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The Transcriptome Complexity in Cancer and Leukemia: Alternative Splicing and Beyond

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: 20 February 2025 | Viewed by 10218

Special Issue Editor

Dr. Christos K. Kontos

E-Mail Website
Guest Editor
Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
Interests: colorectal cancer; leukemia; tumor biomarkers; anticancer drugs; apoptosis; BCL2 family; alternative splicing; kallikrein-related peptidases (KLKs); nanopore sequencing; next-generation sequencing (NGS)
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The complexity and diversity of the human transcriptome have been in the center of transcriptomics for more than two decades. Alternative splicing is a key biological process in human cells, as primary transcripts from more than 95% of human multi-exon genes are subjected to alternative splicing, during their post-transcriptional maturation. Due to its key role, its deregulation has been characterized as one of the hallmarks of cancer and hematological malignancies, while its targeting is considered as a promising therapeutic strategy.

This Special Issue focuses on the information of the readers regarding the contribution of alternative splicing of primary RNA molecules to transcriptome diversity and complexity, particularly in human cancer and leukemia. The authors are encouraged to submit their original research studies concerning this topic. Review articles will also be taken into consideration. The Guest Editor is willing to evaluate also manuscripts describing other aspects of transcriptomics, proposed by the authors.

Dr. Christos K. Kontos
Guest Editor

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Keywords

  • messenger RNA (mRNA)
  • long non-coding RNA (lncRNA)
  • circular RNA (circRNA)
  • transcriptional regulation
  • transcriptomics
  • solid tumors
  • hematological malignancies
  • biomarkers
  • therapeutic targets
  • therapy resistance

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Published Papers (5 papers)

