Clinical implications of non-coding RNAs in cancer
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2024
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Abstract
AbstractNon-coding RNAs (ncRNAs), play critical roles in regulating cellular processes, but their involvement in cancer, particularly breast cancer, remains underexplored. This thesis is divided into three chapters. In the first chapter, we provide a comprehensive background on breast cancer, ncRNAs and the emerging significance of ncRNAs in breast cancer pathology. In Chapters two and three, we investigate the clinical implications of two specific ncRNAs—ZNF582-AS1, a lncRNA, and mt-tRF-Tyr-GTA-001, a mitochondrial tRNA-derived fragment (mt-tRF)—in breast cancer progression and patient outcomes.
In chapter two, we analyzed The Cancer Genome Atlas (TCGA) dataset to identify lncRNAs associated with breast cancer survival. ZNF582-AS1 expression was found to be significantly lower in breast tumors compared to adjacent normal tissues. Patients with low ZNF582-AS1 expression were more likely to have high-grade or ER-negative tumors and had poorer disease-free survival (DFS) and overall survival (OS). A validation study using fresh tumor samples from 361 breast cancer patients confirmed these findings. Meta-analysis of multiple datasets supported that high ZNF582-AS1 expression was associated with lower risks of relapse and death, independent of tumor grade, disease stage, patient age, and hormone receptor status. Promoter methylation was identified as a possible mechanism suppressing ZNF582-AS1 expression. Bioinformatic analyses suggested that ZNF582-AS1 could inhibit tumor growth by downregulating the HER2-mediated signaling pathway. Moreover, online data indicated that HIF-1-related transcription factors may suppress ZNF582-AS1 expression, and the lncRNA might bind to hsa-miR-940, a known oncogenic miRNA in breast cancer.
In chapter three, we focused on mitochondrial tRNA-derived fragments and their role in breast cancer. Analysis of TCGA small RNA-seq data revealed that mt-tRF-Tyr-GTA-001, a fragment derived from mitochondrial tRNA with tyrosine anticodon GTA, was significantly downregulated in breast tumors compared to normal tissues. Patients with low mt-tRF-Tyr-GTA-001 expression had a higher risk of death, independent of clinical variables. This association was validated in our independent cohort using qRT-PCR. The expression of mt-tRF-Tyr-GTA-001 was positively correlated with ribonucleases ANG and RNase 4, enzymes responsible for tRF generation. Functional analyses suggested that mt-tRF-Tyr-GTA-001 could suppress cell transformation, tumor growth, and invasion. In silico predictions identified potential binding targets involved in cell cycle regulation, including transcription factors E2Fs, CCNE1, and FOXM1. Additionally, mt-tRF-Tyr-GTA-001 was correlated with immune cell populations such as M0 macrophages and resting mast cells, highlighting its potential role in innate immunity.
In conclusion, our study demonstrates that ncRNAs, particularly ZNF582-AS1 and mt-tRF-Tyr-GTA-001, may play pivotal roles in suppressing breast cancer progression. Understanding their molecular functions and regulatory mechanisms could provide novel insights into breast cancer prognosis and potential therapeutic strategies.
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Molecular biology, breast cancer, lncRNA, mitochondrial tRNA-derived fragment, ncRNA, tRNA-derived fragment, ZNF582-AS1
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149 pages
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