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Genome-wide expression profiling in colorectal cancer focusing on lncRNAs in the adenoma-carcinoma transition

BACKGROUND: Long non-coding RNAs (lncRNAs) play a fundamental role in colorectal cancer (CRC) development, however, lncRNA expression profiles in CRC and its precancerous stages remain to be explored. We aimed to study whole genomic lncRNA expression patterns in colorectal adenoma–carcinoma transiti...

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Autores principales: Kalmár, Alexandra, Nagy, Zsófia Brigitta, Galamb, Orsolya, Csabai, István, Bodor, András, Wichmann, Barnabás, Valcz, Gábor, Barták, Barbara Kinga, Tulassay, Zsolt, Igaz, Peter, Molnár, Béla
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6836529/
https://www.ncbi.nlm.nih.gov/pubmed/31694571
http://dx.doi.org/10.1186/s12885-019-6180-5
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author Kalmár, Alexandra
Nagy, Zsófia Brigitta
Galamb, Orsolya
Csabai, István
Bodor, András
Wichmann, Barnabás
Valcz, Gábor
Barták, Barbara Kinga
Tulassay, Zsolt
Igaz, Peter
Molnár, Béla
author_facet Kalmár, Alexandra
Nagy, Zsófia Brigitta
Galamb, Orsolya
Csabai, István
Bodor, András
Wichmann, Barnabás
Valcz, Gábor
Barták, Barbara Kinga
Tulassay, Zsolt
Igaz, Peter
Molnár, Béla
author_sort Kalmár, Alexandra
collection PubMed
description BACKGROUND: Long non-coding RNAs (lncRNAs) play a fundamental role in colorectal cancer (CRC) development, however, lncRNA expression profiles in CRC and its precancerous stages remain to be explored. We aimed to study whole genomic lncRNA expression patterns in colorectal adenoma–carcinoma transition and to analyze the underlying functional interactions of aberrantly expressed lncRNAs. METHODS: LncRNA expression levels of colonic biopsy samples (20 CRCs, 20 adenomas (Ad), 20 healthy controls (N)) were analyzed with Human Transcriptome Array (HTA) 2.0. Expression of a subset of candidates was verified by qRT-PCR and in situ hybridization (ISH) analyses. Furthermore, in silico validation was performed on an independent HTA 2.0, on HGU133Plus 2.0 array data and on the TCGA COAD dataset. MiRNA targets of lncRNAs were predicted with miRCODE and lncBase v2 algorithms and miRNA expression was analyzed on miRNA3.0 Array data. MiRNA-mRNA target prediction was performed using miRWALK and c-Met protein levels were analyzed by immunohistochemistry. Comprehensive lncRNA-mRNA-miRNA co-expression pattern analysis was also performed. RESULTS: Based on our HTA results, a subset of literature-based CRC-associated lncRNAs showed remarkable expression changes already in precancerous colonic lesions. In both Ad vs. normal and CRC vs. normal comparisons 16 lncRNAs, including downregulated LINC02023, MEG8, AC092834.1, and upregulated CCAT1, CASC19 were identified showing differential expression during early carcinogenesis that persisted until CRC formation (FDR-adjusted p < 0.05). The intersection of CRC vs. N and CRC vs. Ad comparisons defines lncRNAs characteristic of malignancy in colonic tumors, where significant downregulation of LINC01752 and overexpression of UCA1 and PCAT1 were found. Two candidates with the greatest increase in expression in the adenoma-carcinoma transition were further confirmed by qRT-PCR (UCA1, CCAT1) and by ISH (UCA1). In line with aberrant expression of certain lncRNAs in tumors, the expression of miRNA and mRNA targets showed systematic alterations. For example, UCA1 upregulation in CRC samples occurred in parallel with hsa-miR-1 downregulation, accompanied by c-Met target mRNA overexpression (p < 0.05). CONCLUSION: The defined lncRNA sets may have a regulatory role in the colorectal adenoma-carcinoma transition. A subset of CRC-associated lncRNAs showed significantly differential expression in precancerous samples, raising the possibility of developing adenoma-specific markers for early detection of colonic lesions.
