Abstract
Nuclear enriched abundant transcript 1 (NEAT1), a long non-coding RNA (lncRNA), is a critical player in the pathogenesis and progression of ovarian cancer. Its abnormal expression in patients’ follicular fluid (FF), granulosa cells, and oocytes has been linked to key processes such as cell proliferation, apoptosis, nuclear maturation, and follicle development. NEAT1’s regulation of oocyte maturation and its influence on tumor dynamics and cellular communication within the FF is well-established. In the ovarian tumor microenvironment, NEAT1 contributes to cellular proliferation, invasion, chemoresistance, and apoptosis. Moreover, its dysregulation correlates with poor prognosis and increased tumor aggressiveness, underscoring its potential as a therapeutic target. The interaction of NEAT1 with miRNAs and signaling pathways further highlights its significant role in ovarian cancer progression and its potential as a biomarker. This review explores NEAT1’s contributions to ovarian cancer progression, its influence within the follicular fluid microenvironment, and its therapeutic potential as a target to combat ovarian cancer development and drug resistance.
- NEAT1
- ovarian cancer
- long non-coding RNA (lncRNA)
- chemoresistance
- tumor progression
- epithelial-to-mesenchymal transition (EMT)
- PI3K/AKT/mTOR pathway
- competing endogenous RNA (ceRNA)
- miRNA regulation
- therapeutic target
- review
Introduction
Ovarian cancer remains one of the deadliest gynecological malignancies, primarily due to its asymptomatic onset and late-stage diagnosis, which complicates treatment and worsens prognosis (1, 2). Despite advancements in surgical techniques and chemotherapy, survival rates remain alarmingly low, largely due to the development of chemoresistance (3). Consequently, there is an urgent need to uncover the molecular mechanisms driving ovarian cancer to identify novel therapeutic targets (1, 4). In recent years, non-coding RNAs (ncRNAs) have emerged as key regulators in cancer biology, influencing tumor development, progression, and resistance mechanisms (5). Among these, long non-coding RNAs (lncRNAs) have gained significant attention for their ability to modulate gene expression at multiple levels (6).
ncRNAs are a diverse class of RNA molecules that do not encode proteins but are crucial in regulating gene expression through mechanisms such as chromatin remodeling, transcriptional regulation, and post-transcriptional modifications (7). microRNAs (miRNAs) and lncRNAs are major types of ncRNAs and are particularly significant in cancer biology (8). miRNAs are small regulatory RNAs, about 22 nucleotides long, that suppress gene expression by binding to target mRNAs, leading to their degradation or translation inhibition (9). Dysregulation of specific miRNAs in ovarian cancer is frequently associated with aberrant expression of oncogenes or tumor suppressor genes, contributing to tumor progression, metastasis, and chemoresistance (10). For instance, the miR-200 family is well-known for inhibiting epithelial-to-mesenchymal transition (EMT), a critical process in cancer metastasis, and its down-regulation is linked to poorer prognosis in ovarian cancer patients (11).
LncRNAs, typically exceeding 200 nucleotides in length, play equally critical roles in regulating ovarian cancer development and progression (12). LncRNAs act as molecular scaffolds, guiding chromatin modification and influencing gene expression, mRNA splicing, and stability (7). Oncogenic lncRNAs such as HOX transcript antisense RNA (HOTAIR) have been shown to promote ovarian cancer cell proliferation, invasion, and metastasis by altering chromatin states and modulating gene expression (13). Furthermore, lncRNAs are emerging as valuable biomarkers due to their stability in circulation, providing potential non-invasive diagnostic and prognostic tools (14).
ncRNAs are found in follicular fluid (FF) and play a role in the development of the follicle and oocyte (15). FF is composed of a rich reservoir of hormones, cytokines, extracellular vesicles, and ncRNAs (16). FF contributes significantly to tumor dynamics by modulating cell-cell communication and affecting the behavior of cancer cells and immune cells (17). FF-derived ncRNAs, including both miRNAs and lncRNAs, mediate tumor competition and promote the malignant potential of ovarian cancer cells by targeting tumor suppressor pathways involved in apoptosis, cell cycle regulation, and metastasis (18). Understanding how FF components, particularly ncRNAs, shape the tumor microenvironment (TME) is crucial for identifying novel therapeutic strategies.
