The long noncoding RNA SPRY4-IT1 increases the proliferation of human breast cancer cells by upregulating ZNF703 expression

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Abstract

Background

Long noncoding RNAs (lncRNAs) have emerged recently as a new class of genes that regulate cellular processes, such as cell growth and apoptosis. The SPRY4 intronic transcript 1 (SPRY4-IT1) is a 708-bp lncRNA on chromosome 5 with a potential functional role in tumorigenesis. The clinical significance of SPRY4-IT1 and the effect of SPRY4-IT1 on cancer progression are unclear.

Methods

Quantitative reverse transcriptase PCR (qRT-PCR) was performed to investigate the expression of SPRY4-IT1 in 48 breast cancer tissues and four breast cancer cell lines. Gain and loss of function approaches were used to investigate the biological role of SPRY4-IT1 in vitro. Microarray bioinformatics analysis was performed to identify the putative targets of SPRY4-IT1, which were further verified by rescue experiments, and by western blotting and qRT-PCR.

Results

SPRY4-IT1 expression was significantly upregulated in 48 breast cancer tumor tissues comparedwith normal tissues. Additionally, increased SPRY4-IT1 expression was found to be associated with a larger tumor size and an advanced pathological stage in breast cancer patients. The knockdown of SPRY4-IT1 significantly suppressed proliferation and caused apoptosis of breast cancer cells in vitro. Furthermore, we discovered that ZNF703 was a target of SPRY4-IT1 and was downregulated by SPRY4-IT1 knockdown. Moreover, we provide the first demonstration that ZNF703 plays an oncogenic role in ER (−) breast carcinoma cells.

Conclusions

SPRY4-IT1 is a novel prognostic biomarker and a potential therapeutic candidate for breast cancer.

Electronic supplementary material

The online version of this article (doi:10.1186/s12943-015-0318-0) contains supplementary material, which is available to authorized users.

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Most cited references 26

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GAS5, a non-protein-coding RNA, controls apoptosis and is downregulated in breast cancer.

M. Mourtada-Maarabouni, M Pickard, V. L. Hedge … (2009)

Effective control of both cell survival and cell proliferation is critical to the prevention of oncogenesis and to successful cancer therapy. Using functional expression cloning, we have identified GAS5 (growth arrest-specific transcript 5) as critical to the control of mammalian apoptosis and cell population growth. GAS5 transcripts are subject to complex post-transcriptional processing and some, but not all, GAS5 transcripts sensitize mammalian cells to apoptosis inducers. We have found that, in some cell lines, GAS5 expression induces growth arrest and apoptosis independently of other stimuli. GAS5 transcript levels were significantly reduced in breast cancer samples relative to adjacent unaffected normal breast epithelial tissues. The GAS5 gene has no significant protein-coding potential but expression encodes small nucleolar RNAs (snoRNAs) in its introns. Taken together with the recent demonstration of tumor suppressor characteristics in the related snoRNA U50, our observations suggest that such snoRNAs form a novel family of genes controlling oncogenesis and sensitivity to therapy in cancer.

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Functionality or transcriptional noise? Evidence for selection within long noncoding RNAs.

Jasmina Ponjavic, Chris P. Ponting, Gerton Lunter (2007)

Long transcripts that do not encode protein have only rarely been the subject of experimental scrutiny. Presumably, this is owing to the current lack of evidence of their functionality, thereby leaving an impression that, instead, they represent "transcriptional noise." Here, we describe an analysis of 3122 long and full-length, noncoding RNAs ("macroRNAs") from the mouse, and compare their sequences and their promoters with orthologous sequence from human and from rat. We considered three independent signatures of purifying selection related to substitutions, sequence insertions and deletions, and splicing. We find that the evolution of the set of noncoding RNAs is not consistent with neutralist explanations. Rather, our results indicate that purifying selection has acted on the macroRNAs' promoters, primary sequence, and consensus splice site motifs. Promoters have experienced the greatest elimination of nucleotide substitutions, insertions, and deletions. The proportion of conserved sequence (4.1%-5.5%) in these macroRNAs is comparable to the density of exons within protein-coding transcripts (5.2%). These macroRNAs, taken together, thus possess the imprint of purifying selection, thereby indicating their functionality. Our findings should now provide an incentive for the experimental investigation of these macroRNAs' functions.

