Crucial miRNA–mRNA Regulatory Network Involved in Prostate Carcinogenesis Identified
Key findings
- A prostate cancer (PCa) regulatory network is regulated by two key miRNAs, miR-188-5p and miR-193a-5p
- miR-193a-5p acts as a tumor suppressor by targeting a tumor promoter isoform of TP73
- miR-188-5p acts as an onco-miRNA by targeting UBE2I which tags TP73 for degradation
- TP73 and UBE2I are key components of a bottleneck in the PCa regulatory network
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Prostate cancer (PCa) typically progresses in an androgen-dependent manner and initially responds to conventional therapies such as hormone deprivation. These strategies typically succeed in removing circulating androgens and slowing cancer progression. Often, PCa eventually progresses to a more aggressive, androgen-independent state. Although prostate-specific antigen (PSA) is currently used as a biomarker for early detection, there is a need for more reliable and informative biomarkers to detect malignancy potential, predict patient outcome, evaluate recurrence risk and to select the optimal therapeutic strategy.
Chin-Lee Wu, MD, PhD, associate pathologist and director of Genitourinary Pathology Services, and team recently conducted a study aimed at identifying regulatory networks involved in prostate cancer (PCa) that revealed a PCa gene network regulated by two key miRNAs, miR-188-5p and miR-193a-5p. Their findings were reported in the journal Cell Death and Disease.
In previous studies, the team identified 26 microRNAs (miRNAs) differentially expressed between prostate tumors and adjacent healthy tissue in patients and identified the mRNAs regulated by these miRNAs. In addition, they found indications that Ribonuclease L (RNASEL) may have a critical role in PCa.
In this current study, the team looked for any potential relationship between these miRNAs and RNASEL with the goal to define the entire regulatory network mediated by miRNAs in PCa and to identify new biomarkers for PCa within this network.
First, the team identified dysregulated miRNAs and mRNAs from gene expression profiles from patients with primary PCa who are listed in The Cancer Genome Atlas (TCGA). A PCa-gene expression network was deduced using these miRNAs and their predicted target genes. The proposed network also incorporated downstream targets of those genes in order to identify all biological pathways connected to the network.
This led to the discovery of the PCa gene network with each miRNA pairing with a key target mRNA.
miR-193a-5p
The researchers found that miR-193a-5p pairs with mRNA that encodes a tumor suppressor, TP73, which normally triggers growth arrest or programmed cell death (apoptosis) in defective cells. Interestingly, TP73 has two classes of isoforms with opposing functions. One class of isoform behaves as a tumor suppressors while the other class behaves as a tumor promoter. Therefore, the regulatory effect of miRNA on TP73 depends upon the ratio of TP73 isoforms.
The data suggested that miR-193a-5p preferably interacts with the tumor promoter isoform. In this scenario, miR-193a-5p functions as a tumor suppressor. Consistent with these findings, clinical outcomes in patients from TCGA with PCa showed that low miR-193a-5p expression combined with high TP73 expression frequently occurred in those with advanced T-stage PCa (disease limited to the primary tumor).
miR-188-5p
Data also demonstrated that the second miRNA, miR-188-5p, directly downregulates mRNA for UBE2I, a gene that encodes a protein that marks TP73 for degradation such that miR-188-5p functions as an onco-miRNA. Consistent with this model, PCa patients from the TCGA with high miR188-5p expression combined with low UBE2I expression frequently experienced advanced N-stage PCa (spread to lymph nodes) with greater recurrence and progression.
The Bottleneck
After incorporating RNASEL, TP73, UBE2I and their downstream targets, the CCND1-RNASEL-CDKN1A-TP73-MDM2-UBE2I axis emerged as a bottleneck in this PCa regulatory network. Together, these proteins regulate cell cycle arrest and apoptosis and influence cancer cell proliferation, migration and invasion.
Together, dysregulation of miR-193a-5p and miR-188-5p is associated with aggressive cancer progression and poor prognosis in PCa patients. The researchers believe the coordination of TP73 isoforms and UBE2I in this key regulatory network is critical for controlling disease progression.
These findings may lead to stratifying patients based on new biomarkers and the development of more effective therapeutic strategies.
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