Among the lncRNAs involved in ovarian cancer, nuclear enriched abundant transcript 1 (NEAT1) stands out as a prominent regulator involved in various cancers, including ovarian cancer (19). Highly up-regulated NEAT1 has been associated with poor prognosis, increased tumor aggressiveness, and enhanced chemoresistance in several malignancies (20). NEAT1 influences key oncogenic processes by interacting with miRNAs and proteins, regulating crucial pathways such as PI3K/AKT/mTOR, which are vital for cell survival, proliferation, and metastasis (21, 22). Recent studies have reinforced NEAT1’s role in ovarian cancer progression, particularly in chemoresistance. NEAT1 enhances cell survival by regulating pathways such as PI3K/AKT/mTOR, contributing to ovarian cancer cells’ resistance to treatments like PARP inhibitors (PARPi) (23). Furthermore, NEAT1’s impact extends to the TME, supporting tumor dynamics and chemoresistance (24). Targeting NEAT1 has been shown to modulate homologous recombination repair mechanisms, increasing cancer cell sensitivity to therapies (25).
This review examines NEAT1’s role in ovarian cancer progression, focusing on its regulatory mechanisms within the TME, particularly its presence in FF. We will also explore NEAT1’s potential as a therapeutic target, offering insights into how disrupting its pathways could provide new avenues for overcoming chemoresistance and improving treatment outcomes for ovarian cancer patients.
Role of NEAT1 in Ovarian Cancer Progression
Importance of NEAT1 in reproductive functions and ovarian cancer progression. While short ncRNAs have gained recognition for their roles in regulating reproductive functions, the influence of lncRNAs on female fertility remains underexplored (26). LncRNAs such as NEAT1 stands out as a key regulator of transcription and RNA processing (7, 27). As a crucial paraspeckle component, NEAT1 is essential in various physiological processes (28). Studies on NEAT1 knockout (KO) mice have revealed significant reproductive dysfunction, including corpus luteum abnormalities and reduced progesterone levels, despite regular ovulation (29). In hamster ovary cells, NEAT1 over-expression suppressed p53 expression and inhibited apoptosis, whereas NEAT1 knockdown enhanced p53 expression and promoted apoptosis. This indicates that NEAT1 may mitigate premature ovarian failure by inhibiting p53 (30). NEAT1 plays a critical role in bone marrow-derived mesenchymal stem cells (BM-MSCs) transplantation, which improves ovarian and hypothalamic IGF-1-kisspeptin signaling, the hypothalamic-pituitary-gonadal (HPG) axis, granulosa cell survival, steroidogenesis, angiogenesis, energy balance, and reduces oxidative stress in premature ovarian insufficiency (POI) rats. Elevated anti-apoptotic lncRNAs and microRNAs in BM-MSCs further aid in mitigating ovarian insufficiency (31). Additionally, NEAT1 has been shown to regulate oocyte maturation by modulating key factors such as PRKCA and JAK3, further underscoring its critical role in fertility regulation (32).
The aberrant expression of lncRNAs is frequently implicated in the development and progression of various cancers, including high-grade serous ovarian cancer (HGSOC) (33). In particular, NEAT1 is notably elevated in HGSOC, where its over-expression is associated with poor prognosis and aggressive tumor behavior (34, 35). NEAT1 has been shown to enhance ovarian cancer cell proliferation, migration, and invasion, as demonstrated through both in vitro and in vivo studies (35).
A key mechanism by which NEAT1 drives HGSOC progression is through the NEAT1/miR-506 axis, in which NEAT1 functions as a competing endogenous RNA (ceRNA), sequestering miR-506 and thereby driving oncogenic processes such as cell migration and proliferation (34). Additionally, extracellular vesicles derived from M2-polarized tumor-associated macrophages (TAMs) contribute to immune evasion in ovarian cancer by modulating the NEAT1/miR-101-3p/ZEB1/PD-L1 axis, further enhancing the tumor’s ability to escape immune surveillance (36).
Multiple oncogenic pathways modulated by NEAT1. NEAT1 exerts a multifaceted influence on ovarian cancer by modulating multiple signaling pathways that drive tumor growth and metastasis (37) (Table I). For instance, NEAT1 regulates ovarian cancer cell proliferation, colony formation, apoptosis, migration, and invasion through the miR-4500/BZW1 axis. By sponging miR-4500, NEAT1 enhances BZW1 expression, contributing to tumor progression (38). Additionally, NEAT1 promotes angiogenesis, a critical process for tumor survival, by regulating fibroblast growth factor 9 (FGF9) via the miR-365 axis. This interaction enhances the angiogenic potential of ovarian cancer cells and co-incubated human umbilical vein endothelial cells, supporting the formation of new blood vessels essential for tumor growth (39).
Summary of NEAT1 mechanisms, pathways, and regulatory functions in cancer.
