WIF1 and DKK3 in prostate cancer: from molecular pathways to therapeutic targets: a narrative review

Introduction

Background

Prostate cancer is among the most prevalent cancers in men, contributing significantly to new cancer cases and cancer-related deaths worldwide. Its development and progression are driven by a complex interplay of genetic mutations, environmental factors, and multiple signaling pathways. This intricate process includes the activation of oncogenes, inactivation of tumor suppressor genes, sustained angiogenesis, epithelial-mesenchymal transition (EMT), cytoskeletal reorganization, and the promotion of invasion and metastasis.

Rationale and knowledge gap

Among the key tumor suppressor genes implicated in prostate cancer are WIF1 and DKK3. These genes are known to act as extracellular inhibitors of the canonical Wnt signaling pathway, playing potentially crucial roles in tumor suppression. WIF1 and DKK3 are believed to significantly impact the pathogenesis of prostate cancer by inhibiting major signaling pathways that promote tumor growth and spread.

Objective

This review examines the biological functions of WIF1 and DKK3, their regulatory mechanisms, and their association with prostate cancer. By understanding how these genes influence tumor cell behavior and signaling pathways, we aim to highlight their therapeutic potential and provide insights into future research directions for developing effective treatments against prostate cancer. We present this article in accordance with the Narrative Review reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-24-304/rc).

Methods

To ensure a comprehensive review of the roles of WIF1 and DKK3 in prostate cancer, a detailed literature search was conducted on January 1, 2024, using PubMed, Scopus, and Web of Science. The search strategy included both MeSH (Medical Subject Headings) terms and free text, such as “WIF1”, “DKK3”, “prostate cancer”, “Wnt signaling”, “tumor suppression”, “apoptosis”, “PI3K/Akt pathway”, and “NF-κB pathway”, covering publications from January 2000 to January 2024. Inclusion criteria focused on peer-reviewed articles, reviews, and meta-analyses in English that examined the molecular biology, expression patterns, and therapeutic implications of WIF1 and DKK3 in prostate cancer. Exclusion criteria filtered out non-peer-reviewed articles, non-English studies, case reports, and editorials. The selection process involved an initial independent screening of titles and abstracts by two reviewers to exclude irrelevant studies, followed by a full-text review of potentially relevant articles by the same reviewers. Discrepancies were resolved through discussion or consultation with a third reviewer if necessary. Key data, including study design, methods, key findings, and relevance, were extracted using a standardized form. Additional relevant studies were identified through manual screening of reference lists. Emphasis was placed on high-impact studies published in top-tier journals, with priority given to those providing significant insights into the mechanisms of WIF1 and DKK3 in prostate cancer. This rigorous methodology ensured a thorough, unbiased review of the literature (Table 1).

Overview of WIF1 and DKK3

WIF1 gene

WIF1 is a secreted protein that inhibits the Wnt signaling pathway by directly binding to Wnt ligands. The WIF1 sequence is highly conserved and is located on human chromosome 12q14.1. The encoded protein is a highly conserved secretory protein composed of 379 amino acids. Its N-terminus contains a 50-amino acid signal sequence, followed by a WIF domain of approximately 150 amino acids, which is a highly conserved WIF-1 domain (WD) sequence across species. Additionally, it includes five epidermal growth factor (EGF)-like domains and a short hydrophilic C-terminal region of about 45 amino acids (1,2).

DKK3 gene

The DKK3 gene belongs to the Dickkopf family, which consists of four members (DKK1-4) and a DKK3 related gene called Soggy (3). DKK3 is a secreted glycoprotein with a molecular weight of 38 kDa and acts as an antagonist of the Wnt receptor complex. It is located on human chromosome 11p15.1, spans 47,100 bp, and comprises 9 exons, and 2 promoters. The promoters contain a high-cytosine-guanine nucleotide region, known as a CpG island (4,5). The N-terminal signal peptide also includes two conserved cysteine-rich domains (Cys-1 and Cys-2) separated by a variable linker region. Compared to other DKK proteins, DKK3 has unique C-terminal and N-terminal regions before Cys-1 and after Cys-2, respectively, distinguishing it from other family members. DKK3 features an N-terminal signal peptide, two conserved cysteine-rich domains (DKK_N and colipase fold domains) separated by linker regions, and a unique Soggy domain (6).

