Patients with Cholangiocarcinoma Present Specific RNA Profiles in Serum and Urine Extracellular Vesicles Mirroring the Tumor Expression: Novel Liquid Biopsy Biomarkers for Disease Diagnosis

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Abstract

Cholangiocarcinoma (CCA) comprises a group of heterogeneous biliary cancers with dismal prognosis. The etiologies of most CCAs are unknown, but primary sclerosing cholangitis (PSC) is a risk factor. Non-invasive diagnosis of CCA is challenging and accurate biomarkers are lacking. We aimed to characterize the transcriptomic profile of serum and urine extracellular vesicles (EVs) from patients with CCA, PSC, ulcerative colitis (UC), and healthy individuals. Serum and urine EVs were isolated by serial ultracentrifugations and characterized by nanoparticle tracking analysis, transmission electron microscopy, and immunoblotting. EVs transcriptome was determined by Illumina gene expression array [messenger RNAs (mRNA) and non-coding RNAs (ncRNAs)]. Differential RNA profiles were found in serum and urine EVs from patients with CCA compared to control groups (disease and healthy), showing high diagnostic capacity. The comparison of the mRNA profiles of serum or urine EVs from patients with CCA with the transcriptome of tumor tissues from two cohorts of patients, CCA cells in vitro, and CCA cells-derived EVs, identified 105 and 39 commonly-altered transcripts, respectively. Gene ontology analysis indicated that most commonly-altered mRNAs participate in carcinogenic steps. Overall, patients with CCA present specific RNA profiles in EVs mirroring the tumor, and constituting novel promising liquid biopsy biomarkers.

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FunRich: An open access standalone functional enrichment and interaction network analysis tool.

Mohashin Pathan, Shivakumar Keerthikumar, Ching-Seng Ang … (2015)

As high-throughput techniques including proteomics become more accessible to individual laboratories, there is an urgent need for a user-friendly bioinformatics analysis system. Here, we describe FunRich, an open access, standalone functional enrichment and network analysis tool. FunRich is designed to be used by biologists with minimal or no support from computational and database experts. Using FunRich, users can perform functional enrichment analysis on background databases that are integrated from heterogeneous genomic and proteomic resources (>1.5 million annotations). Besides default human specific FunRich database, users can download data from the UniProt database, which currently supports 20 different taxonomies against which enrichment analysis can be performed. Moreover, the users can build their own custom databases and perform the enrichment analysis irrespective of organism. In addition to proteomics datasets, the custom database allows for the tool to be used for genomics, lipidomics and metabolomics datasets. Thus, FunRich allows for complete database customization and thereby permits for the tool to be exploited as a skeleton for enrichment analysis irrespective of the data type or organism used. FunRich (http://www.funrich.org) is user-friendly and provides graphical representation (Venn, pie charts, bar graphs, column, heatmap and doughnuts) of the data with customizable font, scale and color (publication quality).

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Primary sclerosing cholangitis – a comprehensive review

Tom H. Karlsen, Trine Folseraas, Douglas Thorburn … (2017)

Primary sclerosing cholangitis (PSC) is a rare disorder characterised by multi-focal bile duct strictures and progressive liver disease. Inflammatory bowel disease is usually present and there is a high risk of cholangiocarcinoma and colorectal cancer. Most patients ultimately require liver transplantation, after which disease recurrence may occur. With limited therapeutic options and a lack of proven surveillance strategies, patients currently have significant unmet needs. In the present seminar, we provide a comprehensive review of the status of the field. We emphasise developments related to patient stratification and disease behaviour, and provide an overview of management options from a practical, patient-centered perspective. We survey advances made in the understanding of PSC pathogenesis and summarise the ongoing efforts to develop an effective therapy based on these insights.

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DD3: a new prostate-specific gene, highly overexpressed in prostate cancer.

M J Bussemakers, A. van Bokhoven, G. Verhaegh … (1999)

Prostate cancer is the most commonly diagnosed malignancy and the second leading cause of cancer-related deaths in the Western male population. Despite the tremendous efforts that have been made to improve the early detection of this disease and to design new treatment modalities, there is still an urgent need for new markers and therapeutic targets for the management of prostate cancer patients. Using differential display analysis to compare the mRNA expression patterns of normal versus tumor tissue of the human prostate, we identified a cDNA, DD3, which is highly overexpressed in 53 of 56 prostatic tumors in comparison to nonneoplastic prostatic tissue of the same patients. Reverse transcription-PCR analysis using DD3-specific primers indicated that the expression of DD3 is very prostate specific because no product could be amplified in 18 different normal human tissues studied. Also, in a sampling of other tumor types and a large number of cell lines, no expression of DD3 could be detected. Molecular characterization of the DD3 transcription unit revealed that alternative splicing and alternative polyadenylation occur. The fact that no extensive open reading frame could be found suggests that DD3 may function as a noncoding RNA. The DD3 gene was mapped to chromosome 9q21-22, and no homology of DD3 to any gene present in the computer databases was found. Our data indicate that DD3 is one of the most prostate cancer-specific genes yet described, and this makes DD3 a promising marker for the early diagnosis of prostate cancer and provides a powerful tool for the development of new treatment strategies for prostate cancer patients.