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Research

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12 pages, 997 KiB  
Article
28S rRNA-Derived Fragments Represent an Independent Molecular Predictor of Short-Term Relapse in Prostate Cancer
by Marios A. Diamantopoulos, Konstantina K. Georgoulia, Panagiotis Levis, Georgios Kotronopoulos, Konstantinos Stravodimos, Christos K. Kontos, Margaritis Avgeris and Andreas Scorilas
Int. J. Mol. Sci. 2024, 25(1), 239; https://doi.org/10.3390/ijms25010239 - 23 Dec 2023
Cited by 1 | Viewed by 1282
Abstract
Prostate cancer (PCa) is a global health concern, being a leading cause of cancer-related mortality among males. Early detection and accurate prognosis are crucial for effective management. This study delves into the diagnostic and prognostic potential of 28S rRNA-derived fragments (rRFs) in PCa. [...] Read more.
Prostate cancer (PCa) is a global health concern, being a leading cause of cancer-related mortality among males. Early detection and accurate prognosis are crucial for effective management. This study delves into the diagnostic and prognostic potential of 28S rRNA-derived fragments (rRFs) in PCa. Total RNA extracted from 89 PCa and 53 benign prostate hyperplasia (BPH) tissue specimens. After 3’-end polyadenylation, we performed reverse transcription to create first-strand cDNA. Using an in-house quantitative real-time PCR (qPCR) assay, we quantified 28S rRF levels. Post-treatment biochemical relapse served as the clinical endpoint event for survival analysis, which we validated internally through bootstrap analysis. Our results revealed downregulated 28S rRF levels in PCa compared to BPH patients. Additionally, we observed a significant positive correlation between 28S rRF levels and higher Gleason scores and tumor stages. Furthermore, PCa patients with elevated 28S rRF expression had a significantly higher risk of post-treatment disease relapse independently of clinicopathological data. In conclusion, our study demonstrates, for the first time, the prognostic value of 28S rRF in prostate adenocarcinoma. Elevated 28S rRF levels independently predict short-term PCa relapse and enhance risk stratification. This establishes 28S rRF as a potential novel molecular marker for PCa prognosis. Full article
(This article belongs to the Special Issue The Transcriptome Complexity in Cancer and Leukemia: Alternative Splicing and Beyond)
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13 pages, 2083 KiB  
Article
Quantitative Analysis of Isoform Switching in Cancer
by Georgii Dolgalev and Ekaterina Poverennaya
Int. J. Mol. Sci. 2023, 24(12), 10065; https://doi.org/10.3390/ijms241210065 - 13 Jun 2023
Cited by 2 | Viewed by 1604
Abstract
Over the past 8 years, multiple studies examined the phenomenon of isoform switching in human cancers and discovered that isoform switching is widespread, with hundreds to thousands of such events per cancer type. Although all of these studies used slightly different definitions of [...] Read more.
Over the past 8 years, multiple studies examined the phenomenon of isoform switching in human cancers and discovered that isoform switching is widespread, with hundreds to thousands of such events per cancer type. Although all of these studies used slightly different definitions of isoform switching, which in part led to a rather poor overlap of their results, they all leveraged transcript usage, a proportion of the transcript’s expression in the total expression level of the parent gene, to detect isoform switching. However, how changes in transcript usage correlate with changes in transcript expression is not sufficiently explored. In this article, we adopt the most common definition of isoform switching and use a state-of-the-art tool for the analysis of differential transcript usage, SatuRn, to detect isoform switching events in 12 cancer types. We analyze the detected events in terms of changes in transcript usage and the relationship between transcript usage and transcript expression on a global scale. The results of our analysis suggest that the relationship between changes in transcript usage and changes in transcript expression is far from straightforward, and that such quantitative information can be effectively used for prioritizing isoform switching events for downstream analyses. Full article
(This article belongs to the Special Issue The Transcriptome Complexity in Cancer and Leukemia: Alternative Splicing and Beyond)
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14 pages, 2097 KiB  
Article
MicroRNA-675-5p Overexpression Is an Independent Prognostic Molecular Biomarker of Short-Term Relapse and Poor Overall Survival in Colorectal Cancer
by Spyridon Christodoulou, Christina D. Sotiropoulou, Panteleimon Vassiliu, Nikolaos Danias, Nikolaos Arkadopoulos and Diamantis C. Sideris
Int. J. Mol. Sci. 2023, 24(12), 9990; https://doi.org/10.3390/ijms24129990 - 10 Jun 2023
Cited by 1 | Viewed by 1354
Abstract
Colorectal cancer (CRC) is the main cause of cancer-related deaths globally, highlighting the importance of accurate biomarkers for early detection and accurate prognosis. MicroRNAs (miRNAs) have emerged as effective cancer biomarkers. The aim of this study was to investigate the prognostic potential of [...] Read more.
Colorectal cancer (CRC) is the main cause of cancer-related deaths globally, highlighting the importance of accurate biomarkers for early detection and accurate prognosis. MicroRNAs (miRNAs) have emerged as effective cancer biomarkers. The aim of this study was to investigate the prognostic potential of miR-675-5p as a molecular prognostic biomarker in CRC. For this reason, a quantitative PCR assay was developed and applied to determine miR-675-5p expression in cDNAs from 218 primary CRC and 90 paired normal colorectal tissue samples. To assess the significance of miR-675-5p expression and its association with patient outcome, extensive biostatistical analysis was performed. miR-675-5p expression was found to be significantly downregulated in CRC tissue samples compared to that in adjacent normal colorectal tissues. Moreover, high miR-675-5p expression was associated with shorter disease-free (DFS) and overall survival (OS) in CRC patients, while it maintained its unfavorable prognostic value independently of other established prognostic factors. Furthermore, TNM stage stratification demonstrated that higher miR-675-5p levels were associated with shorter DFS and OS intervals, particularly in patients with CRC of TNM stage II or III. In conclusion, our findings suggest that miR-675-5p overexpression constitutes a promising molecular biomarker of unfavorable prognosis in CRC, independent of other established prognostic factors, including TNM staging. Full article
(This article belongs to the Special Issue The Transcriptome Complexity in Cancer and Leukemia: Alternative Splicing and Beyond)
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16 pages, 2670 KiB  
Article
Impact of IDH Mutations, the 1p/19q Co-Deletion and the G-CIMP Status on Alternative Splicing in Diffuse Gliomas
by Lu Zhang, Sabrina Fritah, Petr V. Nazarov, Tony Kaoma and Eric Van Dyck
Int. J. Mol. Sci. 2023, 24(12), 9825; https://doi.org/10.3390/ijms24129825 - 6 Jun 2023
Viewed by 1920
Abstract
By generating protein diversity, alternative splicing provides an important oncogenic pathway. Isocitrate dehydrogenase (IDH) 1 and 2 mutations and 1p/19q co-deletion have become crucial for the novel molecular classification of diffuse gliomas, which also incorporates DNA methylation profiling. In this study, [...] Read more.
By generating protein diversity, alternative splicing provides an important oncogenic pathway. Isocitrate dehydrogenase (IDH) 1 and 2 mutations and 1p/19q co-deletion have become crucial for the novel molecular classification of diffuse gliomas, which also incorporates DNA methylation profiling. In this study, we have carried out a bioinformatics analysis to examine the impact of the IDH mutation, as well as the 1p/19q co-deletion and the glioma CpG island methylator phenotype (G-CIMP) status on alternative splicing in a cohort of 662 diffuse gliomas from The Cancer Genome Atlas (TCGA). We identify the biological processes and molecular functions affected by alternative splicing in the various glioma subgroups and provide evidence supporting the important contribution of alternative splicing in modulating epigenetic regulation in diffuse gliomas. Targeting the genes and pathways affected by alternative splicing might provide novel therapeutic opportunities against gliomas. Full article
(This article belongs to the Special Issue The Transcriptome Complexity in Cancer and Leukemia: Alternative Splicing and Beyond)
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Review