Effects on tumor cell biology

Cell proliferation

WIF1 and DKK3 inhibit tumor cell proliferation by reducing the nuclear accumulation of β-catenin, thereby inhibiting the expression of target genes such as c-Myc and Cyclin D1 (7-10). WIF1 promotes the phosphorylation of β-catenin by complexes such as Axin, APC, GSK3β, and CK1, marking it for ubiquitination and targeting it for proteasomal degradation, thereby reducing the proliferative drive of tumor cells. Additionally, WIF1 decreases β-catenin accumulation in the nucleus, downregulates the expression of Cyclin D1 and CDK4, and induces cell cycle arrest. DKK3 reduces the phosphorylation of retinoblastoma (Rb) protein by inhibiting the activity of the Cyclin D1-CDK4/6 complex, maintaining Rb in an unphosphorylated state, allowing it to bind to the E2F transcription factor, thereby inhibiting E2F activity and preventing the cell cycle from transitioning from the G1 phase to the S phase (11-15). WIF1 also reduces the expression of genes related to the self-renewal of cancer stem cells (CSCs) such as Oct4, Nanog, and Sox2 by inhibiting the Wnt/β-catenin signaling pathway, thus decreasing the number of CSCs and their tumor-forming ability (16,17).

Cell migration and invasion

WIF1 and DKK3 inhibit the Wnt/β-catenin signaling pathway, reducing the expression of matrix metalloproteinases (MMPs) such as MMP-2 and MMP-9, thereby decreasing the degradation of the extracellular matrix (ECM) and inhibiting tumor cell migration and invasion (18,19). Additionally, they indirectly inhibit MMP activity by regulating the expression of tissue inhibitors of metalloproteinases (TIMP) (20-22). WIF1 and DKK3 also inhibit EMT by reducing the expression of key EMT transcription factors such as Snail, Slug and Twist, thereby decreasing tumor cell migration and invasion (23-26). WIF1 regulates microtubule dynamics, affecting the expression of microtubule-associated proteins such as Tau and MAPs, reducing microtubule instability. Simultaneously, WIF1 inhibits the activity of actin-related proteins such as Cofilin, interfering with the formation and reorganization of actin fibers, thus hindering tumor cell migration and invasion (27-29). DKK3 enhances cell adhesion and barrier functions by regulating the expression of other cell adhesion molecules, such as Claudins and Occludins, further inhibiting cell migration and invasion (30).

Cell apoptosis

WIF1 and DKK3 downregulate the expression of anti-apoptotic Bcl-2 family proteins such as Bcl-2 and upregulate the expression of pro-apoptotic Bcl-2 family proteins such as Bax, increasing the Bax/Bcl-2 ratio, and releasing the inhibition on the apoptotic pathway. They promote the recruitment of death receptors such as Fas-associated death domain (FADD), activating the extrinsic apoptotic pathway via Caspase-8, and by promoting mitochondrial membrane permeability transition (MPT), increase the release of mitochondrial apoptotic factors such as cytochrome c and Smac/DIABLO, activating Caspase-9 and Caspase-3, initiating the intrinsic apoptotic pathway, thereby enhancing tumor cell apoptosis (31-33). DKK3 promotes apoptosis by downregulating the expression of inhibitors of apoptosis proteins (IAPs) such as X-linked inhibitor of apoptosis protein (XIAP) and cIAP, releasing their inhibition on Caspases. MDM2 is an E3 ubiquitin ligase that negatively regulates the stability and activity of p53 by ubiquitinating and degrading p53. WIF1 increases p53 protein stability by downregulating MDM2 expression, enhancing p53-mediated apoptosis (34). DKK3 upregulates the expression of p53 target genes such as Bax, upregulates PUMA, and NOXA, further inducing apoptosis (35,36). Additionally, WIF1 and DKK3 upregulate the expression of cell cycle inhibitors such as p21 through the p53 pathway, inducing G1/S and G2/M phase cell cycle arrest, thereby preventing cell proliferation, and promoting apoptosis (37-39).

