University of Oulu

Naakka E, Barros-Filho MC, Adnan-Awad S, Al-Samadi A, Marchi FA, Kuasne H, Korelin K, Suleymanova I, Brown AL, Scapulatempo-Neto C, Lourenço SV, Castilho RM, Kowalski LP, Mäkitie A, Araújo VC, Leivo I, Rogatto SR, Salo T and Passador-Santos F (2022) miR-22 and miR-205 Drive Tumor Aggressiveness of Mucoepidermoid Carcinomas of Salivary Glands. Front. Oncol. 11:786150. doi: 10.3389/fonc.2021.786150

miR-22 and miR-205 drive tumor aggressiveness of mucoepidermoid carcinomas of salivary glands

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Author: Naakka, Erika1,2; Barros-Filho, Mateus Camargo3; Adnan-Awad, Shady2,4;
Organizations: 1Department of Oral and Maxillofacial Diseases, University of Helsinki, Helsinki, Finland
2Translational Immunology Research Program (TRIMM), University of Helsinki, Helsinki, Finland
3Centro Internacional de Pesquisa (CIPE) – A.C.Camargo Cancer Center, São Paulo, Brazil
4Hematology Research Unit, Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
5Department of Oral Pathology, Faculdade São Leopoldo Mandic, Campinas, Brazil
6Molecular Oncology Research Center, Barretos, and Diagnósticos da América (DASA), Barueri, Brazil
7Department of Pathology, A.C.Camargo Cancer Center, São Paulo, Brazil
8Department of General Pathology, Dental School, University of São Paulo, São Paulo, Brazil
9Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, United States
10Department of Head and Neck Surgery and Otorhinolaryngology, A.C.Camargo Cancer Center, São Paulo, Brazil
11Department of Head and Neck Surgery, University of Sao Paulo Medical School, São Paulo, Brazil
12Department of Otorhinolaryngology – Head and Neck Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
13Research Program in Systems Oncology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
14Division of Ear, Nose and Throat Diseases, Department of Clinical Sciences, Intervention and Technology, Karolinska Institute and Karolinska Hospital, Stockholm, Sweden
15Institute of Biomedicine, Pathology, University of Turku and Turku University Hospital, Turku, Finland
16Department of Clinical Genetics, University Hospital of Southern Denmark, Vejle, Denmark
17Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark
18Department of Pathology, Helsinki University Hospital, Helsinki, Finland
19Cancer and Translational Medicine Research Unit, University of Oulu, Oulu, Finland
20Medical Research Center, Oulu University Hospital, Oulu, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 2.5 MB)
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Language: English
Published: Frontiers Media, 2022
Publish Date: 2022-05-20


Objectives: To integrate mRNA and miRNA expression profiles of mucoepidermoid carcinomas (MECs) and normal salivary gland (NSGs) tissue samples and identify potential drivers.

Material and Methods: Gene and miRNA expression arrays were performed in 35 MECs and six NSGs.

Results: We found 46 differentially expressed (DE) miRNAs and 3,162 DE mRNAs. Supervised hierarchical clustering analysis of the DE transcripts revealed two clusters in both miRNA and mRNA profiles, which distinguished MEC from NSG samples. The integrative miRNA-mRNA analysis revealed a network comprising 696 negatively correlated interactions (44 miRNAs and 444 mRNAs) involving cell signaling, cell cycle, and cancer-related pathways. Increased expression levels of miR-205-5p and miR-224-5p and decreased expression levels of miR-139-3p, miR-145-3p, miR-148a-3p, miR-186-5p, miR-338-3p, miR-363-3p, and miR-4324 were significantly related to worse overall survival in MEC patients. Two overexpressed miRNAs in MEC (miR-22 and miR-205) were selected for inhibition by the CRISPR-Cas9 method. Cell viability, migration, and invasion assays were performed using an intermediate grade MEC cell line. Knockout of miR-205 reduced cell viability and enhanced ZEB2 expression, while miR-22 knockout reduced cell migration and invasion and enhanced ESR1 expression. Our results indicate a distinct transcriptomic profile of MEC compared to NSG, and the integrative analysis highlighted miRNA-mRNA interactions involving cancer-related pathways, including PTEN and PI3K/AKT.

Conclusion: The in vitro functional studies revealed that miR-22 and miR-205 deficiencies reduced the viability, migration, and invasion of the MEC cells suggesting they are potential oncogenic drivers in MEC.

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Series: Frontiers in oncology
ISSN: 2234-943X
ISSN-E: 2234-943X
ISSN-L: 2234-943X
Volume: 11
Article number: 786150
DOI: 10.3389/fonc.2021.786150
Type of Publication: A1 Journal article – refereed
Field of Science: 3122 Cancers
Funding: This work was supported by grants from Fundação de Amparo à Pesquisa do Estado de São Paulo - FAPESP (2012/10382-5) and (2013/04045-9), and Doctoral Programme in Clinical Research (KLTO), Faculty of Medicine, University of Helsinki, Finland; Sigrid Jusélius Foundation; the Cancer Society of Finland, Jane and Aatos Erkko Foundation, and Helsinki University Central Hospital research funds. SR acknowledges support from Research Council Lillebaelt Hospital, Denmark.
Copyright information: © 2022 Naakka, Barros-Filho, Adnan-Awad, Al-Samadi, Marchi, Kuasne, Korelin, Suleymanova, Brown, Scapulatempo-Neto, Lourenço, Castilho, Kowalski, Mäkitie, Araújo, Leivo, Rogatto, Salo and Passador-Santos. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.