Role of androgen receptor signaling in chemoresistance in urothelial cancer: a narrative review

Introduction

Urinary bladder cancer remains one of the most prevalent malignancies, particularly among men, with worldwide cancer-related mortality rising considerably in recent years (1,2). Histologically, urothelial carcinoma accounts for most of bladder tumors. Clinically, bladder cancer encompasses two distinct types, non-muscle-invasive and muscle-invasive diseases. In patients with non-muscle-invasive tumor, transurethral tumor resection frequently achieves initial control and may offer a cure, but the risk of disease recurrence, occasionally with progression to more invasive phenotypes, remains substantial even after currently available intravesical chemotherapy (3,4). In contrast, patients with muscle-invasive bladder cancer, even in the absence of distant metastasis, continue to face a high likelihood of progression despite undergoing radical cystectomy combined with systematic chemotherapy administered in neoadjuvant and/or adjuvant setting(s) (4-6). Moreover, overall oncologic outcomes in those with metastatic disease remain dismal despite the recent shift from chemotherapy alone to a combination of immunotherapy (i.e., pembrolizumab) and targeted therapy (i.e., enfortumab vedotin) as a preferred first-line treatment option (4,5,7). Urothelial carcinoma arising in the upper urinary tract represents an additional clinical challenge, as these tumors more commonly display with invasive disease at diagnosis, often requiring systematic therapy in conjunction with radical surgery (8). Together, these issues highlight the urgent need for predictive biomarkers and novel strategies capable of enhancing therapeutic response in patients with urothelial cancer.

Sex hormone receptors, including androgen receptor (AR) and estrogen receptors, constitute a family of nuclear receptors that are activated by intracellular binding of cognate ligands. Specifically, androgens and AR are known to contribute to a broad range of not only physiological processes but also pathologic conditions. Indeed, AR has been well established as a therapeutic target in some endocrine-related malignancies, such as prostate cancer, where AR blockade constitutes a standard component of systemic treatment. Growing evidence further implicates the oncologic role of AR signaling in urothelial tumorigenesis and tumor progression (9-11), which may clearly justify sex disparities in urothelial cancer, especially male dominance in the incidence of bladder or upper urinary tract tumor (1,2). Interestingly, although the prognostic impact of AR expression in urothelial carcinoma remains inconclusive (12,13), increasing data suggest that AR overexpression and/or activation may contribute to inducing resistance to conventional non-surgical treatments for bladder cancer, including chemotherapy, as well as intravesical BCG immunotherapy (14) and radiotherapy (15).

The present review article aimed to summarize available data implying the involvement of AR signaling in modulating sensitivity to chemotherapy for urothelial cancer and outlines the potential molecular mechanisms underlying this association. We present this article in accordance with the Narrative Review reporting checklist (available at https://cco.amegroups.com/article/view/10.21037/cco-2025-1-165/rc).

Methods

We conducted a computerized bibliographic search of the databases, including PubMed, Embase, Scopus, Google Scholar, and World Health Organization (WHO) Global Index Medicus, using the relevant keywords variably combined. Original research articles were prioritized, supplemented by additional relevant studies identified in their reference lists. Table S1 summarizes further details regarding the search strategy and selection criteria.

Impact of AR itself on chemoresistance

Several chemotherapeutic agents, such as mitomycin-C (MMC), gemcitabine (GEM), and anthracyclines [e.g., doxorubicin (DXR), epirubicin], are intravesically instilled often in patients with non-muscle-invasive bladder tumor to prevent disease recurrence (and progression) following transurethral surgery (3,4). Cisplatin (CDDP)-based systematic combination regimens [e.g., GC (GEM + CDDP), MVAC (methotrexate + vinblastine + adriamycin/DXR + CDDP)] remain the principal components of standard therapy for muscle-invasive and/or metastatic disease (4-7). Of these agents, resistance to CDDP, DXR, GEM, and MMC has been linked to the expression or activity of AR in bladder cancer cells (Table 1). Below, we describe the impact of AR itself on resistance to individual agents.

CDDP

CDDP is a central component of systemic combination chemotherapy regimens for urothelial cancer. Five studies have specifically investigated the role of androgen signaling in CDDP resistance in bladder cancer (16-20).

