Potential molecular mechanism in self-renewal is associated with miRNA dysregulation in sacral chordoma - A next-generation RNA sequencing study

Arpad Bozsodi; Beata Scholtz; Gergo Papp; Zoltan Sapi; Adam Biczo; Peter Pal Varga; Aron Lazary

doi:10.1016/j.heliyon.2022.e10227

Potential molecular mechanism in self-renewal is associated with miRNA dysregulation in sacral chordoma - A next-generation RNA sequencing study

Heliyon. 2022 Aug 13;8(8):e10227. doi: 10.1016/j.heliyon.2022.e10227. eCollection 2022 Aug.

Authors

Arpad Bozsodi^{1

2}, Beata Scholtz³, Gergo Papp⁴, Zoltan Sapi⁴, Adam Biczo¹, Peter Pal Varga¹, Aron Lazary^{1

5}

Affiliations

¹ National Center for Spinal Disorders, Buda Health Center, Királyhágó u. 1-3, Budapest, H-1126, Hungary.
² School of PhD Studies, Semmelweis University, Üllői út 26, Budapest, H-1085, Hungary.
³ Genomic Medicine and Bioinformatic Core Facility, Dept. of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, Debrecen, H-4032, Hungary.
⁴ 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26, Budapest, H-1085, Hungary.
⁵ Department of Spine Surgery, Department of Orthopaedics, Semmelweis University, Királyhágó u. 1-3, Budapest, H-1126, Hungary.

Abstract

Background: Chordoma, the most frequent malignant primary spinal neoplasm, characterized by a high rate of recurrence, is an orphan disease where the clarification of the molecular oncogenesis would be crucial to developing new, effective therapies. Dysregulated expression of non-coding RNAs, especially microRNAs (miRNA) has a significant role in cancer development.

Methods: Next-generation RNA sequencing (NGS) was used for the combinatorial analysis of mRNA-miRNA gene expression profiles in sacral chordoma and nucleus pulposus samples. Advanced bioinformatics workflow was applied to the data to predict miRNA-mRNA regulatory networks with altered activity in chordoma.

Results: A large set of significantly dysregulated miRNAs in chordoma and their differentially expressed target genes have been identified. Several molecular pathways related to tumorigenesis and the modulation of the immune system are predicted to be dysregulated due to aberrant miRNA expression in chordoma. We identified a gene set including key regulators of the Hippo pathway, which is targeted by differently expressed miRNAs, and validated their altered expression by RT-qPCR. These newly identified miRNA/RNA interactions are predicted to have a role in the self-renewal process of chordoma stem cells, which might sustain the high rate of recurrence for this tumor.

Conclusions: Our results can significantly contribute to the designation of possible targets for the development of anti-chordoma therapies.

Keywords: Chordoma; Next-generation sequencing; Transcriptome profile; mRNA; miRNA.