Expression of miR-296-5p as predictive marker for radiotherapy resistance in early-stage laryngeal carcinoma

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Abstract

Purpose

Definitive radiation therapy is the mainstay of treatment for early stage laryngeal squamous cell carcinoma (LSCC). However, up to 30% of the patients do not respond to radiotherapy. Unfortunately, we are unable to predict which tumors are likely to respond to radiation, and which will be resistant and persist. Therefore, the development of novel markers to predict response to radiotherapy is urgently needed. This study was designed to evaluate the expression pattern of microRNAs (miRNAs) in LSCC in order to identify markers capable of segregating radioresistant and radiosensitive tumors and to investigate the relationship between the expression of these miRNAs and the prognosis of LSCC.

Methods

The expression profile of 667 miRNAs was determined in an initial screening of nine early-stage LSCC samples (5 radioresistant and 4 radiosensitive) using TaqMan Low-Density Array (TLDA). Real-time polymerase chain reactions were performed to validate the expression of selected miRNAs in an expanded LSCC cohort (20 radioresistant and 14 radiosensitive). The miRNA expression level was scored as high or low based on the median of the expression in the LSCC samples.

Results

A comprehensive miRNA expression profiling enabled the identification of four miRNAs (miR-296-5p miR-452, miR-183* and miR-200c) differentially expressed in radioresistant LSCC. Moreover, the analysis of additional 34 LSCC samples, confirmed the expression of miR-296-5p as significantly related to radioresistance (p = 0.002) as well as an association of this marker with recurrence (p = 0.025) in early stage laryngeal cancer.

Conclusions

This study indicates that miR-296-5p expression is associated with resistance to radiotherapy and tumor recurrence in early stage LSCC, showing the feasibility of this marker as a novel prognostic factor for this malignance. Furthermore, miR-296-5p expression could be helpful in the identification of tumors resistant to radiotherapy; thus aiding the clinicians in the choice of the best therapeutic scheme to be used in each case.

Electronic supplementary material

The online version of this article (doi:10.1186/s12967-015-0621-y) contains supplementary material, which is available to authorized users.

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Most cited references 34

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Comprehensive MicroRNA profiling for head and neck squamous cell carcinomas.

Angela Hui, Melania Pintilie, John Waldron … (2010)

The objective of this study is to investigate the significance of microRNAs (miRNA) in patients with locally advanced head and neck squamous cell carcinoma (HNSCC). A global miRNA profiling was done on 51 formalin-fixed archival HNSCC samples using quantitative reverse transcription-PCR approach, correlated with patients' clinical parameters. Functional characterization of HNSCC-associated miRNAs was conducted on three HNSCC cell lines. Cell viability and proliferation were investigated using MTS and clonogenic assays, respectively; cell cycle analyses were assessed using flow cytometry. Thirty-eight of the 117 (33%) consistently detected miRNAs were significantly differentially expressed between malignant versus normal tissues. Concordant with previous reports, overexpression of miR-21, miR-155, let-7i, and miR-142-3p and underexpression of miR-125b and miR-375 were detected. Upregulation of miR-423, miR-106b, miR-20a, and miR-16 as well as downregulation of miR-10a were newly observed. Exogenous overexpression of miR-375 in HNSCC cell lines reduced proliferation and clonogenicity and increased cells in sub-G(1). Similar cellular effects were observed in knockdown studies of the miR-106b-25 cluster but with accumulation of cells in G(1) arrest. No major difference was detected in miRNA profiles among laryngeal, oropharyngeal, or hypopharyngeal cancers. miR-451 was found to be the only significantly overexpressed miRNA by 4.7-fold between nonrelapsed and relapsed patients. We have identified a group of aberrantly expressed miRNAs in HNSCC and showed that underexpression of miR-375 and overexpression of miR-106b-25 cluster might play oncogenic roles in this disease. Further detailed examinations of miRNAs will provide opportunities to dissect the complex molecular abnormalities driving HNSCC progression.

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AngiomiRs--key regulators of angiogenesis.