The levels of AR protein expression were found to be substantially elevated in CDDP-resistant sublines established through long-term stepwise drug exposure (vs. control sublines), as well as in muscle-invasive cancer specimens from non-responders (vs. responders) to CDDP-based neoadjuvant therapy prior to cystectomy (16). In vitro experiments further demonstrated that sublines endogenously or exogenously expressing AR (vs. AR negative or knockdown cells) and AR-positive cell lines cultured with androgens (vs. mock treatment) or normal fetal bovine serum (vs. androgen depleted conditions with charcoal-stripped serum) were significantly more resistant to CDDP treatment (16). Correspondingly, concurrent treatment with an AR antagonist [e.g., enzalutamide (18), hydroxyflutamide (16)], as well as an AR degradation enhancer ASC-J9^® (17), increased the cytotoxic activity of CDDP in AR-positive cells. Importantly, in CDDP-resistant AR-positive sublines, hydroxyflutamide (16) and ASC-J9^® (17) at least partially restored drug sensitivity. However, the additive effects of ASC-J9^® on cell proliferation and apoptosis were similarly seen in CDDP-treated J82 cells (17), where AR protein was reported to be negative (23,24) but its expression was not confirmed (17), implying the involvement of the non-AR pathway in the enhancement of CDDP cytotoxicity by ASC-J9^®. Similarly, enzalutamide enhanced CDDP-mediated apoptosis, along with inducing the expression of pro-apoptotic markers, BAX, cleaved caspase-3, and cleaved PARP, and reducing the expression of anti-apoptotic Bcl-2 (18). Enzalutamide also augmented the expression of an epithelial marker E-cadherin and decreased that of mesenchymal markers such as β-catenin, N-cadherin, Slug, and vimentin in CDDP-treated AR-positive TCCSUP cells (18). However, the differences in the expression levels of these apoptosis or epithelial-to-mesenchymal transition related markers appeared to be modest between CDDP alone and CDDP plus enzalutamide (18). Moreover, all the AR-positive bladder cancer cell lines used in this study (18) were positive for prostate-specific antigen, an AR downstream target known to be expressed specifically in the prostate, but not even in AR-positive cells in most of other organs, raising concerns regarding the authenticity of the cell lines [or specificity of the primers for polymerase chain reaction (PCR) and the antibody for western blot]. A recent study additionally demonstrated that a selective inhibitor for aldo-keto reductase 1C3 (AKR1C3), a steroidogenic enzyme responsible for androgen synthesis, particularly testosterone production, restored sensitivity to combined GEM + CDDP treatment in GC-resistant cells (19). Another study also showed that knockdown of AKR1C3 reversed CDDP resistance induced by DHRS2 down-regulation (20).

Other contributors, as potential upstream regulators which strengthen AR-driven CDDP resistance, include a histone demethylase KDM7A (25) and a long non-coding RNA Uc.63+ (26). KDM7A was shown to directly bind to the promoter of AR and regulated its expression and activity in bladder cancer cells. Moreover, enzalutamide or a chemical inhibitor of KDM7A strongly suppressed the growth of AR-positive CDDP-resistant cells, although no CDDP was concurrently treated. Silencing and overexpression of Uc.63+ in UMUC3 cells with endogenous AR was also shown to induce and reduce, respectively, CDDP sensitivity, while those in AR-negative cells showed no significant effects on CDDP cytotoxicity. Compared with the parental cells, Uc.63+ expression was significantly elevated in a CDDP-resistant UMUC3 subline. In addition, the expression levels of Uc.63+ modulated via silencing or overexpression in UMUC3 cells were correlated with those of AR.

Collectively, these findings support the association between AR activation and CDDP resistance in bladder cancer. Nonetheless, one study failed to observe significant differences in the cytotoxic effects of various concentrations of CDDP in AR-positive UMUC3 cells following exposure to 1 nM dihydrotestosterone or expression of AR siRNAs (21), indicating that AR-driven CDDP resistance might possibly context-dependent.

DXR

DXR is used intravesically for non-muscle-invasive bladder tumors but is also a core component of the systematic MVAC regimen for more advanced disease. Two studies have suggested the involvement of AR signaling in modulating sensitivity to DXR in bladder cancer (17,21).