Related signaling pathways

WIF1-related signaling pathways

Wnt/β-catenin signaling pathway

As an antagonist of the Wnt signaling pathway, WIF1 inhibits the activation of the Wnt/β-catenin signaling pathway by directly binding to Wnt ligands, preventing them from binding to the Frizzled receptor and reducing β-catenin accumulation in the nucleus. This inhibition suppresses tumor growth and invasion (40). Additionally, WIF1 increases the activity of GSK-3β, promoting the phosphorylation and degradation of β-catenin, reducing its stability and nuclear accumulation. This prevents the binding of β-catenin to T-cell factor/lymphoid enhancer factor (TCF/LEF) family transcription factors, inhibiting the transcription of β-catenin-dependent genes (41). WIF1 also affects the expression of downstream target genes involved in cell cycle regulation (e.g., Cyclin D1), anti-apoptosis (e.g., Bcl-2), and invasion (e.g., MMP7) by inhibiting the Wnt/β-catenin signaling pathway (42). Furthermore, WIF1 can synergize with other Wnt signaling pathway antagonists (e.g., DKK1, sFRP) to jointly inhibit the activation of the Wnt/β-catenin signaling pathway, enhancing the inhibitory effects on tumor cell growth and migration (43) (Figure 1).

Figure 1 The inhibition of the Wnt/β-catenin signaling pathway by WIF1. TCF, T-cell factor; LEF, lymphoid enhancer factor.

Non-canonical Wnt signaling pathway

WIF1 influences non-canonical Wnt signaling pathways through various mechanisms. The Wnt/Ca²⁺ pathway activates G-proteins through Frizzled receptors, increasing intracellular calcium ion concentration and subsequently activating calcium-dependent effectors such as calmodulin-dependent protein kinase (CaMK) and protein kinase C (PKC). WIF1 inhibits the activation of the Wnt/Ca²⁺ pathway by binding to Wnt ligands such as Wnt5a, thereby reducing calcium-dependent signal transduction and affecting cell motility and morphology (44). Additionally, the Wnt/PCP (planar cell polarity) signaling pathway plays a crucial role in regulating cell polarity and movement through small GTPase pathways such as RhoA, Rac1, and JNK. WIF1 inhibits this pathway’s activation by preventing Wnt11 from binding to Frizzled receptors, reducing cancer cell migration and tissue invasion capabilities (45). The Wnt/STOP signaling pathway promotes cell growth and survival by preventing protein degradation. WIF1 neutralizes Wnt ligands, inhibiting this pathway’s activity, reducing protein stability, and consequently inhibiting cell proliferation (46). Finally, WIF1 can synergize with other non-canonical Wnt signaling pathway antagonists (e.g., sFRP, DKK2) to reduce the activity of non-canonical Wnt signaling pathways, inhibiting tumor cell migration and invasion (47,48) (Figure 2).

Figure 2 The inhibition of the non-canonical Wnt signaling pathway by WIF1. PCP, planar cell polarity; JNK, c-Jun N-terminal kinase.

Other related signaling pathways

WIF1 inhibits the activation of the PI3K/Akt pathway, reducing Akt phosphorylation levels, thereby inhibiting the expression of its downstream target genes such as mTOR and Cyclin D. This decreases the cell survival signals mediated by this pathway, promoting cell apoptosis (49). By affecting the expression of downstream molecules of the PI3K/Akt pathway, such as MMP2 and MMP9, WIF1 inhibits cell migration and invasion (50). WIF1 also inhibits the NF-κB signaling pathway, reducing NF-κB nuclear translocation and DNA binding activity, thereby downregulating MMP-9 expression and inhibiting tumor cell invasion (51). Additionally, WIF1 can inhibit the phosphorylation of Smad2/3 in the TGF-β signaling pathway, thereby promoting the expression of genes that inhibit cell proliferation and induce cell apoptosis (52) (Figure 3).