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The Genetic Signatures of Noncoding RNAs

John S. Mattick (2009)

The majority of the genome in animals and plants is transcribed in a developmentally regulated manner to produce large numbers of non–protein-coding RNAs (ncRNAs), whose incidence increases with developmental complexity. There is growing evidence that these transcripts are functional, particularly in the regulation of epigenetic processes, leading to the suggestion that they compose a hitherto hidden layer of genomic programming in humans and other complex organisms. However, to date, very few have been identified in genetic screens. Here I show that this is explicable by an historic emphasis, both phenotypically and technically, on mutations in protein-coding sequences, and by presumptions about the nature of regulatory mutations. Most variations in regulatory sequences produce relatively subtle phenotypic changes, in contrast to mutations in protein-coding sequences that frequently cause catastrophic component failure. Until recently, most mapping projects have focused on protein-coding sequences, and the limited number of identified regulatory mutations have been interpreted as affecting conventional cis-acting promoter and enhancer elements, although these regions are often themselves transcribed. Moreover, ncRNA-directed regulatory circuits underpin most, if not all, complex genetic phenomena in eukaryotes, including RNA interference-related processes such as transcriptional and post-transcriptional gene silencing, position effect variegation, hybrid dysgenesis, chromosome dosage compensation, parental imprinting and allelic exclusion, paramutation, and possibly transvection and transinduction. The next frontier is the identification and functional characterization of the myriad sequence variations that influence quantitative traits, disease susceptibility, and other complex characteristics, which are being shown by genome-wide association studies to lie mostly in noncoding, presumably regulatory, regions. There is every possibility that many of these variations will alter the interactions between regulatory RNAs and their targets, a prospect that should be borne in mind in future functional analyses.

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Author and article information

Contributors

Yongguo Shi: 1138303166@qq.com

Juan Li: lijuan123@163.com

Yangchen Liu: liuyctx@163.com

Jie Ding: 430397952@qq.com

Yingrui Fan: yingrui668@163.com

Yun Tian: 82560036@qq.com

Li Wang: 911165@qq.com

Yifan Lian: Yifan23@sohu.com

Keming Wang: kemingwang@njmu.edu.cn

Yongqian Shu: shuyongqian@csco.org.cn

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): 22 February 2015

Publication date PMC-release: 22 February 2015

Publication date Collection: 2015

Volume: 14

Electronic Location Identifier: 51

Affiliations

[ ]Department of Oncology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu PR China

[ ]Taixing People’s Hospital, Taixing, Jiangsu PR China

[ ]Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu PR China

Article

Publisher ID: 318

DOI: 10.1186/s12943-015-0318-0

PMC ID: 4350857

PubMed ID: 25742952

SO-VID: 104e9b7d-389b-4304-8574-358c977a7ef3

License:

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 : 2 November 2014

Date accepted : 9 February 2015

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: spry4-it1,znf703,proliferation,breast cancer

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: spry4-it1, znf703, proliferation, breast cancer

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The long noncoding RNA SPRY4-IT1 increases the proliferation of human breast cancer cells by upregulating ZNF703 expression

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Abstract

Background

Methods

Results

Conclusions

Electronic supplementary material

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Karger: Oncology

Most cited references 26

GAS5, a non-protein-coding RNA, controls apoptosis and is downregulated in breast cancer.

Functionality or transcriptional noise? Evidence for selection within long noncoding RNAs.

The Genetic Signatures of Noncoding RNAs

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Cited by 72

Most referenced authors 471