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

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

Arpad Bozsodi  1   2 , Beata Scholtz  3 , Gergo Papp  4 , Zoltan Sapi  4 , Adam Biczo  1 , Peter Pal Varga  1 , Aron Lazary  1   5
Affiliations

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

Arpad Bozsodi et al. Heliyon. .

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.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Differentially expressed miRNAs in chordoma tumors (CH) and nucleus pulposus (NP) cell lines. a) Heatmap of the 126 differentially expressed (DE) miRNAs in chordoma. Normalized expression values from Chimira/EdgeR analysis were scaled and log2 transformed. The color scale of the heatmap illustrates the relative expression levels of the DE miRNAs. Numerical representation and DE miRNA names are in Supplementary Table 4. b) Principal component analysis of the samples based on Chimira/DESeq2 analysis.
Figure 2
Figure 2
Top dysregulated miRNAs in chordoma. Relative expression (log2FoldChange) and direction of the dysregulation are represented (red: upregulated, green: downregulated miRNAs).
Figure 3
Figure 3
Results of functional classification analysis (a) and pathway analysis (b) of the predicted targets of upregulated and downregulated miRNAs in chordoma. (a) The protein function GO categories identified by Panther DB functional analysis (GO-Slim Molecular function) are shown. (b) Overrepresented pathways were identified with the ConsensusPath DB algorithm. The x-axis shows the -log2(p-value) of the enrichment. Top panel: Enriched pathways for downregulated genes predicted to be targeted by upregulated miRNAs. Bottom panel: Enriched pathways for upregulated genes predicted to be targeted by downregulated miRNAs.
Figure 4
Figure 4
Predicted miRNA-mRNA regulatory network of self-renewal in chordoma. Bold arrows indicate the direction of RNA expression dysregulation: red = upregulated, black = downregulated. Upregulated miRNAs validated by RT-qPCR are in bold.
Figure 5
Figure 5
RT-qPCR validation of miRNA expression in chordoma (CH) and nucleus pulposus (NP) samples. Normalized expression was calculated with the 2−dCt method, with RNU44 as the reference gene. All differences were statistically significant (Mann-Whitney test, p ≤ 0.001).
Figure 6
Figure 6
RT-qPCR validation of mRNA expression in chordoma (CH) and nucleus pulposus (NP) samples. Normalized expression was calculated with the 2−dCt method, with PPIA as the reference gene (p-values are from Mann-Whitney tests).
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