Figure 3 The inhibition of the PI3K/Akt, NF-κB, and TGF-β signaling pathways by WIF1. mTOR, mechanistic target of rapamycin; MMP, matrix metalloproteinase; TGF, transforming growth factor.

DKK3-related signaling pathways

Wnt/β-catenin signaling pathway

Unlike DKK1, DKK2, and DKK4, DKK3 does not bind to low-density lipoprotein receptor-related protein 5/6 (LRP5/6) or the Kremen1 receptor (53). The ability of DKK3 to regulate the Wnt/β-catenin signaling pathway is controversial and may involve a Wnt-independent mechanism that leads to β-catenin inactivation. This process reduces β-catenin’s nuclear accumulation and transcriptional activity, thereby decreasing the expression of downstream target genes such as MYC, Cyclin D1, and AXIN2, which in turn lowers the proliferation and survival capacity of tumor cells (54-56). Additionally, DKK3 indirectly affects β-catenin activity by regulating non-canonical Wnt signals (e.g., Wnt/PCP and Wnt/Ca²⁺ pathways), thereby playing a complex regulatory role in various cellular behaviors and signaling networks by balancing the activity of different Wnt signaling pathways (57,58) (Figure 4).

Figure 4 The DKK3-related signaling pathways in Wnt/β-catenin and non-canonical Wnt signaling. PCP, planar cell polarity; MYC, v-myc avian myelocytomatosis viral oncogene homolog.

PI3K/Akt signaling pathway

DKK3 inhibits the activation of the PI3K/Akt signaling pathway by reducing the phosphorylation levels of PI3K, thereby inhibiting Akt activation and reducing Akt-mediated activation of mTOR. This ultimately suppresses the activity of the mTOR signaling pathway, preventing tumor cell growth and proliferation (59-61). Adelaiye-Ogala et al. (62) demonstrated that the inhibition of AKT not only significantly reduces cell proliferation but also enhances AR’s transcriptional activity by remodeling chromatin structure. This indicates that when DKK3 is inhibited, the PI3K/Akt pathway can partially compensate for the loss of AR signaling, thereby maintaining tumor cell survival. Moreover, Heller et al. (63) emphasized that suppressing AR leads to compensatory activation of the PI3K/Akt/mTOR pathway, which complicates treatment efficacy and contributes to resistance. Yan and Huang (64) noted that the activation of the PI3K/Akt pathway is often associated with the loss of PTEN (Phosphatase and Tensin Homolog), which can enhance AR signaling and accelerate tumor progression. By inhibiting this pathway, DKK3 reduces the expression and activity of glucose transporters such as GLUT1 (glucose transporter 1), lowering glucose uptake and glycolysis levels in tumor cells, thereby inhibiting their growth and survival (65,66). Furthermore, by reducing Akt activity, DKK3 decreases the expression of proteins related to cytoskeletal reorganization and cell movement (e.g., MMPs and Rho family small GTPases), thereby inhibiting tumor cell migration and invasion (Figure 5).

Figure 5 DKK3’s inhibition of the PI3K/Akt signaling pathway. mTOR, mechanistic target of rapamycin; PTEN, phosphatase and tensin homolog.

NF-κB signaling pathway

DKK3 inhibits the activity of Inhibitor of kappa B (IκB) kinase (IKK), preventing the degradation of IκB, thus inhibiting the nuclear translocation and activation of NF-κB transcription factors, subsequently suppressing the NF-κB signaling pathway (67,68). This inhibition leads to reduced expression of MMPs and VEGF, thereby inhibiting tumor cell migration and invasion capabilities (69,70). By inhibiting the role of NF-κB in the transcription of inflammatory factors, DKK3 reduces the inflammatory response in the tumor microenvironment, thereby inhibiting tumor progression (71) (Figure 6).

