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Sequencing Small Non-coding RNA from Formalin-fixed Tissues and Serum-derived Exosomes from Castration-resistant Prostate Cancer Patients
Published on: November 19, 2019
Revealing metastatic castration-resistant prostate cancer master regulator through lncRNAs-centered regulatory
Rafaella Sousa Ferraz1, João Vitor Ferreira Cavalcante2, Leandro Magalhães1
1Laboratory of Human and Medical Genetics, Institute of Biological Sciences, Federal University of Para, Belem, Brazil.
Background:
Metastatic castration-resistant prostate cancer (mCRPC) is an aggressive form of cancer unresponsive to androgen deprivation therapy (ADT) that spreads quickly to other organs. Despite reduced androgen levels after ADT, mCRPC development and lethality continues to be conducted by the androgen receptor (AR) axis. The maintenance of AR signaling in mCRPC is a result of AR alterations, androgen intratumoral production, and the action of regulatory elements, such as noncoding RNAs (ncRNAs). ncRNAs are key elements in cancer signaling, acting in tumor growth, metabolic reprogramming, and tumor progression. In prostate cancer (PCa), the ncRNAs have been reported to be associated with AR expression, PCa proliferation, and castration resistance. In this study, we aimed to reconstruct the lncRNA-centered regulatory network of mCRPC and identify the lncRNAs which act as master regulators (MRs).
Methods:
We used publicly available RNA-sequencing to infer the regulatory network of lncRNAs in mCRPC. Five gene signatures were employed to conduct the master regulator analysis. Inferred MRs were then subjected to functional enrichment and symbolic regression modeling. The latter approach was applied to identify the lncRNAs with greater predictive capacity and potential as a biomarker in mCRPC.
Results:
We identified 31 lncRNAs involved in cellular proliferation, tumor metabolism, and invasion-metastasis cascade. SNHG18 and HELLPAR were the highlights of our results. SNHG18 was downregulated in mCRPC and enriched to metastasis signatures. It accurately distinguished both mCRPC and primary CRPC from normal tissue and was associated with epithelial-mesenchymal transition (EMT) and cell-matrix adhesion pathways. HELLPAR consistently distinguished mCRPC from primary CRPC and normal tissue using only its expression.
Conclusion:
Our results contribute to understanding the regulatory behavior of lncRNAs in mCRPC and indicate SNHG18 and HELLPAR as master regulators and potential new diagnostic targets in this tumor.
Insights
This study identifies key noncoding RNAs (ncRNAs) that regulate metastatic castration-resistant prostate cancer (mCRPC). SNHG18 and HELLPAR show potential as diagnostic biomarkers for mCRPC, offering new therapeutic targets.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Metastatic castration-resistant prostate cancer (mCRPC) is an aggressive malignancy driven by the androgen receptor (AR) axis, even after androgen deprivation therapy (ADT).
- Noncoding RNAs (ncRNAs) play critical roles in cancer progression, including prostate cancer (PCa), by influencing AR signaling, proliferation, and castration resistance.
Purpose of the Study:
- To reconstruct the long noncoding RNA (lncRNA)-centered regulatory network in mCRPC.
- To identify lncRNAs acting as master regulators (MRs) in mCRPC development and progression.
Main Methods:
- Utilized publicly available RNA-sequencing data to infer the lncRNA regulatory network in mCRPC.
- Applied master regulator analysis using five gene signatures, followed by functional enrichment and symbolic regression modeling.
- Evaluated lncRNAs for predictive capacity and potential as biomarkers in mCRPC.
Main Results:
- Identified 31 lncRNAs implicated in cellular proliferation, tumor metabolism, and the invasion-metastasis cascade.
- Highlighted SNHG18 and HELLPAR as significant findings; SNHG18 was downregulated in mCRPC and linked to metastasis and epithelial-mesenchymal transition (EMT).
- SNHG18 and HELLPAR demonstrated strong potential in distinguishing mCRPC and primary castration-resistant prostate cancer (CRPC) from normal tissues.
Conclusions:
- The study enhances understanding of lncRNA regulatory mechanisms in mCRPC.
- SNHG18 and HELLPAR are identified as master regulators and promising novel diagnostic targets for mCRPC.
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