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3D Cell Culture-Based Global miRNA Expression Analysis Reveals miR-142-5p as a Theranostic Biomarker of Rectal Cancer Following Neoadjuvant Long-Course Treatment

1
National Cancer Institute, LT-08660 Vilnius, Lithuania
2
Life Sciences Center, Institute of Biosciences, Vilnius University, LT-08412 Vilnius, Lithuania
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Life Sciences Center, Institute of Biotechnology, Vilnius University, LT-08412 Vilnius, Lithuania
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Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, LT-08406 Vilnius, Lithuania
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University of Applied Sciences, Faculty of Health Care, LT-08303 Vilnius, Lithuania
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Thermo Fisher Scientific, LT-02241 Vilnius, Lithuania
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Institute of Informatics, Faculty of Mathematics and Informatics, Vilnius University, LT-08303 Vilnius, Lithuania
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OncoRay—National Center for Radiation Research in Oncology, Faculty of Medicine, Technische Universität, D–01307 Dresden, Germany
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Department of Radiation Oncology, University Hospital Carl Gustav Carus, Technische Universität, D–01307 Dresden, Germany
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Helmholtz–Zentrum Dresden–Rossendorf, Institute of Radiooncology–OncoRay, D–01328 Dresden, Germany
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German Cancer Consortium (DKTK), partner site Dresden, D–69192 Heidelberg, Germany
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German Cancer Research Center (DKFZ), D–69192 Heidelberg, Germany
*
Authors to whom correspondence should be addressed.
These authors contributed equally to the work.
Biomolecules 2020, 10(4), 613; https://doi.org/10.3390/biom10040613
Received: 11 March 2020 / Revised: 5 April 2020 / Accepted: 13 April 2020 / Published: 16 April 2020
(This article belongs to the Section Molecular Medicine)
Altered expression of miRNAs in tumor tissue encourages the translation of this specific molecular pattern into clinical practice. However, the establishment of a selective biomarker signature for many tumor types remains an inextricable challenge. For this purpose, a preclinical experimental design, which could maintain a fast and sensitive discovery of potential biomarkers, is in demand. The present study suggests that the approach of 3D cell cultures as a preclinical cancer model that is characterized to mimic a natural tumor environment maintained in solid tumors could successfully be employed for the biomarker discovery and validation. Subsequently, in this study, we investigated an environment-dependent miRNA expression changes in colorectal adenocarcinoma DLD1 and HT29 cell lines using next-generation sequencing (NGS) technology. We detected a subset of 16 miRNAs differentially expressed in both cell lines cultivated in multicellular spheroids compared to expression levels in cells grown in 2D. Furthermore, results of in silico miRNA target analysis showed that miRNAs, which were differentially expressed in both cell lines grown in MCS, are involved in the regulation of molecular mechanisms implicated in cell adhesion, cell-ECM interaction, and gap junction pathways. In addition, integrins and platelet-derived growth factor receptors were determined to be the most significant target genes of deregulated miRNAs, which was concordant with the environment-dependent gene expression changes validated by RT-qPCR. Our results revealed that 3D microenvironment-dependent deregulation of miRNA expression in CRC cells potentially triggers essential molecular mechanisms predominantly including the regulation of cell adhesion, cell–cell, and cell–ECM interactions important in CRC initiation and development. Finally, we demonstrated increased levels of selected miR-142-5p in rectum tumor tissue samples after neoadjuvant long course treatment compared to miR-142-5p expression levels in tumor biopsy samples collected before the therapy. Remarkably, the elevation of miR-142-5p expression remained in tumor samples compared to adjacent normal rectum tissue as well. Therefore, the current study provides valuable insights into the molecular miRNA machinery of CRC and proposes a potential miRNA signature for the assessment of CRC in further clinical research. View Full-Text
Keywords: colorectal carcinoma; rectal cancer; 3D cell culture; miRNA; tumor microenvironment; cell adhesion; cancer biomarkers; neoadjuvant therapy; miR-142 colorectal carcinoma; rectal cancer; 3D cell culture; miRNA; tumor microenvironment; cell adhesion; cancer biomarkers; neoadjuvant therapy; miR-142
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MDPI and ACS Style

Kunigenas, L.; Stankevicius, V.; Dulskas, A.; Budginaite, E.; Alzbutas, G.; Stratilatovas, E.; Cordes, N.; Suziedelis, K. 3D Cell Culture-Based Global miRNA Expression Analysis Reveals miR-142-5p as a Theranostic Biomarker of Rectal Cancer Following Neoadjuvant Long-Course Treatment. Biomolecules 2020, 10, 613. https://doi.org/10.3390/biom10040613

AMA Style

Kunigenas L, Stankevicius V, Dulskas A, Budginaite E, Alzbutas G, Stratilatovas E, Cordes N, Suziedelis K. 3D Cell Culture-Based Global miRNA Expression Analysis Reveals miR-142-5p as a Theranostic Biomarker of Rectal Cancer Following Neoadjuvant Long-Course Treatment. Biomolecules. 2020; 10(4):613. https://doi.org/10.3390/biom10040613

Chicago/Turabian Style

Kunigenas, Linas; Stankevicius, Vaidotas; Dulskas, Audrius; Budginaite, Elzbieta; Alzbutas, Gediminas; Stratilatovas, Eugenijus; Cordes, Nils; Suziedelis, Kestutis. 2020. "3D Cell Culture-Based Global miRNA Expression Analysis Reveals miR-142-5p as a Theranostic Biomarker of Rectal Cancer Following Neoadjuvant Long-Course Treatment" Biomolecules 10, no. 4: 613. https://doi.org/10.3390/biom10040613

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