Detection of Differentially Expressed Long Non-Coding RNAs and Protein-Coding Genes in Metastatic Castration-Resistant Prostate Cancer : Special emphasis on their value as biomarkers
Sattari, Mina (2025)
Tampere University
2025
Lääketieteen, biotieteiden ja biolääketieteen tekniikan tohtoriohjelma - Doctoral Programme in Medicine, Biosciences and Biomedical Engineering
Lääketieteen ja terveysteknologian tiedekunta - Faculty of Medicine and Health Technology
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Väitöspäivä
2025-09-12
Julkaisun pysyvä osoite on
https://urn.fi/URN:ISBN:978-952-03-4037-7
https://urn.fi/URN:ISBN:978-952-03-4037-7
Tiivistelmä
Prostate cancer (PCa) is one of the most commonly diagnosed cancers in men and a leading cause of cancer-related death worldwide. While many cases remain localized and manageable, a subset progresses to metastatic castration-resistant prostate cancer (mCRPC), a more aggressive form of the disease characterized by poor prognosis and limited treatment options. Although therapies targeting the androgen receptor (AR) pathway have improved outcomes, resistance, both inherent and acquired, remains a major clinical challenge. Understanding the molecular mechanisms underlying PCa progression and therapy resistance is critical for identifying prognostic biomarkers and new therapeutic targets.
This doctoral research aimed to characterize the transcriptional and regulatory landscape of PCa by investigating long non-coding RNAs (lncRNAs) and protein- coding genes (PCGs) involved in disease progression, metastasis, and resistance to therapy. Integrative analyses were performed using patient-derived primary and metastatic tumor samples, in vitro models, and xenografts. High-throughput methods, including RNA sequencing, ATAC-seq, ChIP-seq, and functional assays, were applied alongside gene editing techniques to explore the regulation and impact of these genes at the genomic, transcriptomic, and epigenomic levels.
In the first study, a group of lncRNAs termed Tampere PCa associated transcripts (TPCATs) was identified as being regulated by AR and ERG, two key transcription factors in PCa. Among them, EPCART was functionally validated to promote cell migration and proliferation. Its expression correlated with disease recurrence, suggesting its potential as both a prognostic biomarker and therapeutic target.
The second study focused on lncRNAs associated with metastasis in mCRPC. By analyzing matched primary tumors and metastases, 27 lncRNAs were identified as differentially expressed. These lncRNAs were found to be regulated by AR, FOXA1, and HOXB13, and several showed strong associations with clinical outcomes. Notably, lnc-SCFD2-2 and lnc-R3HCC1L-8 were identified as independent prognostic indicators for disease progression.
The third study investigated PCGs associated with metastatic disease, identifying 85 differentially expressed genes between primary tumors and metastases. Many of these genes were shown to be regulated by AR and its co-factors. TMEM18 was found to be androgen-regulated and also showed a strong association with poor prognosis at both mRNA and protein levels.
Together, these studies revealed a shared transcriptional regulatory network involving AR, ERG, FOXA1, and HOXB13 that coordinates the expression of both lncRNAs and PCGs associated with PCa metastasis. This network shapes the molecular features of aggressive and treatment-resistant disease, offering insights into new potential biomarkers and therapeutic strategies.
This doctoral research aimed to characterize the transcriptional and regulatory landscape of PCa by investigating long non-coding RNAs (lncRNAs) and protein- coding genes (PCGs) involved in disease progression, metastasis, and resistance to therapy. Integrative analyses were performed using patient-derived primary and metastatic tumor samples, in vitro models, and xenografts. High-throughput methods, including RNA sequencing, ATAC-seq, ChIP-seq, and functional assays, were applied alongside gene editing techniques to explore the regulation and impact of these genes at the genomic, transcriptomic, and epigenomic levels.
In the first study, a group of lncRNAs termed Tampere PCa associated transcripts (TPCATs) was identified as being regulated by AR and ERG, two key transcription factors in PCa. Among them, EPCART was functionally validated to promote cell migration and proliferation. Its expression correlated with disease recurrence, suggesting its potential as both a prognostic biomarker and therapeutic target.
The second study focused on lncRNAs associated with metastasis in mCRPC. By analyzing matched primary tumors and metastases, 27 lncRNAs were identified as differentially expressed. These lncRNAs were found to be regulated by AR, FOXA1, and HOXB13, and several showed strong associations with clinical outcomes. Notably, lnc-SCFD2-2 and lnc-R3HCC1L-8 were identified as independent prognostic indicators for disease progression.
The third study investigated PCGs associated with metastatic disease, identifying 85 differentially expressed genes between primary tumors and metastases. Many of these genes were shown to be regulated by AR and its co-factors. TMEM18 was found to be androgen-regulated and also showed a strong association with poor prognosis at both mRNA and protein levels.
Together, these studies revealed a shared transcriptional regulatory network involving AR, ERG, FOXA1, and HOXB13 that coordinates the expression of both lncRNAs and PCGs associated with PCa metastasis. This network shapes the molecular features of aggressive and treatment-resistant disease, offering insights into new potential biomarkers and therapeutic strategies.
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