Shusheng Wang, Eric Olson (2009)

The formation of new blood vessels through the process of angiogenesis is critical in vascular development and homeostasis. Aberrant angiogenesis leads to a variety of diseases, such as ischemia and cancer. Recent studies have revealed important roles for miRNAs in regulating endothelial cell (EC) function, especially angiogenesis. Mice with EC-specific deletion of Dicer, a key enzyme for generating miRNAs, display defective postnatal angiogenesis. Specific miRNAs (angiomiRs) have recently been shown to regulate angiogenesis in vivo. miRNA-126, an EC-restricted miRNA, regulates vascular integrity and developmental angiogenesis. miR-378, miR-296, and the miR-17-92 cluster contribute to tumor angiogenesis. Manipulating angiomiRs in the settings of pathological vascularization represents a new therapeutic approach.

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miR-296 regulates growth factor receptor overexpression in angiogenic endothelial cells.

Thomas Würdinger, Bakhos A Tannous, Okay Saydam … (2008)

A key step in angiogenesis is the upregulation of growth factor receptors on endothelial cells. Here, we demonstrate that a small regulatory microRNA, miR-296, has a major role in this process. Glioma cells and angiogenic growth factors elevate the level of miR-296 in primary human brain microvascular endothelial cells in culture. The miR-296 level is also elevated in primary tumor endothelial cells isolated from human brain tumors compared to normal brain endothelial cells. Growth factor-induced miR-296 contributes significantly to angiogenesis by directly targeting the hepatocyte growth factor-regulated tyrosine kinase substrate (HGS) mRNA, leading to decreased levels of HGS and thereby reducing HGS-mediated degradation of the growth factor receptors VEGFR2 and PDGFRbeta. Furthermore, inhibition of miR-296 with antagomirs reduces angiogenesis in tumor xenografts in vivo.

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Author and article information

Contributors

Danielle Maia: dellymaia@gmail.com

Ana Carolina de Carvalho: ca_oak@yahoo.com.br

Maria Aderuza Horst: aderuza@gmail.com

André Lopes Carvalho: alopescarvalho@uol.com.br

Cristovam Scapulatempo-Neto: cristovamscapula@uol.com.br

Andre Luiz Vettore: andre.vettore@gmail.com

Journal

Journal ID (nlm-ta): J Transl Med

Journal ID (iso-abbrev): J Transl Med

Title: Journal of Translational Medicine

Publisher: BioMed Central (London )

ISSN (Electronic): 1479-5876

Publication date (Electronic): 12 August 2015

Publication date PMC-release: 12 August 2015

Publication date Collection: 2015

Volume: 13

Electronic Location Identifier: 262

Affiliations

[ ]Laboratory of Molecular Cancer Biology, Department of Biological Sciences, Federal University of São Paulo, Rua Pedro de Toledo, 669-11° andar, São Paulo, SP 04039-032 Brazil

[ ]Molecular Oncology Research Center, Barretos Cancer Hospital, Rua Antenor Duarte Vilela, 1331, Barretos, SP 14784-400 Brazil

[ ]Department of Head and Neck Surgery, Barretos Cancer Hospital, Rua Antenor Duarte Villela, 1331, Barretos, 14784-400 Brazil

[ ]Department of Pathology, Barretos Cancer Hospital, Rua Antenor Duarte Villela, 1331, Barretos, 14784-400 Brazil

[ ]Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore, Singapore

Article

Publisher ID: 621

DOI: 10.1186/s12967-015-0621-y

PMC ID: 4533949

PubMed ID: 26264462

SO-VID: 8f932143-a672-4690-a8e4-e91cca6a7ffc

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 : 8 March 2015

Date accepted : 28 July 2015

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ScienceOpen disciplines: Medicine

Keywords: early-stage laryngeal cancers,molecular marker,micrornas,radioresistance,mir-296-5p

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ScienceOpen disciplines: Medicine

Keywords: early-stage laryngeal cancers, molecular marker, micrornas, radioresistance, mir-296-5p

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Expression of miR-296-5p as predictive marker for radiotherapy resistance in early-stage laryngeal carcinoma

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Abstract

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Conclusions

Electronic supplementary material

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Journal of Circulating Biomarkers

Most cited references 34

Comprehensive MicroRNA profiling for head and neck squamous cell carcinomas.

AngiomiRs--key regulators of angiogenesis.

miR-296 regulates growth factor receptor overexpression in angiogenic endothelial cells.

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