Figure 6 DKK3’s inhibition of the NF-κB signaling pathway. MMP, matrix metalloproteinase; VEGF, vascular endothelial growth factor.

MAPK/ERK signaling pathway

Extracellular signal-regulated kinase (ERK) is a key downstream effector molecule in the MAPK signaling pathway, involved in cell proliferation, differentiation, and survival. DKK3 reduces ERK phosphorylation levels, inhibiting its activation and weakening the transmission of the ERK signaling pathway (72). Additionally, DKK3 can inhibit the activity of upstream kinases in the MAPK/ERK signaling pathway, such as Raf and MEK, further reducing ERK phosphorylation and overall activity of the MAPK/ERK signaling pathway (73,74). By inhibiting ERK activation, DKK3 reduces the expression of MMPs and Snail, thereby inhibiting tumor cell migration and invasion capabilities (75,76). Finally, DKK3 inhibits ERK signaling in tumor-associated fibroblasts and immune cells, reducing pro-tumor inflammation and supportive responses in the tumor microenvironment (77,78) (Figure 7).

Figure 7 DKK3’s inhibition of the MAPK/ERK signaling pathway.

Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway

DKK3 reduces the phosphorylation of JAK, inhibiting the activation of STAT proteins, affecting the nuclear translocation of STAT proteins and reducing their accumulation in the nucleus, thereby preventing the activation of the signaling pathway (79,80). This inhibition suppresses cell proliferation and promotes apoptosis (81). Additionally, by inhibiting this pathway, DKK3 enhances the cytotoxicity of immune cells against tumor cells, reducing tumor immune evasion (82,83) (Figure 8).

Figure 8 DKK3’s inhibition of the JAK/STAT signaling pathway. STAT, signal transducer and activator of transcription.

Correlation with prostate cancer

Prostate cancer is one of the major malignant tumors threatening the health and lives of men worldwide, with high incidence and mortality rates globally. In the United States, new prostate cancer cases account for 27.3% of all new male cancer cases, and the mortality rate of prostate cancer ranks second only to lung cancer among cancer-related deaths in men (84). The incidence of prostate cancer is highest among African American men, followed by European and Asian men (85). With the westernization of lifestyle and dietary habits, and the aging population, the incidence of prostate cancer in Asian countries is also increasing annually. Although extensive research has been conducted on prostate cancer, the specific mechanisms of its occurrence and development, as well as the contributing factors, remain to be elucidated. With in-depth research on the epigenetic mechanisms of prostate cancer, it has been found that the molecular biological abnormalities of oncogenes, tumor suppressor genes, and related regulatory genes are closely related to the occurrence and development of prostate cancer. WIF1 and DKK3 are representative tumor suppressor genes among them. Their expression is significantly reduced in high-grade and advanced prostate cancer, suggesting their close association with tumor progression and malignancy (86-88). The hypermethylation of WIF1 and DKK3 gene promoter regions leads to the suppression of their expression, and patients with such low expression have poor prognosis and shorter survival times. Therefore, WIF1 and DKK3 can be used as important indicators for prognosis evaluation (89). Research shows that WIF1 and DKK3 inhibit the nuclear translocation of β-catenin in prostate cancer cell lines by blocking the Wnt/β-catenin signaling pathway, downregulating the expression of Cyclin D1 and c-Myc, and inhibiting cell proliferation. They also reduce the expression of CSC markers such as CD44 and ALDH1, inhibiting the self-renewal capacity of CSCs (90). Overexpression of WIF1 and DKK3 downregulates the expression of anti-apoptotic protein Bcl-2 and upregulates the expression of pro-apoptotic protein Bax, increasing the sensitivity of cells to apoptotic signals. They induce the activation of Caspase-3, Caspase-8, and Caspase-9, initiating the caspase cascade and inducing apoptosis (91). Additionally, by enhancing the stability and transcriptional activity of p53, WIF1 and DKK3 increase the expression of downstream apoptotic genes PUMA and NOXA, promoting mitochondria-mediated apoptosis (92). They also reduce the expression of anti-apoptotic proteins such as XIAP, Mcl-1, and Survivin, further promoting apoptosis (93). By upregulating E-cadherin and downregulating N-cadherin and Vimentin, they inhibit EMT, reducing cell migration and invasion (94). They also regulate the expression and activity of MMP-2 and MMP-9, reducing ECM degradation and inhibiting migration and invasion (95). WIF1 and DKK3 also interfere with cytoskeletal reorganization by regulating the expression of cytoskeleton-related proteins such as RhoA, Cdc42, Actin, and Tubulin, inhibiting migration (96). Finally, they reduce the expression of TGF-β and VEGF in the tumor microenvironment, further inhibiting migration and invasion (97).

