Nuclear Receptors in Bladder Cancer: Insights into miRNA-Mediated Regulation and Potential Therapeutic Implications

Abstract

Nuclear receptors (NRs) are ligand-activated transcription factors that regulate gene expression and are involved in diverse physiological and pathological processes, including carcinogenesis. In bladder cancer (BCa), dysregulation of NR signaling pathways has been linked to tumor initiation, progression, therapy resistance, and immune evasion. Recent evidence highlights the intricate crosstalk between NRs and microRNAs (miRNAs), which are small non-coding RNAs that posttranscriptionally modulate gene expression. This review provides an integrated overview of the molecular interactions between key NRs and miRNAs in BCa. We investigated how miRNAs regulate NR expression and function and, conversely, how NRs influence miRNA biogenesis, thereby forming regulatory feedback loops that shape tumor behavior. Specific miRNA-NR interactions affecting epithelial-to-mesenchymal transition, metabolic reprogramming, angiogenesis, and chemoresistance are discussed in detail. Additionally, we highlight therapeutic strategies targeting NR-miRNA networks, including selective NR modulators, miRNA mimics and inhibitors, as well as RNA-based combinatorial approaches focusing on their utility as diagnostic biomarkers and personalized treatment targets. Understanding the molecular complexity of NR-miRNA regulation in BCa may open new avenues for improving therapeutic outcomes and advancing precision oncology in urological cancers.

Keywords: RNA-based therapy; bladder cancer; gene regulation; miRNAs; nuclear receptors; therapeutic response.

Figure 1

Interplay between NRs and miRNAs in bladder homeostasis and cancer. NRs regulate gene expression by binding to specific ligands and modulating transcriptional programs involved in cell differentiation, contraction, and metabolism, contributing to normal bladder functions (1,2). miRNAs, which are synthesized through canonical biogenesis pathways involving Dicer and the RNA-induced silencing complex (RISC), fine-tune gene expression posttranscriptionally (3). Cross-regulation occurs as NRs modulate miRNA biogenesis and transcription, whereas miRNAs regulate NR expression, establishing feedback loops. Dysregulation of these interactions contributes to BCa pathophysiology by increasing proliferation, metastasis, inflammation, and evasion of apoptosis (4). Solid black straight arrows indicate direct sequential processes, red and black up arrows indicate increased activity, while dashed arrow represents inhibition process. Created with BioRender.com (accessed on 1 May 2025).

Figure 2

Androgen receptor (AR) signaling network and its regulation by ncRNAs in BCa. The figure illustrates key molecular interactions involved in AR signaling and its downstream effects in BCa. Androgen binding activates AR, promoting tumor progression through the PI3K/AKT/mTOR axis, immune evasion, and tumor growth. AR also modulates the expression of various ncRNAs, including miR-21, miR-525-5p, miR-4736, and circRNAs, which contribute to increased proliferation, invasion, and metastasis. Conversely, tumor-suppressive miRNAs, such as miR-124, miR-449a, and miR-200a-3p, negatively regulate AR or its downstream targets, thereby limiting proliferation and vascular mimicry. Pharmacological inhibition, the use of miRNA inhibitors (ADM-21), and AR-miRNA crosstalk represent potential therapeutic strategies to modulate aggressiveness and immune escape in BCa. Solid straight black arrows indicate activation, red and black up arrows indicate increased expression, red and black down arrows indicate repressed activity, dashed red and black arrows represent inhibition process. Created with BioRender.com (accessed on 1 May 2025).

Figure 3

Role of the ER in the proliferation and invasion of BCa. In contrast to other cancer types, ERα and ERβ have anti- and pro-oncogenic effects on BCa. ERα can reduce cell proliferation and invasion by inhibiting EGFR, AKT, and RACGAP through regulatory mechanisms that could involve miRNA participation. In turn, ERα can be repressed by STAT3 and DNMT3B, which facilitates its methylation. In addition, miR-19, miR-22, miR-206, and miR-221/222 downregulated ERα. On the other hand, ERβ increases cell proliferation and invasion by indirectly inhibiting DAB2IP and promoting cisplatin resistance via β-catenin overexpression. Selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs) may inhibit ER signaling in BCa since decreased levels of biologically active estrogens could lead to increased BCa malignancy. Solid black straight arrows indicate activation, dashed red arrows represent indirect inhibition and solid red arrows indicate direct inhibition process. Created with BioRender.com (accessed on 1 May 2025).