Beyond these pathways, NEAT1 modulates several other miRNA networks involved in cancer progression (40). For example, the NEAT1/miR-214-3p axis promotes ovarian cancer progression by regulating angiogenesis, which is essential for tumor metastasis. Another significant interaction is the NEAT1/let-7 g axis, in which NEAT1 down-regulates let-7 g, leading to up-regulation of mesoderm-specific transcript (MEST) and promoting tumor progression through the ATGL pathway.
In ovarian granulosa cells, NEAT1 also protects by inhibiting apoptosis and autophagy through the miR-654/STC2-mediated MAPK signaling pathway. This mechanism contributes to ovarian cancer progression and underscores NEAT1’s broader regulatory functions in ovarian biology. These diverse miRNA regulatory networks collectively underscore NEAT1’s ability to orchestrate various oncogenic processes in ovarian cancer.
NEAT1’s role in epithelial-mesenchymal transition and metastasis. NEAT1 is pivotal in promoting EMT, a critical process in cancer metastasis (41-43). By sponging miR-1321, NEAT1 down-regulates tight junction protein 3 (TJP3), enhancing migration, invasion, and EMT in ovarian cancer cells. Knockdown of NEAT1 has been shown to significantly reduce metastatic potential, underscoring its value as a promising therapeutic target for preventing the spread of ovarian cancer (44). Additionally, NEAT1 promotes ovarian cancer metastasis through sponging miR-382-3p, which allows the up-regulation of Rho-associated coiled-coil-containing protein kinase 1 (ROCK1, a gene closely associated with metastasis) (45). This ceRNA relationship amplifies the metastatic capacity of ovarian cancer cells, positioning NEAT1 as a central regulator of both local tumor growth and distant metastasis.
NEAT1 and chemotherapy resistance. Chemotherapy resistance remains a significant challenge in the treatment of ovarian cancer, and the lncRNA NEAT1 plays a pivotal role in this resistance by regulating several key pathways (25). NEAT1 contributes to paclitaxel resistance in ovarian cancer cells by modulating ZEB1 expression via the miR-194 axis, promoting cell survival and proliferation under chemotherapeutic stress (46). Additionally, NEAT1 enhances homologous recombination (HR) repair, increasing resistance to PARP inhibitors (PARPi) such as Olaparib. Knockdown of NEAT1 has been shown to decrease the expression of DNA repair factors RAD51 and FOXM1, thereby increasing DNA damage and sensitizing ovarian cancer cells to chemotherapy (23). NEAT1 also plays a crucial role in suppressing cisplatin resistance. By regulating the miR-770-5p/PARP1 axis, NEAT1 knockdown reduces PARP1 expression, which enhances sensitivity to DNA-damaging agents like cisplatin (47). In addition, the alternative polyadenylation (APA) regulator CSTF3 has been identified as a contributor to platinum resistance in ovarian cancer. CSTF3 promotes the generation of the short isoform NEAT1_1, which is associated with platinum resistance. Knockdown of CSTF3 reduces NEAT1_1 expression, further enhancing the sensitivity of ovarian cancer cells to platinum-based chemotherapy (48). These findings highlight NEAT1 as a potential therapeutic target for overcoming multiple forms of chemoresistance.
Role of FF in Ovarian Cancer
FF components. FF is critical in reproductive physiology and the ovarian TME. Its complex composition, which includes hormones (e.g., estrogen, progesterone), cytokines, growth factors, and reactive oxygen species (ROS), is essential for oocyte development and contributes to the tumorigenic process in ovarian cancer (49-55) (Table II).
Estrogen, for example, promotes cell growth and extracellular matrix (ECM) remodeling, facilitating the attachment and spread of cells within the fallopian tube epithelium (FTEC). This environment can support the transformation of immortalized human fimbrial epithelial cells, enhancing the potential for tumor formation and dissemination, particularly in high-grade serous carcinoma (HGSC) models. ROS in FF can induce DNA damage in FTEC cells, especially in the presence of p53 mutations, further promoting genomic instability and carcinogenesis (56).
During the follicular phase of the menstrual cycle, FF serves as a nutrient-rich medium that surrounds and nourishes the oocyte. When the follicular cyst ruptures during ovulation, the released FF transiently exposes the ovarian surface epithelium and fallopian tube cells to its contents, including ROS and cytokines, which may promote malignant transformation. The incessant ovulation hypothesis posits that this monthly exposure of ovarian surface cells to FF, followed by cycles of damage and repair, increases the risk of genetic instability and ovarian cancer development.