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34 pages, 2561 KiB  
Review
Harnessing the Transcriptional Signatures of CAR-T-Cells and Leukemia/Lymphoma Using Single-Cell Sequencing Technologies
by Yu-Mei Liao, Shih-Hsien Hsu and Shyh-Shin Chiou
Int. J. Mol. Sci. 2024, 25(4), 2416; https://doi.org/10.3390/ijms25042416 - 19 Feb 2024
Cited by 1 | Viewed by 3277
Abstract
Chimeric antigen receptor (CAR)-T-cell therapy has greatly improved outcomes for patients with relapsed or refractory hematological malignancies. However, challenges such as treatment resistance, relapse, and severe toxicity still hinder its widespread clinical application. Traditional transcriptome analysis has provided limited insights into the complex [...] Read more.
Chimeric antigen receptor (CAR)-T-cell therapy has greatly improved outcomes for patients with relapsed or refractory hematological malignancies. However, challenges such as treatment resistance, relapse, and severe toxicity still hinder its widespread clinical application. Traditional transcriptome analysis has provided limited insights into the complex transcriptional landscape of both leukemia cells and engineered CAR-T-cells, as well as their interactions within the tumor microenvironment. However, with the advent of single-cell sequencing techniques, a paradigm shift has occurred, providing robust tools to unravel the complexities of these factors. These techniques enable an unbiased analysis of cellular heterogeneity and molecular patterns. These insights are invaluable for precise receptor design, guiding gene-based T-cell modification, and optimizing manufacturing conditions. Consequently, this review utilizes modern single-cell sequencing techniques to clarify the transcriptional intricacies of leukemia cells and CAR-Ts. The aim of this manuscript is to discuss the potential mechanisms that contribute to the clinical failures of CAR-T immunotherapy. We examine the biological characteristics of CAR-Ts, the mechanisms that govern clinical responses, and the intricacies of adverse events. By exploring these aspects, we hope to gain a deeper understanding of CAR-T therapy, which will ultimately lead to improved clinical outcomes and broader therapeutic applications. Full article
(This article belongs to the Special Issue The Transcriptome Complexity in Cancer and Leukemia: Alternative Splicing and Beyond)
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