Figure 4

Molecular roles of ONR and its regulation by miRNAs in BCa progression. Several RNRs play pivotal roles in BCa through the modulation of tumor cell behavior and interaction with the tumor microenvironment. HNF4G, which is directly targeted by miR-34a, promotes proliferation and progression via hyaluronan synthase 2 (HAS2). Nur77 and HNF4α influence apoptosis, invasion, and chemoresistance, although the regulation of Nur77 by miR-34a in BCa remains to be clarified. RORC activates the PD-L1/ITGB6/STAT3 signaling axis, thereby enhancing inflammation and therapy resistance. Additionally, RORα may regulate tumor immune responses. These ONR-mediated pathways represent potential targets for therapeutic intervention in BCa. Question mark (?) indicates speculative not validated function, solid straight black arrows indicate activation, dashed black arrow represents indirect inhibition, black down arrow indicates repressed activity and solid red arrow indicates direct inhibition process. Figure created with BioRender.com (accessed on 1 May 2025).

Figure 5

Roles of PPARγ and PPARα in BCa. (a) The formation of the PPARγ heterodimer with RxRa (S427/Y) regulates the tumor microenvironment by inhibiting the expression of inflammatory cytokines, leading to a state of immune evasion. (b) PPARγ point mutants transform cells into PPARγ-dependent cells by activating the pathway without the need for a ligand. (c) PPARγ transcriptionally activates the VEGF promoter via an indirect mechanism. (d) Through the microRNA miR30a-3p, the lncRNA UCA1 increases the expression of PPARα, which accumulates lipids that prevent epirubicin-induced apoptosis. Solid straight arrows indicate activation, dashed black and blue arrows indicate indirect activation, up black and red arrows indicate increased expression, red arrows represents inhibition process. Figure created with BioRender.com (accessed on 1 May 2025).

Figure 6

Regulation of GCR signaling by miRNAs in BCa progression and therapy response. The GCR axis plays a dual role in BCa, modulating survival, proliferation, and sensitivity to glucocorticoid therapy. miR-144 is repressed by the lncRNA Sweet-P, and miR-133b targets components of the PI3K/AKT pathway, contributing to therapy resistance and increased cell survival. Conversely, when coadministered with glucocorticoid therapy, miR-203 promotes apoptosis. GCR overexpression leads to oncogenic activation via NF-κB, enhancing migration, metastasis, and EMT. These interactions illustrate the potential of miRNAs to modulate glucocorticoid-based treatment efficacy and tumor aggressiveness. Solid straight black arrows indicate activation, dashed black arrow represents indirect inactivation, up red arrows indicate increased expression. Figure created with BioRender.com (accessed on 1 May 2025).

Figure 7

NR-targeted strategies and RNA-based therapeutics in BCa. (A) Schematic highlighting major therapeutic approaches directed at NRs implicated in BCa progression. AR antagonists (e.g., enzalutamide), PPARγ agonists, SERMs, SARMs, and next-generation NR inhibitors have demonstrated potential in modulating tumor cell proliferation and survival. RNA-based therapies, including miRNA mimics (e.g., miR-34a targeting HNF4G) and siRNA knockdown of AR, offer a complementary strategy involving interference with NR expression and activity. Additional miRNAs, such as miR-145, miR-124, and miR-27b, have been shown to modulate NR-related pathways, including PPARγ, VDR, and NR4A1 signaling, thus affecting inflammation, apoptosis, and therapeutic resistance. (B) Combining strategies integrating NRs and RNA-based tools may increase therapeutic efficacy and offer avenues for personalized BCa management. Solid straight black arrows indicate direct activation, curved dashed black arrows indicate indirect inhibition, dashed black arrows indicate indirect activation. Created with BioRender.com (accessed on 1 May 2025).