Additionally, components such as hepatocyte growth factor (HGF) within FF can activate oncogenic pathways such as the HGF/c-MET signaling axis, which supports the migration and invasion of ovarian cancer cells, further contributing to tumor progression (57). These complex signaling events underline the critical role of FF in shaping the tumor microenvironment and driving cancer progression.
Impact on tumor dynamics. The TME is a complex network consisting of the ECM, basement membrane, tumor-infiltrating immune cells, endothelial cells, adipocytes, cancer-associated fibroblasts (CAF), stromal cells, and cancer stem cells (CSC) (58) (Figure 1). Within this microenvironment, FF-derived components, including hormones, cytokines, and ncRNAs, significantly influence tumor progression by modulating cell-cell communication, immune responses, and angiogenesis (17).
The tumor microenvironment (TME) is a complex and dynamic system composed of cancer cells, stromal cells, immune cells, blood vessels, and extracellular matrix components. This figure illustrates the interactions within the TME that contribute to tumor progression, metastasis, and therapeutic resistance. Key elements include exchanging signaling molecules and exosomes between cancer-associated fibroblasts (CAFs) and cancer stem cells (CSC). Immune cells such as tumor-associated macrophages (TAMs) and endothelial cells promote angiogenesis, immune suppression, and extracellular matrix remodeling. Exosomes, which carry non-coding RNAs (ncRNAs), including GAS5, play critical roles in regulating gene expression, cell proliferation, and survival, further driving tumor growth and resistance to therapy. Understanding these interactions, especially the role of exosome-mediated communication, is essential for developing targeted therapies that disrupt the pro-tumorigenic processes in the TME. Images were adopted and modified from Servier Medical Art.
Moreover, TME comprises diverse stromal cells that secrete cytokines, playing a crucial role in cancer progression. Similarly, the ovary contains stromal cells contributing to its physiological and pathological processes. Previous research has shown that the supernatant of cultured ovarian cancer-associated fibroblasts exhibits a significant up-regulation of interleukin-8 (IL-8). This cytokine has been found to promote the migration of ovarian cancer cells while simultaneously reducing autophagy, thereby facilitating tumor progression and survival (57).
Studies indicate that ovarian cancer development begins in fallopian tube secretory epithelial (FTSE) cells (59). Studies also indicate that the FF-exposed fallopian tube epithelial cells (FTECs) may serve as the origin of serous tubal intraepithelial carcinomas (STIC), which metastasize to the ovary (60, 61). The attachment of these cells to the ovarian ECM, mainly type I collagen, is critical in tumor implantation and metastasis (62). Tumor suppressor gene mutations, such as in PTEN, further enhance the survival and proliferation of FTECs within this ECM-rich environment, promoting HGSOC development (63).
Early p53 signature gene mutations transform FTSE cells into serous tubal intraepithelial carcinomas (STIC), which later metastasize to the ovaries and spread to other organs in the peritoneal cavity (64). In FTE-derived HGSOC, tumor heterogeneity within FTE cells significantly influences tumor cell survival, metastasis, and chemoresistance. This heterogeneity is typically inherited from the parent cell of origin, a concept that aids in understanding the genomic composition of tumor tissues and the development of ovarian cancer. Studies have shown that HGSOC and normal fallopian tube epithelial cells share common markers, such as Pax8, WT1, and ESR1, which are widely expressed in HGSOC (65). This indicates that specific subtypes of ovarian cancer possess transcriptomic features similar to normal FTECs, indicating their potential origin from fallopian tube cells.
During ovulation, the ECM that FTECs encounter plays a role in their implantation into the ovary, highlighting the importance of cell migration in ovarian cancer development. The ovulation site exposes the underlying ECM, and FTECs tend to attach to the type I collagen in the ovarian ECM (66). A p53 mutation alone is insufficient for murine oviductal epithelial (MOE) cells to survive in a 3D collagen-rich microenvironment. However, shRNA knockdown of PTEN can restore the relative viability of MOE cells in 3D collagen. PTEN dysregulation or loss leads to hyperactivation of the PI3K/AKT signaling pathway, and sustained PI3K signaling has been found to enhance MOE cell growth in a 3D collagen microenvironment (67).
FF enhances tumor dynamics by activating key signaling pathways such as AKT, ERK, and TGF-β. These pathways collectively promote cell proliferation, invasion, and angiogenesis, ultimately accelerating ovarian cancer progression (68). In conclusion, the FF and TME play critical roles in ovarian cancer progression by modulating key signaling pathways and enhancing cell migration and invasion, thereby promoting tumor growth, metastasis, and resistance to therapy (69).