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Author and article information

Journal

Journal ID (nlm-ta): Cells

Journal ID (iso-abbrev): Cells

Journal ID (publisher-id): cells

Title: Cells

Publisher: MDPI

ISSN (Electronic): 2073-4409

Publication date (Electronic): 14 March 2020

Publication date Collection: March 2020

Volume: 9

Issue: 3

Electronic Location Identifier: 721

Affiliations

[1 ]Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ainhoa.lapitz@ 123456biodonostia.org (A.L.); aarbelaizcossio@ 123456gmail.com (A.A.); adelaida.lacastamunoa@ 123456osakidetza.eus (A.L.C.); alvaro.santos@ 123456biodonostia.org (A.S.-L.); laura.izquierdo@ 123456biodonostia.org (L.I.-S.); matxus.perugorria@ 123456biodonostia.org (M.J.P.); raul.jimenezaguero@ 123456osakidetza.eus (R.J.-A.); ioana.rianofernandez@ 123456osakidetza.eus (I.R.); luis.bujandafernandezdepierola@ 123456osakidetza.eus (L.B.)

[2 ]Department of Health and Medical Sciences, Biotech Research & Innovation Centre (BRIC), 2200 Copenhagen, Denmark; colm.rourke@ 123456bric.ku.dk (C.J.O.); jesper.andersen@ 123456bric.ku.dk (J.B.A.)

[3 ]CIC bioGUNE, Genome Analysis Platform, 48160 Derio, Spain; joluito@ 123456gmail.com (J.L.L.); amaransay@ 123456cicbiogune.es (A.M.A.)

[4 ]Hospital of Cruces, 48903 Bilbao, Spain; cesar.ibarraponcedeleon@ 123456osakidetza.eus (C.I.); albertosancam@ 123456gmail.com (A.S.-C.)

[5 ]“Complejo Hospitalario de Navarra”, 31008 Pamplona, Spain; jp.jimeno.garcia@ 123456navarra.es

[6 ]Carlos III National Institute of Health, Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), 28220 Madrid, Spain; jfalcon@ 123456cicbiogune.es

[7 ]Department of Medicine II, Saarland University Medical Centre, Saarland University, 66421 Homburg, Germany; Marcin.Krawczyk@ 123456uks.eu (M.K.); frank.lammert@ 123456uks.eu (F.L.)

[8 ]Department of General, Transplant and Liver Surgery, Laboratory of Metabolic Liver Diseases, Centre for Preclinical Research, 02-091 Warsaw, Poland

[9 ]Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Exosomes Laboratory, 48160 Derio, Spain; egonzalez@ 123456cicbiogune.es

[10 ]Department of Gastroenterology, “Università Politecnica delle Marche”, 60121 Ancona, Italy; m.marzioni@ 123456staff.univpm.it

[11 ]Experimental Hepatology and Drug Targeting (HEVEFARM), Biomedical Research Institute of Salamanca (IBSAL), 37007 Salamanca, Spain; rociorm@ 123456usal.es (R.I.R.M.); jjgmarin@ 123456usal.es (J.J.G.M.)

[12 ]Division of Cancer Medicine, Surgery and Transplantation, Norwegian PSC Research Center, Oslo University Hospital, 0372 Oslo, Spain; t.h.karlsen@ 123456medisin.uio.no

[13 ]IKERBASQUE, Basque Foundation for Science, 48013 Bilbao, Spain

Author notes

[* ]Correspondence: pedro.rodrigues@ 123456biodonostia.org (P.M.R.); jesus.banales@ 123456biodonostia.org (J.M.B.); Tel.: +34-9-4300-6125 (P.M.R.); +34-9-4300-6067 (J.M.B.)

Author information

Ainhoa Lapitz https://orcid.org/0000-0002-7928-5760

Jose L. Lavin https://orcid.org/0000-0003-0914-3211

Juan P. Jimeno https://orcid.org/0000-0003-2571-6593

Marcin Krawczyk https://orcid.org/0000-0002-0113-0777

Maria J. Perugorria https://orcid.org/0000-0002-7636-0972

Ioana Riaño https://orcid.org/0000-0001-8410-2706

Rocio I.R. Macias https://orcid.org/0000-0002-4748-0326

Jose J.G. Marin https://orcid.org/0000-0003-1186-6849

Juan M. Falcón-Pérez https://orcid.org/0000-0003-3133-0670

Jesper B. Andersen https://orcid.org/0000-0003-1760-5244

Ana M. Aransay https://orcid.org/0000-0002-8271-612X

Article

Publisher ID: cells-09-00721

DOI: 10.3390/cells9030721

PMC ID: 7140677

PubMed ID: 32183400

SO-VID: ae7787a9-2801-4b5e-a839-518328a2a435

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

History

Date received : 17 February 2020

Date accepted : 09 March 2020

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Patients with Cholangiocarcinoma Present Specific RNA Profiles in Serum and Urine Extracellular Vesicles Mirroring the Tumor Expression: Novel Liquid Biopsy Biomarkers for Disease Diagnosis

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Journal of Circulating Biomarkers

Most cited references 69

FunRich: An open access standalone functional enrichment and interaction network analysis tool.

Primary sclerosing cholangitis – a comprehensive review

DD3: a new prostate-specific gene, highly overexpressed in prostate cancer.

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