Therapeutic potential

WIF1 and DKK3 are potential therapeutic targets for prostate cancer. WIF1 gene therapy utilizes gene transfer techniques such as adenovirus or lentivirus vectors to introduce the WIF1 gene into prostate cancer cells, effectively inhibiting the activity of the Wnt/β-catenin signaling pathway and reducing cell proliferation, migration, and invasion abilities (98). In epigenetic therapy, demethylating agents (e.g., 5-aza-2'-deoxycytidine) and histone deacetylase (HDAC) inhibitors restore WIF1 gene expression, enhancing its anti-cancer effects (99). In targeted therapy, recombinant WIF1 protein or small molecule inhibitors of the Wnt signaling pathway can also effectively inhibit cancer cell proliferation (100). In immunotherapy, WIF1 increases the sensitivity of the immune microenvironment, improving therapeutic effects when used in combination with immune checkpoint inhibitors (101). Additionally, WIF1 can act as a chemosensitizer when combined with conventional chemotherapy drugs (e.g., paclitaxel, cisplatin), enhancing the efficacy of chemotherapy drugs. DKK3 can enhance the sensitivity to radiotherapy and chemotherapy, improving therapeutic outcomes by regulating fibroblasts and endothelial cells in the tumor microenvironment, reducing neovascularization, and inhibiting recurrence and metastasis. Combining DKK3 with other targeted drugs or immunotherapies can exert multiple synergistic mechanisms, overcoming the limitations of single-target therapies and improving clinical outcomes for prostate cancer (102,103).

Discussion

Research review

This review aimed to consolidate the current understanding of the tumor suppressor genes WIF1 and DKK3 in the context of prostate cancer. Key findings from the literature highlight that both WIF1 and DKK3 play significant roles in inhibiting tumor progression through multiple mechanisms. WIF1 inhibits the Wnt/β-catenin signaling pathway, reduces nuclear β-catenin accumulation, and downregulates oncogenes such as c-Myc and Cyclin D1. It also promotes apoptosis by modulating the expression of apoptotic proteins and inhibits EMT by downregulating transcription factors like Snail and Slug. Similarly, DKK3 regulates the Wnt/β-catenin pathway indirectly, inhibits the PI3K/Akt and NF-κB pathways, and enhances apoptosis by stabilizing p53 and modulating pro-apoptotic genes. DKK3 also inhibits cell migration and invasion by affecting cytoskeletal dynamics and reducing the activity of MMPs.

Limitations and quality of the study

Despite the comprehensive nature of this review, certain limitations must be acknowledged. The heterogeneity of study designs and methodologies across the reviewed literature poses challenges in drawing consistent conclusions. The reliance on preclinical studies and cell lines limits the direct applicability of findings to clinical settings. Additionally, many studies did not consider the broader tumor microenvironment, which plays a crucial role in cancer progression. The potential publication bias and the exclusion of non-English language studies might have limited the scope of this review. Future studies should aim for standardized methodologies and consider clinical trials to validate the preclinical findings.