In an earlier study, the expression levels of AR mRNA and protein were shown to be markedly up-regulated in established DXR-resistant sublines, compared with corresponding parental lines (21). Moreover, concurrent dihydrotestosterone (1 nM) treatment in parental UMUC3 cells significantly reduced the cytotoxic effect of DXR, whereas AR silencing resulted in enhancement of DXR cytotoxicity (21). Similarly, the synergistic inhibitory effects of DXR and ASC-J9^® were confirmed in at least one AR-positive cell line (17). These findings collectively suggest that AR activity is inversely associated with sensitivity to DXR in bladder cancer cells.

GEM

GEM is administered not only intravesically but also systematically as a component of the GC regimen in patients with bladder cancer. Two studies have suggested the involvement of AR signaling in modulating sensitivity to GEM in bladder cancer (19,22).

First, compared with the parental cells, an established GEM-resistant subline was found to show considerably increased AR expression (22). Enzalutamide treatment restored sensitivity to GEM in these resistant cells (22). These findings suggest that AR activation in bladder cancer cells is associated with GEM resistance. Additionally, in a recent study (19), an AKR1C3 inhibitor enhanced the cytotoxic effects of GEM + CDDP in GC-resistant cells, implying that intracrine androgen production might contribute to GEM resistance, although GEM and CDDP were simultaneously treated and the impact on GEM alone was thus not separately assessed.

MMC

MMC is used primarily as intravesical chemotherapy in patients with non-muscle-invasive bladder tumor. Similar to DXR, ASC-J9^® synergized with MMC in at least one AR-positive bladder cancer cell line (17). These data suggest the enhancement of MMC cytotoxicity by AR inactivation, while evidence remains limited.

Potential downstream effectors of AR involving CDDP resistance

A key question emerging from above studies linking AR to CDDP resistance is how AR signaling mechanistically alters tumor cell susceptibility to CDDP-induced cytotoxicity. CDDP primarily induces apoptosis through the formation of DNA crosslinks and subsequently activates the DNA damage response. Therefore, AR-driven modulation of DNA damage response factors, cell survival pathways, drug transporters, and transcriptional programs may significantly affect treatment outcomes. Potential downstream molecules directly or indirectly regulated by AR signaling have now been implicated in CDDP resistance in bladder cancer (Table 2).

β-catenin

The Wnt/β-catenin pathway is a crucial system involved in regulating fundamental cellular processes including cell differentiation, proliferation, and migration. It has been well documented that β-catenin represents a key regulator of CDDP response in various types of malignancies (36), including bladder cancer (38).

A study demonstrated the impact of AR activation in bladder cancer cells on Wnt/β-catenin signaling (24). In AR-positive cell lines, androgen treatment induced the expression of an active form of β-catenin and its downstream target c-myc, as well as the nuclear translocation and transcriptional activity of β-catenin, while an antiandrogen hydroxyflutamide blocked these androgen-mediated effects. Co-immunoprecipitation further showed the physical interaction between AR and β-catenin. Immunohistochemistry in radical cystectomy specimens also showed a strong correlation of AR and β-catenin expression in the nuclei of bladder cancer cells. Additionally, as described earlier, enzalutamide reduced the expression levels of β-catenin examined as an epithelial marker in AR-positive bladder cancer cells (18), further supporting AR-mediated regulation of β-catenin.

BXDC2

BXDC2, also named BRIX1, is known to involve the assembly and biosynthesis of ribosomes (39). However, its functions in neoplastic diseases remain poorly defined.

A study indicated the role of BXDC2 in CDDP resistance in bladder cancer cells, in relation to AR signaling (27). AR overexpression in AR-negative cells and dihydrotestosterone treatment in AR-positive cells down-regulated the expression of BXDC2, while AR knockdown and hydroxyflutamide treatment showed opposite effects. An inverse correlation of AR and BXDC2 expression was confirmed in surgical specimens. The level of BXDC2 expression was lower in CDDP-resistant cells than in control cells, and BXDC2 knockdown significantly reduced sensitivity to CDDP, but not other chemotherapeutic drugs examined, including methotrexate, vinblastine, DXR, and GEM. Mechanistically, an ERK activator reduced the expression of BXDC2, while BXDC2 loss diminished that of cleaved caspase-3, suggesting reducing apoptotic signaling.

circFNTA

Circular RNAs are a type of single-stranded, non-coding RNAs that form a covalently closed loop. A circular RNA, circFNTA, was shown to promote the proliferation and invasion of bladder cancer cells (28,40).