FF-derived non-coding RNAs in tumor competition. FF contains diverse vesicles and bioactive molecules, including exosomes, which play a pivotal role in supporting follicular development and oocyte maturation (70). ncRNAs within FF, particularly miRNAs and lncRNAs, play a pivotal role in mediating tumor competition by modulating the behavior of cancer cells and their interactions with the TME (69, 71). The miRNAs in FF, such as miR-21 and miR-155, are frequently over-expressed in ovarian cancer and contribute to oncogenesis by targeting tumor suppressor genes like PTEN (72-74). The transfer of these oncogenic miRNAs via extracellular vesicles to neighboring cancer cells further enhances the malignancy of ovarian tumors.
In addition, lncRNAs within FF, such as NEAT1 and TUG1, have been implicated in promoting ovarian cancer progression. NEAT1, for example, interacts with HuR and miR-124-3p, driving carcinogenesis, while TUG1 affects EMT, a critical process in metastasis. These ncRNAs can act as molecular regulators within the TME, influencing cancer cell survival, invasion, and chemoresistance (75) (Figure 2). The expression of specific lncRNAs, such as NBAT-1, is markedly reduced in ovarian cancer, correlating with poor patient prognosis. These tissue-specific lncRNAs exert differential effects on tumor dynamics, making them potential therapeutic targets. By disrupting the pro-tumorigenic effects of FF-derived ncRNAs, it may be possible to modulate the TME in a way that impairs tumor growth and enhances the efficacy of existing treatments (76).
The scheme illustrates the role of long non-coding RNA (lncRNA) in mediating tumor competition within the ovarian cancer microenvironment. lncRNAs modulate various oncogenic processes, including cell proliferation, invasion, metastasis, and chemoresistance. They influence tumor dynamics by regulating gene expression, inhibiting epithelial-to-mesenchymal transition, and suppressing cell survival pathways. The diagram highlights the interactions between lncRNAs and key signaling pathways that limit the competitive advantage of malignant cells, shaping the tumor microenvironment. Images were adopted and modified from Servier Medical Art.
The intricate interplay between FF components and the TME is crucial in ovarian cancer development. Understanding how ncRNAs within FF mediate tumor competition and influence the ovarian microenvironment is essential for identifying novel therapeutic strategies to target the TME in ovarian cancer.
FF and immune modulation. FF contributes to ovarian cancer progression through its hormonal and cytokine composition and plays a significant role in modulating the tumor’s immune environment (77). FF-derived factors, including cytokines and ncRNAs, influence the recruitment and polarization of immune cells, particularly tumor-associated macrophages (TAMs), which contribute to immune suppression and support tumor growth (17).
TAMs are often polarized into the M2 phenotype, which promotes tumor progression by secreting anti-inflammatory cytokines and facilitating ECM remodeling. In ovarian cancer, the ECM protein transforming growth factor beta induced (TGFBI) is highly up-regulated in serous tubal intraepithelial carcinoma (STIC) lesions and the primary HGSOC stroma. TGFBI is predominantly produced by CD163+ M2 macrophages. High levels of TGFBI have been shown to correlate with an increased proportion of immunosuppressive cells, suggesting that TGFBI not only facilitates tumor growth and metastasis but also promotes immune evasion by modulating macrophage activity and distribution (78).
Additionally, ncRNAs present in FF further enhance immune suppression by influencing the behavior of immune cells within the TME (79). For example, miR-21, one of the miRNAs frequently over-expressed in ovarian cancer, contributes to immunosuppressive signaling by down-regulating tumor suppressor genes such as PTEN, which has downstream effects on immune surveillance mechanisms. These interactions underscore the complex role that FF-derived ncRNAs play in creating an immune-tolerant environment that supports ovarian cancer progression (80).
Targeting the tumor immune microenvironment. The collective actions of FF-derived factors and ncRNAs within the TME play a critical role in the development of ovarian cancer by shaping the immune landscape to favor tumor growth and metastasis (81). Understanding the interactions between FF components, immune cells, and stromal cells in the fallopian tubes and ovarian tissues is vital for designing novel therapeutic strategies to overcome immune suppression in ovarian cancer.
By focusing on the modulation of macrophages, such as inhibiting the activity of TGFBI or reprogramming M2 macrophages toward a pro-inflammatory, anti-tumor M1 phenotype, it may be possible to disrupt the immunosuppressive environment that supports ovarian cancer progression (78). Targeting ncRNAs that regulate immune cell behavior also offers promising avenues for therapeutic interventions to reverse immune tolerance and enhance anti-tumor immunity. Ultimately, strategies aimed at modifying the immune microenvironment hold the potential to improve patient outcomes by enhancing the efficacy of existing treatments and offering new avenues for immunotherapy in ovarian cancer.
