Unveiling the oncogenic functions of lncRNA PSMG3-AS1: a review of its biological roles in cancer

Abstract

Long non-coding RNAs (lncRNAs) have emerged as crucial regulators of various biological processes, including gene expression, cell differentiation, and response to external stimuli. Among them, PSMG3-AS1 has gained attention due to its involvement in the regulation of tumorigenesis across multiple cancers. This review provides an overview of the biogenesis, distribution, and functional roles of lncRNAs, with a particular focus on PSMG3-AS1 and its impact on cancer development. PSMG3-AS1 has been shown to play an oncogenic role in diverse malignancies such as breast cancer, cervical squamous cell carcinoma, endometrial cancer, gastric cancer, Glioma, hepatocellular carcinoma, lung cancer, oral squamous cell carcinoma, and prostate carcinoma, where its overexpression correlates with poor prognosis and enhanced tumor aggressiveness. Mechanistically, PSMG3-AS1 promotes cancer progression by interacting with multiple regulatory networks, including miRNA-mediated pathways and epigenetic modifications, which influence key cellular processes such as proliferation, migration, and invasion. By functioning as a molecular sponge for specific miRNAs, PSMG3-AS1 modulates the tumor-suppressive effects of these miRNAs, contributing to an oncogenic environment. Additionally, the ability of PSMG3-AS1 to regulate gene expression through DNA methylation further underscores its role in cancer progression. The accumulating evidence suggests that PSMG3-AS1 may serve as both a prognostic biomarker and a potential therapeutic target. However, further research is necessary to fully understand the molecular mechanisms by which PSMG3-AS1 influences cancer biology and to explore its clinical implications in cancer diagnosis and treatment.

Introduction

Cancer remains a leading cause of mortality globally, contributing to over 10 million deaths in 2019. This escalating burden reflects an interplay of demographic shifts, such as population aging, and modifiable risk factors including tobacco and alcohol use, unhealthy diets, physical inactivity, and environmental pollutants [1, 2]. The disease imposes significant health and economic challenges, disproportionately affecting high-income countries in terms of disability-adjusted life-years (DALYs) [3]. Cancer mortality accounts for one in six deaths worldwide, with 5.5 million men and 4.4 million women succumbing to the disease in 2020 [4]. This toll extends beyond individuals to their families, creating profound societal impacts. For example, maternal deaths from cancer in sub-Saharan Africa reveal a common occurrence of childhood orphans [5]. Such instances underscore the broader implications of cancer, ranging from premature mortality and economic strain to its role as a barrier to increasing global life expectancy [6]. Addressing these multifaceted challenges necessitates a comprehensive approach to cancer prevention, treatment, and support systems.

Advances in genomics have reshaped understanding of the human genome, revealing that protein-coding genes constitute less than 2% of its entirety [7]. Previously dismissed as “junk DNA,” non-coding RNAs (ncRNAs) have emerged as pivotal regulatory elements with diverse biological functions [8]. Modern techniques, such as RNA sequencing, have identified various ncRNAs, including circular RNAs (circRNAs), long non-coding RNAs (lncRNAs), and microRNAs (miRNAs), which serve as key players in cellular regulation and disease mechanisms [9, 10]. NcRNAs are categorized into housekeeping and regulatory types. While housekeeping ncRNAs, such as tRNAs and rRNAs, maintain cellular functions, regulatory ncRNAs, including lncRNAs and circRNAs, play roles in gene expression modulation [11, 12]. As this is a review of lncRNAs, we hereafter consolidate and synthesize current knowledge on one particularly promising candidate (PSMG3‑AS1) highlighting its biological roles, mechanisms, and implications in cancer.

Long non-coding RNAs (lncRNAs) are integral to the regulation of gene expression, influencing processes such as chromatin remodeling, transcription, and post-transcriptional modifications [13, 14]. These RNA molecules, longer than 200 nucleotides and non-coding in nature, have been implicated in fundamental biological functions, including cell proliferation, differentiation, and apoptosis [15, 16]. Beyond cancer, dysregulated lncRNAs contribute to a variety of diseases, including cardiovascular and neurodegenerative disorders, as well as metabolic disorders [17–19]. In oncology, aberrant lncRNA expression drives tumor progression, metastasis, and therapeutic resistance [20]. Acting as competing endogenous RNAs (ceRNAs), lncRNAs regulate gene expression by binding to miRNAs, further emphasizing their complexity in cancer pathophysiology [21–23]. As a result, lncRNAs have emerged as valuable biomarkers and therapeutic targets, offering opportunities for improved diagnostics and individualized treatments.