In one of the studies (28), associations of circFNTA with AR signaling and CDDP resistance were investigated in bladder cancer. AR was found to increase the levels of circFNTA expression via binding to the promoter of a RNA editing gene ADAR2, but not via direct transcriptional regulation of circFNTA. Then, knockdown of circFNTA resulted in an increase in the cytotoxic activity of CDDP in both cell lines and a mouse xenograft model, implicating circFNTA as a mediator of AR-driven drug resistance.

ELK1

A transcriptional factor ELK1 has been known to involve key cellular processes, including proliferation, apoptosis, migration, and differentiation, via regulating a variety of genes including a proto-oncogene c-fos (41). Studies in urothelial cancer further indicated that ELK1 could promote tumorigenesis (30) and tumor progression (29), and that AR upregulated the expression of ELK1 and c-fos in non-neoplastic (30) and tumor (29) cells. In addition, correlations between the expression levels of AR vs. ELK1 (and/or its activated form phospho-ELK1) were observed in bladder cancer (29) and upper urinary tract urothelial carcinoma (42) specimens. Meanwhile, AKR1C3 inhibition reduced the levels of ELK1 expression in AR-positive bladder cancer cells (19).

Another study indicated the role of ELK1 in CDDP resistance in bladder cancer (35). ELK1 knockdown cells were significantly more sensitive to CDDP treatment. Moreover, immunohistochemistry in transurethral resection specimens from patients who subsequently underwent CDDP-based neoadjuvant therapy, followed by radical cystectomy, revealed that phospho-ELK1 positivity was significantly (P=0.039) more often seen in non-responders (71%) than in responders (38%).

Silodosin is a selective α₁-adrenergic receptor antagonist widely prescribed for the symptomatic treatment of benign prostatic hyperplasia (43). As documented in smooth muscle cells in the prostate (44), silodosin was found to reduce ELK1 expression in AR-positive non-neoplastic urothelial cells (30) and bladder cancer cells (35,45), but not in AR-negative cells. Interestingly, other α₁-blockers prescribed for men with benign prostatic hyperplasia, including tamsulosin and naftopidil, did not show significant effects on ELK1 expression (and urothelial cancer outgrowth) (45). Silodosin also enhanced the cytotoxic activity of CDDP in ELK1-positive cells, but not in ELK1 knockdown cells, suggesting the effect of silodosin via down-regulation of ELK1 expression, while silodosin did not significantly alter GEM cytotoxicity (35).

FOXO1

FOXO1 belongs to the forkhead transcription factor and is known to generally function as a tumor suppressor (46). More specifically, FOXO1 is phosphorylated by several proteins, including PI3K/AKT signaling, leading to its inactivation and, for example, subsequent uncontrollable cell cycle progression and cell migration/invasion. In urothelial cancer, inactivation or knockdown of FOXO1 has been shown to induce its development and progression (31). Additionally, in non-neoplastic urothelial and bladder cancer lines, AR overexpression in AR-negative cells or androgen treatment in AR-positive cells resulted in significant decreases in the mRNA/protein expression and transcriptional activity of FOXO1, as well as increases in the expression of an inactivated form phospho-FOXO1 (31). These changes were reversed by AR knockdown or antiandrogen treatment. In bladder cancer specimens, a strong correlation of AR and phospho-FOXO1 expression was also confirmed (31).

A study indicated associations of FOXO1 activity with sensitivity to CDDP in bladder cancer (32). Reduced levels of FOXO1 expression were observed particularly in a CDDP-resistant subline lacking AR, where basal expression was high (31), whereas both AR-positive and AR-negative CDDP-resistant sublines showed elevated levels of phospho-FOXO1 expression. Moreover, FOXO1 knockdown/silencing and inhibitor treatment significantly reduced the cytotoxic activity of CDDP, as well as CDDP-induced apoptosis. There was also a tendency between immunoreactivity to phospho-FOXO1 in muscle-invasive bladder cancer and resistance to CDDP-based neoadjuvant therapy prior to cystectomy (responders 38.9% vs. non-responders 67.9%; P=0.053).