Therapeutic Prospects for Targeting NEAT1 in Ovarian Cancer
NEAT1 is critical in mediating communication between cancer cells and their microenvironment, enhancing EMT, angiogenesis, and immune evasion. By interacting with other components of FF, NEAT1 facilitates metastasis and contributes to the aggressiveness of ovarian cancer. Recent studies have positioned NEAT1 as a promising therapeutic target in ovarian cancer due to its involvement in various oncogenic processes, including cell proliferation, migration, invasion, and chemoresistance. Targeting NEAT1 could inhibit tumor growth, reduce metastasis, and enhance sensitivity to standard treatments such as chemotherapy and PARPi, offering new avenues for improving patient outcomes (23) (Table III).
Therapeutic prospects for targeting NEAT1 in ovarian cancer.
Targeting NEAT1 expression. One direct approach for targeting NEAT1 in ovarian cancer involves reducing its expression using RNA interference technologies, such as small interfering RNA (siRNA) or antisense oligonucleotides (ASOs) (82). NEAT1 silencing has been shown to inhibit ovarian cancer cell proliferation and invasion while promoting apoptosis. Moreover, NEAT1 knockdown impairs the stability of key oncogenic proteins, such as LIN28B, which are crucial for cancer progression. These findings highlight the therapeutic potential of targeting NEAT1 to disrupt cancer-promoting pathways and reduce tumor aggressiveness (34).
Enhancing chemotherapy sensitivity. NEAT1 plays a critical role in chemotherapy resistance, particularly in cisplatin-resistant ovarian cancer. By regulating miRNA networks that protect cancer cells from apoptosis, NEAT1 promotes resistance to chemotherapy. Targeting NEAT1 could restore chemotherapy sensitivity by reversing these resistance mechanisms. For instance, NEAT1 knockdown enhances ovarian cancer cell sensitivity to cisplatin and other platinum-based drugs by down-regulating anti-apoptotic proteins and up-regulating tumor suppressor genes. This suggests that NEAT1-targeted therapies when combined with conventional chemotherapy, could significantly improve treatment efficacy and overcome drug resistance (25).
Overcoming PARP inhibitor resistance. Another promising therapeutic prospect for targeting NEAT1 is overcoming resistance to PARPi, which exploits DNA repair deficiencies in cancer cells. NEAT1 promotes HR repair by stabilizing proteins like RAD51 and FOXM1, key players in DNA damage repair, thereby contributing to PARPi resistance in ovarian cancer cells. NEAT1 knockdown sensitizes cancer cells to PARPi by inhibiting HR repair and increasing DNA damage. This approach could be especially beneficial for patients with BRCA1/2 mutations who develop resistance to PARPi treatments, potentially improving treatment outcomes and offering a strategy to improve treatment outcomes (23, 25).
Targeting NEAT1/miRNA interactions. NEAT1 exerts many oncogenic effects by acting as a ceRNA that sponges tumor-suppressive miRNAs. For example, NEAT1 sponges miRNAs like miR-34a-5p and miR-1321, promoting the expression of oncogenes involved in cell survival, proliferation, and metastasis (44). Therapeutic strategies aimed at disrupting the NEAT1/miRNA axis could restore the tumor-suppressive functions of these miRNAs, thereby reducing cancer cell viability and metastasis. In particular, targeting the NEAT1/miR-506 and NEAT1/miR-1321 axes holds promise for inhibiting ovarian cancer progression by enhancing the tumor-suppressive effects of these miRNAs (83, 84).
NEAT1 as a biomarker for personalized therapy. Given the strong association between NEAT1 over-expression and poor prognosis in ovarian cancer, NEAT1 could serve as a valuable biomarker for predicting treatment responses and tailoring personalized therapies. Patients with high NEAT1 expression may more likely benefit from NEAT1-targeted therapies or combination treatments with chemotherapy and PARPi (23). Moreover, monitoring NEAT1 levels could provide a means to assess therapeutic efficacy and guide treatment adjustments during disease management, making it a potential tool for personalized cancer therapy (40).
CRISPR-based therapeutic approaches. CRISPR/Cas9 genome-editing technology represents an emerging therapeutic strategy for directly targeting lncRNAs (85), such as NEAT1. CRISPR-based approaches could permanently reduce NEAT1 expression in ovarian cancer cells by disrupting its transcriptional activity or regulatory regions. This method offers a potentially long-lasting therapeutic solution, although further research is necessary to evaluate its safety, efficacy, and delivery mechanisms in clinical applications.