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spelling pubmed-68365292019-11-12 Genome-wide expression profiling in colorectal cancer focusing on lncRNAs in the adenoma-carcinoma transition Kalmár, Alexandra Nagy, Zsófia Brigitta Galamb, Orsolya Csabai, István Bodor, András Wichmann, Barnabás Valcz, Gábor Barták, Barbara Kinga Tulassay, Zsolt Igaz, Peter Molnár, Béla BMC Cancer Research Article BACKGROUND: Long non-coding RNAs (lncRNAs) play a fundamental role in colorectal cancer (CRC) development, however, lncRNA expression profiles in CRC and its precancerous stages remain to be explored. We aimed to study whole genomic lncRNA expression patterns in colorectal adenoma–carcinoma transition and to analyze the underlying functional interactions of aberrantly expressed lncRNAs. METHODS: LncRNA expression levels of colonic biopsy samples (20 CRCs, 20 adenomas (Ad), 20 healthy controls (N)) were analyzed with Human Transcriptome Array (HTA) 2.0. Expression of a subset of candidates was verified by qRT-PCR and in situ hybridization (ISH) analyses. Furthermore, in silico validation was performed on an independent HTA 2.0, on HGU133Plus 2.0 array data and on the TCGA COAD dataset. MiRNA targets of lncRNAs were predicted with miRCODE and lncBase v2 algorithms and miRNA expression was analyzed on miRNA3.0 Array data. MiRNA-mRNA target prediction was performed using miRWALK and c-Met protein levels were analyzed by immunohistochemistry. Comprehensive lncRNA-mRNA-miRNA co-expression pattern analysis was also performed. RESULTS: Based on our HTA results, a subset of literature-based CRC-associated lncRNAs showed remarkable expression changes already in precancerous colonic lesions. In both Ad vs. normal and CRC vs. normal comparisons 16 lncRNAs, including downregulated LINC02023, MEG8, AC092834.1, and upregulated CCAT1, CASC19 were identified showing differential expression during early carcinogenesis that persisted until CRC formation (FDR-adjusted p < 0.05). The intersection of CRC vs. N and CRC vs. Ad comparisons defines lncRNAs characteristic of malignancy in colonic tumors, where significant downregulation of LINC01752 and overexpression of UCA1 and PCAT1 were found. Two candidates with the greatest increase in expression in the adenoma-carcinoma transition were further confirmed by qRT-PCR (UCA1, CCAT1) and by ISH (UCA1). In line with aberrant expression of certain lncRNAs in tumors, the expression of miRNA and mRNA targets showed systematic alterations. For example, UCA1 upregulation in CRC samples occurred in parallel with hsa-miR-1 downregulation, accompanied by c-Met target mRNA overexpression (p < 0.05). CONCLUSION: The defined lncRNA sets may have a regulatory role in the colorectal adenoma-carcinoma transition. A subset of CRC-associated lncRNAs showed significantly differential expression in precancerous samples, raising the possibility of developing adenoma-specific markers for early detection of colonic lesions. BioMed Central 2019-11-06 /pmc/articles/PMC6836529/ /pubmed/31694571 http://dx.doi.org/10.1186/s12885-019-6180-5 Text en © The Author(s). 2019 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.
spellingShingle Research Article
Kalmár, Alexandra
Nagy, Zsófia Brigitta
Galamb, Orsolya
Csabai, István
Bodor, András
Wichmann, Barnabás
Valcz, Gábor
Barták, Barbara Kinga
Tulassay, Zsolt
Igaz, Peter
Molnár, Béla
Genome-wide expression profiling in colorectal cancer focusing on lncRNAs in the adenoma-carcinoma transition
title Genome-wide expression profiling in colorectal cancer focusing on lncRNAs in the adenoma-carcinoma transition
title_full Genome-wide expression profiling in colorectal cancer focusing on lncRNAs in the adenoma-carcinoma transition
title_fullStr Genome-wide expression profiling in colorectal cancer focusing on lncRNAs in the adenoma-carcinoma transition
title_full_unstemmed Genome-wide expression profiling in colorectal cancer focusing on lncRNAs in the adenoma-carcinoma transition
title_short Genome-wide expression profiling in colorectal cancer focusing on lncRNAs in the adenoma-carcinoma transition
title_sort genome-wide expression profiling in colorectal cancer focusing on lncrnas in the adenoma-carcinoma transition
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6836529/
https://www.ncbi.nlm.nih.gov/pubmed/31694571
http://dx.doi.org/10.1186/s12885-019-6180-5
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