GABBR2

As GABA (γ-aminobutyric acid) represents the chief inhibitory neurotransmitter in the brain, one of G-protein coupled receptors for GABA, GABBR2, has been implicated in the pathogenesis of various neurological or psychiatric disorders (47). In contrast, its role in malignant diseases remains poorly understood, while previous studies have yielded conflicting results on tumor growth (i.e., promotion vs. suppression vs. no significant impact), possibly dependent of tumor types (48,49). In bladder cancer, knockdown of GABBR2 or treatment of a selective GABA B receptor antagonist, CGP46381, did not significantly change the cell viability and migration (33). More interestingly, associations between AR activity and GABBR2 expression have been explored in bladder cancer (33). Specifically, AR knockdown in bladder cancer cells reduced GABBR2 protein expression, while dihydrotestosterone treatment significantly induced GABBR2 gene expression. Moreover, chromatin immunoprecipitation (ChIP) assay in bladder cancer cells showed the binding of endogenous AR to the promoter region of GABBR2, indicating direct regulation of GABBR2 expression by AR.

The above study (33) further indicated associations of the expression and activity of GABBR2 with sensitivity to CDDP in bladder cancer. A CDDP-resistant subline showed a significantly higher level of GABBR2, compared with control cells. GABBR2 knockdown or treatment with CGP46381 resulted in significant increases in sensitivity to CDDP. Meanwhile, analysis of a publicly available dataset revealed that high GABBR2 expression was associated with a significantly higher mortality in the entire cohort or a subgroup of patients only with invasive (pT1 or higher) tumor.

GULP1

GULP1 represents an adapter protein which is known to facilitate apoptotic cell phagocytosis (50). It has also been documented that GULP1 promotes the rearrangement of the actin cytoskeleton via MAPK activation (51). However, the functional role of GULP1 in the progression of neoplastic diseases remains largely unknown, although the prognostic role of GULP1 expression have been suggested in several types of malignancies, including liver (52) and pancreatic (53) cancers. In bladder cancer lines, overexpression or knockdown of GULP1 resulted in significant reduction or induction, respectively, in cell proliferation (54), while another study failed to show significant effects of GULP1 knockdown on bladder cancer cell viability, migration, and invasion, as well as apoptosis (34).

A study explored the association between AR and GULP1 in bladder cancer (34). AR overexpression in AR-negative cells and dihydrotestosterone treatment in AR-positive cells considerably reduced the levels of GULP1 expression. Correspondingly, knockdown of AR or treatment of hydroxyflutamide induced GULP1 expression. ChIP assay further demonstrated interactions of AR with the GULP1 promoter, indicating direct regulation of GULP1 expression by AR.

Phagocytosis has been linked to acquisition of chemoresistance in non-bladder cancers (55,56). Then, at least three studies have indicated that GULP1, a phagocytosis promoter, involves CDDP resistance in bladder cancer (34,54,57). Specifically, in these studies, silencing or knockdown of GULP1 in bladder cancer cells was shown to significantly reduce sensitivity to CDDP treatment. GULP1 knockdown also resulted in a significant decrease in CDDP-induced apoptosis and a significant increase in CDDP-reduced G2/M population (54). Moreover, high GULP1 expression in muscle-invasive bladder cancers was strongly associated with favorable response to CDDP-based neoadjuvant chemotherapy in patients subsequently undergoing radical cystectomy (54). However, GULP1 knockdown in bladder cancer cells did not show significant effects on the cytotoxic activity of other chemotherapeutic agents, including methotrexate, vinblastine, DXR, and GEM (57).

Nuclear factor (NF)-κB

It has been well documented that activation of NF-κB induces not only carcinogenesis and cancer growth but also CDDP resistance in various malignancies (36,58,59). In an immunohistochemical study, immunoreactivity for an active form, phospho-NF-κB, in muscle-invasive bladder cancer specimens from patients who subsequently underwent CDDP-based neoadjuvant chemotherapy was significantly (P=0.044) more often seen in non-responders (81%) than in responders (54%) (16).

Several studies have further demonstrated cross-talk between AR and NF-κB in bladder cancer cells (16,17,36). Specifically, androgen treatment or AR overexpression induced the expression, nuclear translocation, and transcriptional activity of NF-κB. Correspondingly, antiandrogen treatment or AR knockdown showed the opposite effects. These finding suggest that NF-κB represents a downstream target of AR signaling. In addition, the activity of NF-κB modulated by its activator or inhibitor was found to be associated with that of AR in bladder cancer cells (36), suggesting that NF-κB could also function as an upstream regulator of AR. Meanwhile, ELK1 knockdown resulted in considerable reduction of NF-κB expression in bladder cancer cells, while silodosin treatment significantly reduced the expression and transcriptional activity of NF-κB (35), implying an interconnected regulatory network contributing to CDDP resistance.