Targeting NEAT1 offers multiple therapeutic prospects for treating ovarian cancer. From RNA silencing technologies to enhancing chemotherapy and PARPi sensitivity, disrupting miRNA interactions, or employing CRISPR-based approaches, NEAT1 represents a critical molecular target with the potential to improve treatment outcomes. Continued exploration into NEAT1’s mechanisms and the development of targeted therapies could pave the way for more effective and personalized cancer treatments in ovarian cancer.
Future Directions
Comprehensive understanding of NEAT1 mechanisms. While significant progress has been made in understanding NEAT1’s role in ovarian cancer, a more thorough understanding of the detailed molecular mechanisms by which NEAT1 regulates key oncogenic processes is needed. Future studies should focus on identifying all downstream effectors of NEAT1 and elucidating its role in various signaling pathways, including those related to apoptosis, cell proliferation, EMT, chemotherapy resistance, and immune response by various approaches, such as bioinformatics analysis (86, 87). Moreover, understanding the context-specific roles of NEAT1 in different subtypes of ovarian cancer, especially in HGSOC, will be crucial for developing targeted therapies (88).
Exploring NEAT1 isoforms and functional domains. NEAT1 is transcribed into two isoforms, NEAT1_1 and NEAT1_2, which may have distinct roles in cancer progression. Future studies should aim to delineate the specific functions of each isoform and their contributions to ovarian cancer pathogenesis. Additionally, exploring the functional domains of NEAT1 that are critical for its interaction with proteins and other RNAs, such as miRNAs, will provide insights into how NEAT1 exerts its oncogenic effects. This knowledge could be pivotal for designing more precise therapeutics to disrupt NEAT1’s oncogenic functions (48).
Development of NEAT1-targeted therapies. Oligonucleotide drugs, first demonstrated with Fomivirsen’s approval in 1998, offer a cost-effective and precise approach to modulating genes beyond the scope of small-molecule inhibitors or monoclonal antibodies (89, 90). The success of mRNA COVID-19 vaccines, such as Moderna’s mRNA-1273 and BioNTech’s BNT162, highlights their potential for treating diverse diseases, including cancer, neurodegenerative disorders, respiratory disorders, and diabetic retinopathy (82, 91-93). However, efficient delivery remains challenging, relying on viral systems (e.g., adenovirus, lentivirus) and nonviral methods like lipid nanoparticles, electroporation, and cell-penetrating peptides (CPPs) (94). Targeting NEAT1 with oligo-nucleotides could harness these advancements to disrupt oncogenic pathways in ovarian cancer and improve therapeutic outcomes.
LncRNAs-targeted therapies, including siRNA, antisense oligonucleotides (ASO), and CRISPR-based approaches, show promise in preclinical models but require further refinement for clinical application (95). Emerging RNA-targeted technologies broaden the therapeutic landscape, addressing challenges in delivery, off-target effects, and long-term safety (Figure 3).
The schematic representation highlights the therapeutic potential of targeting NEAT1 in ovarian cancer. NEAT1 modulates critical oncogenic processes within the ovarian cancer microenvironment, including proliferation, invasion, metastasis, and chemoresistance. Various delivery mechanisms, including siRNA, ASOs, CRISPR, viral vectors, lipid nanoparticles, and cell-penetrating peptides (CPPs), are depicted targeting NEAT1. These strategies aim to disrupt NEAT1-mediated pathways and restore tumor-suppressive functions, enhancing treatment outcomes. The illustration also integrates NEAT1’s interactions with the nucleus and cytoplasmic components, emphasizing its role in tumor progression. Images were adopted and modified from Servier Medical Art.
Role of NEAT1 in the tumor microenvironment. Emerging evidence suggests that NEAT1 influences cancer cell behavior and shapes the TME, including its interactions with immune cells and stromal components. Future research should investigate how NEAT1 modulates the TME in ovarian cancer and whether targeting NEAT1 can disrupt tumor-stroma interactions, potentially enhancing immune responses and reducing tumor progression. Understanding NEAT1’s role in the crosstalk between cancer cells and the TME could open new avenues for therapeutic interventions that target the broader tumor ecosystem (24).
