cancer (CRPC) cell lines strongly suppressed tumor xenograft growth in vivo. Together, these results suggest that these overexpressed lncRNAs can potentially serve as a required component of castration-resistance in prostatic tumors.

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Author and article information

Contributors

Yuehua Han: hanyh_2012@aliyun.com

Jun Ye: wzmcyejun@zju.edu.cn

Dang Wu: wudang@zju.edu.cn

Pin Wu: doctorwp@163.com

Zhigang Chen: pridechen@126.com

Jian Chen: gschenjian@gmail.com

Shunliang Gao: 1723892015@qq.com

Jian Huang: Drhuangjian@zju.edu.cn

Journal

Journal ID (nlm-ta): BMC Cancer

Journal ID (iso-abbrev): BMC Cancer

Title: BMC Cancer

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2407

Publication date (Electronic): 11 December 2014

Publication date Collection: 2014

Volume: 14

Issue: 1

Electronic Location Identifier: 932

Affiliations

[ ]Department of Gastroenterology, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310009 China

[ ]Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310009 China

[ ]Department of General Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310009 China

[ ]Department of Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310009 China

Article

Publisher ID: 5109

DOI: 10.1186/1471-2407-14-932

PMC ID: 4295322

PubMed ID: 25496320

SO-VID: db1dfc04-c9b5-46f2-8a48-01200dda80e9

License:

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. 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 : 11 June 2014

Date accepted : 25 November 2014

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: long non-coding rna,tumor suppressor,gastric carcinoma,epithelial-to-mesenchymal transition

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: long non-coding rna, tumor suppressor, gastric carcinoma, epithelial-to-mesenchymal transition

LEIGC long non-coding RNA acts as a tumor suppressor in gastric carcinoma by inhibiting the epithelial-to-mesenchymal transition

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Abstract

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Results

Conclusions

Electronic supplementary material

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Karger: Oncology

Most cited references 21

Long noncoding RNA as modular scaffold of histone modification complexes.

Long non-coding RNA ANRIL is required for the PRC2 recruitment to and silencing of p15(INK4B) tumor suppressor gene.

LncRNA-Dependent Mechanisms of Androgen Receptor-regulated Gene Activation Programs

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