Future research needs

While the associations between WIF1, DKK3, and prostate cancer progression are valuable and novel, it is essential to note that current studies primarily rely on preclinical models. These studies demonstrate that WIF1 and DKK3 inhibit crucial signaling pathways, such as Wnt/β-catenin and PI3K/Akt, which are important in tumor suppression. However, translating these findings into clinical practice necessitates further research using advanced preclinical models that closely mimic human prostate cancer. Additionally, early-phase drug trials are required to evaluate the therapeutic efficacy of restoring WIF1 and DKK3 activity in patients. Such initiatives will clarify the druggability of these tumor suppressors and their potential impact on treatment outcomes. Current efforts focus on developing strategies, including epigenetic therapies, gene therapy, and small-molecule inhibitors, aimed at reactivating WIF1 and DKK3 expression. Although the findings are preliminary, they lay the groundwork for future research validating these genes as therapeutic targets.

Strong evidence supports the role of WIF1 and DKK3 as prognostic markers, with their expression levels closely correlated with tumor stage, aggressiveness, and patient survival outcomes. In advanced prostate cancer, WIF1 and DKK3 are often downregulated due to epigenetic silencing, such as promoter hypermethylation, which is associated with more aggressive tumor behavior and poorer prognosis. While their prognostic importance is clear, the predictive potential of WIF1 and DKK3 in guiding therapeutic responses needs further exploration. Clinical data are still limited regarding whether patients with WIF1 or DKK3 loss will respond favorably to targeted therapies. Therefore, early-phase clinical trials are essential to determine if these genes can serve as predictive biomarkers, helping to personalize treatment strategies.

Conclusions

This narrative review elucidates the pivotal roles of WIF1 and DKK3 as tumor suppressor genes in prostate cancer. Through their inhibition of the Wnt/β-catenin, PI3K/Akt, and NF-κB signaling pathways, WIF1 and DKK3 significantly reduce tumor cell proliferation, enhance apoptosis, and impede cellular migration and invasion. Despite these promising results, current studies exhibit significant heterogeneity in design and methodology, with a heavy reliance on preclinical models and cell lines, limiting the direct clinical applicability of these findings. Moreover, many studies have not fully considered the broader tumor microenvironment, which is a critical factor in cancer progression.

While WIF1 and DKK3 have shown significant potential in preclinical studies, it is important to acknowledge that their application in prostate cancer remains largely in the exploratory phase. Most of the existing research focuses on their molecular mechanisms, with limited clinical studies validating their efficacy as therapeutic targets. Their roles in regulating key pathways such as Wnt/β-catenin, PI3K/Akt, and NF-κB are well-documented, but translating these findings into effective clinical treatments requires further validation through advanced preclinical models and early-phase clinical trials.

Recent research has started to investigate the epigenetic regulation of WIF1 and DKK3, particularly through promoter methylation, which plays a critical role in their downregulation in prostate cancer. Epigenetic therapies aimed at restoring their expression are still in experimental stages. Additionally, while gene therapies targeting these tumor suppressors show promise, they are not yet ready for broad clinical application.

To bridge the gap between preclinical findings and clinical applications, more comprehensive studies are required to assess how reactivating WIF1 and DKK3 affects prostate cancer progression in vivo. Moreover, the predictive value of these genes in treatment response remains an area for further exploration. Combining therapies that restore WIF1 and DKK3 function with existing treatment modalities, such as chemotherapy or immunotherapy, could potentially enhance treatment efficacy and reduce resistance.

Future research should continue to focus on the clinical validation of WIF1 and DKK3 as therapeutic targets, explore their interactions with other signaling pathways, and further investigate the potential of epigenetic therapies, gene therapy, and small molecule inhibitors in restoring their function. Through more rigorous clinical studies, WIF1 and DKK3 may provide novel and personalized therapeutic options for prostate cancer patients, ultimately improving treatment outcomes and survival rates.

Acknowledgments

Funding: This research was supported by the Yichang Science and Technology Innovation Project (No. A23-1-049 to Ziqiu He).

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-24-304/rc

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-24-304/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-24-304/coif). Ziqiu He reports that this research was supported by the Yichang Science and Technology Innovation Project (No. A23-1-049). The other 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.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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