NEAT1 as a biomarker for early detection and treatment response. Given the strong association between NEAT1 over-expression and poor prognosis in ovarian cancer, future studies should evaluate the potential of NEAT1 as a biomarker from FF-derived exosomes for early detection, disease monitoring, and treatment response prediction (35, 96). Longitudinal studies involving larger patient cohorts are necessary to confirm the prognostic value of NEAT1 levels in ovarian cancer. Additionally, non-invasive methods for detecting NEAT1 in circulating tumor cells or extracellular vesicles, such as exosomes, could be developed to monitor disease progression and assess therapeutic efficacy.
Clinical trials and patient-centered research. To translate the promising preclinical findings on lncRNAs into clinical applications will require well-designed clinical trials that evaluate the safety, efficacy, and tolerability of lncRNA-targeted therapies in patients (97). The ongoing clinical trial NCT05995067 examines the involvement of NEAT1 and MALAT1 in EMT, a process linked to the progression of diseases like periodontitis. As a polymicrobial inflammatory condition, periodontitis features EMT-driven tissue degradation, though the contribution of lncRNAs to this process remains insufficiently studied. Moreover, the ongoing clinical trial NCT04937855 explores the role of NEAT1 in mitigating lung injury in acute respiratory distress syndrome (ARDS) by functioning as a ceRNA to sequester miR-27b, thereby activating Nrf2 and reducing inflammation. Insights into lncRNA-mediated regulation of EMT and inflammation could unveil novel therapeutic targets for ARDS and related conditions. Collaborative efforts between researchers, clinicians, and pharmaceutical companies are essential to advance NEAT1-based therapeutics into clinical settings. Furthermore, patient-centered research that considers the quality of life, potential side effects, and accessibility of these therapies will be important in ensuring their success in the real-world clinical landscape.
The future of NEAT1 research in ovarian cancer is filled with exciting possibilities. By addressing key challenges such as understanding NEAT1 mechanisms, developing targeted therapies, exploring its role in the TME, and leveraging its potential as a biomarker, researchers can pave the way for new therapeutic strategies that may significantly improve the outcomes for ovarian cancer patients.
Conclusion
NEAT1 has emerged as a crucial lncRNA with significant roles in ovarian cancer progression, chemoresistance, and tumor metastasis (88). It’s over-expression has been consistently associated with poor prognosis, advanced clinical stages, and increased tumor aggressiveness. Mechanistically, NEAT1 exerts its oncogenic effects by interacting with miRNAs, particularly through its function as a ceRNA, regulating key signaling pathways such as PI3K/AKT/mTOR and facilitating processes like EMT. Additionally, NEAT1 has been shown to promote chemoresistance by influencing miRNAs involved in apoptosis and survival pathways, making it a promising target for overcoming drug resistance in ovarian cancer treatment.
The therapeutic potential of targeting NEAT1 is underscored by preclinical studies demonstrating that NEAT1 knockdown can inhibit tumor growth, reduce cell proliferation, and enhance sensitivity to chemotherapeutic agents such as cisplatin and PARP inhibitors (23). Future therapeutic strategies focusing on NEAT1 silencing or its downstream effectors may provide new avenues for treating patients with ovarian cancer, particularly those with drug-resistant tumors. Moreover, NEAT1’s role in modulating the TME and its potential as a biomarker for early detection and treatment response further highlights its importance in ovarian cancer research (88).
In conclusion, while considerable progress has been made in understanding the biological functions of NEAT1 in ovarian cancer, much remains to be explored. Advancing our knowledge of NEAT1’s precise mechanisms, developing clinically viable NEAT1-targeted therapies, and conducting rigorous clinical trials will be essential in translating these findings into improved outcomes for ovarian cancer patients. As research continues, NEAT1 holds the promise of becoming a pivotal target in the fight against ovarian cancer, offering new hope for more effective, personalized treatment options.
Acknowledgements
The authors gratefully acknowledge the support of Prof. Han-Jung Lee (Department of Natural Resources and Environmental Studies, College of Environmental Studies, National Dong Hwa University) and the generous support of the Richard Lounsbery Foundation.
Footnotes
Authors’ Contributions
Y-C.W.: Writing – original draft, Visualization (figures – design and production). M-H.K.: Writing – original draft, Visualization (figures – design and production). W-L.H.: Writing – original draft. L.D.: Writing – technical editing. C-W.C.: Writing – original draft, technical editing, and formatting.
Conflicts of Interest
No potential conflicts of interest were reported by the Author(s).
Funding
The work was supported by Taiwan’s National Science and Technology Council (NSTC 111-2320-B-259-001- and NSTC 1112320-B-259-002-MY3) (to C-W.C.).
- Received January 1, 2025.
- Revision received January 17, 2025.
- Accepted January 20, 2025.
- Copyright © 2025 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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