Therapeutic prospects and limitations

Existing data highlight a critical role of AR signaling in not only the development and progression of urothelial cancer but also the modulation of sensitivity to conventional non-surgical therapy for bladder cancer. Specifically, most of previous studies have demonstrated that AR activation is associated with chemotherapeutic resistance, although data remain limited for certain agents. Multiple potential downstream effectors of AR involving therapeutic resistance have also been identified, but the downstream landscape of AR-mediated chemoresistance appears to be highly multifactorial. Figure 1 summarizes androgen-mediated AR signals and downstream molecules up-regulated/down-regulated and/or activated/inactivated by AR in urothelial cancer cells as potential effectors. Accordingly, concurrent administration of anti-AR agents, as well as available inhibitors or activators for potential downstream targets, is anticipated to enhance the efficacy of chemotherapeutic agents in patients with urothelial cancer. In addition, the expression of AR and related molecules in surgical specimens may serve as biomarkers useful for predicting therapeutic response and selecting optimal patients.

Figure 1 Androgen-mediated signals, including potential downstream effectors, in urothelial cancer cells. Androgens have been suggested to induce resistance to intravesical or systemic chemotherapy for bladder cancer, through the ligand-mediated AR pathway via up-regulating/activating (red) or down-regulating/inactivating (blue) the downstream targets listed (left, direct targets where AR binding to their promoter regions have been confirmed in bladder cancer cells). A, androgen; AR, androgen receptor; ARE, androgen response element; HSP, heat shock protein.

These observations in preclinical models and surgical specimens have supported early phase clinical translation which evaluates the efficacy of chemotherapy combined with anti-AR therapy. In a phase 1/1b trial (NCT02300610) primarily assessing the safety and tolerability of enzalutamide in combination with GEM + CDDP therapy (6 cycles) in a total of 10 patients with metastatic bladder cancer, complete response was achieved in one with tumor strongly expressing AR (60). Ongoing clinical evaluation includes another phase 1 trial (NCT05839119) testing the efficacy of concurrent androgen deprivation therapy with degarelix, a gonadotropin-releasing hormone antagonist, in those with muscle-invasive bladder cancer undergoing neoadjuvant GEM + CDDP therapy (4 cycles) prior to cystectomy.

Given that surgical or chemical castration and/or anti-androgen treatment have already been widely used for the treatment of, for example, prostate cancer, the availability of clinically approved AR-targeted agents provides an attractive opportunity for rapid integration into bladder cancer treatment paradigms. Nonetheless, robust clinical studies, particularly well-designed prospective cohort trials, are required to determine the true clinical benefit of integrating AR-directed therapeutic strategies into standard intravesical or systemic chemotherapy for urothelial cancer. Potential downstream effectors of AR may also represent promising adjunctive therapeutic targets for overcoming chemoresistance in bladder cancer, especially if their specific inhibitors or activators are available. However, the complexity may indicate that AR activity modulates chemosensitivity not through a single dominant effector but via an integrated network of reinforcing pathways.

Key limitations of the present review include the predominance of preclinical data derived from a limited number of experimental models, the lack of extensive independent validation, and an incomplete mechanistic understanding of how AR drives chemoresistance in urothelial cancer.

Conclusions

Current evidence indicates a critical role of AR signaling in not only the pathogenesis and progression of urothelial cancer but also the modulation of sensitivity to conventional non-surgical therapy for bladder cancer. Notably, available data suggest the association of AR activity with chemosensitivity in bladder cancer. However, it remains far from being fully understood how AR induces chemoresistance. Accordingly, further investigation dissecting AR-centered signaling networks is essential to clarify the biological basis of androgen/AR-mediated modulation of chemotherapy sensitivity in urothelial cancer. In parallel, the development and clinical application of predictive biomarkers are warranted.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://cco.amegroups.com/article/view/10.21037/cco-2025-1-165/rc

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-2025-1-165/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-2025-1-165/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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