Numerous lncRNAs have demonstrated significant roles in cancer progression. For instance, TRPM2-AS promotes angiogenesis in gallbladder cancer (GBC) by regulating the IGF2BP2/TRPM2-AS/PABPC1-NUMB-NOTCH1 axis, correlating with poor patient outcomes [24]. Similarly, LINC00930 inhibits pancreatic cancer proliferation, migration, and epithelial-mesenchymal transition (EMT) via the miR-6792-3p/ZBTB16 pathway, suggesting its potential as a prognostic marker [25–27]. In oral squamous cell carcinoma (OSCC), LINC00839 expression is associated with advanced tumor grade and lymph node involvement, functioning through the miR-195-5p/CCNE1 axis [28]. These examples illustrate the diversity of mechanistic pathways through which lncRNAs contribute to oncogenesis, setting the stage for a focused review on PSMG3‑AS1 and its distinct biological roles.

PSMG3 antisense RNA 1 (PSMG3-AS1) is predominantly localized in the nucleus and mapped to chromosome 7p22.3. Recent studies have begun to characterize its oncogenic functions, with publication frequency doubling in the last five years, yet findings remain fragmented across tumor types. Although emerging data hint at critical roles in proliferation, metastasis, and chemoresistance, a centralized and comprehensive review integrating these findings is lacking. This consolidated synthesis is therefore timely, to clarify emerging trends, reconcile conflicting reports, and identify gaps ripe for further research. This review aims to investigate the implications of PSMG3-AS1 in various cancers, including breast cancer, cervical squamous cell carcinoma, endometrial carcinoma, gastric cancer, glioma, hepatocellular carcinoma, lung carcinoma, oral squamous cell carcinoma, and prostate carcinoma. By elucidating its involvement across diverse malignancies, we seek to provide insights into the therapeutic and prognostic potential of PSMG3-AS1.

Biogenesis, distribution, and biological functions of lncRNAs

Long non-coding RNAs (lncRNAs) have emerged as significant regulators of various biological processes. Advances in RNA sequencing and bioinformatics have identified numerous lncRNAs, revealing their broad diversity, complex biogenesis, and critical roles in cellular physiology.

Biogenesis of lncRNAs

LncRNAs are primarily transcribed by RNA polymerase II, undergoing similar post-transcriptional modifications as mRNAs, such as 5′ capping, splicing, and 3′ polyadenylation. However, they also follow unique processing mechanisms. For instance, some lncRNAs, form mature 3′ ends through ribonuclease P cleavage of tRNA-like structures. Others may incorporate snoRNA-protein complexes at their termini, enhancing stability [29, 30]. Additionally, circular lncRNAs (circRNAs) are generated through back-splicing, forming covalently closed loops that confer resistance to exonuclease-mediated degradation [31].

Epigenetic modifications significantly regulate lncRNA transcription. Histone acetylation, such as H3K56 acetylation, and chromatin remodeling by factors like SWI/SNF can promote lncRNA synthesis [32]. Conversely, methylation, as seen in the paternal allele of the Air lncRNA, can suppress transcription and influence the expression of nearby genes [33]. Furthermore, lncRNA degradation is tightly controlled by cellular machinery, including nuclear exosomes and cytoplasmic pathways involving UPF1 and Xrn1 [33, 34].

Distribution and features of lncRNAs

LncRNAs are ubiquitously expressed across prokaryotic and eukaryotic organisms [35]. Their genomic origins are diverse, arising from promoters, enhancers, intergenic regions, and the antisense strands of protein-coding genes [29]. In humans, thousands of lncRNAs have been cataloged, with estimates ranging from 5,400 to over 10,000 unique transcripts [36]. Despite this abundance, lncRNA expression is typically more cell-, tissue-, and temporally specific than protein-coding genes [37].

Evolutionarily, lncRNAs exhibit lower sequence conservation compared to protein-coding genes, though their structural motifs are often preserved, highlighting their functional importance. Additionally, lncRNAs evolve rapidly, contributing to their dynamic roles across species [38].

Biological functions of lncRNAs

LncRNAs regulate gene expression through diverse mechanisms, including acting as molecular signals, decoys, scaffolds, guides, or SINEUPs [39]. As signals, lncRNAs mark specific cellular events; for example, Xist signals X chromosome inactivation by recruiting chromatin modifiers to induce DNA methylation and histone modification [40]. Decoy lncRNAs trap microRNAs [41, 42] transcription factors, or RNA-binding proteins to influence the activity of target genes [39]. For example, the lncRNA HULC enhances its target transcript PRKACB by sequestering miR-372, which leads to the phosphorylation of the cAMP-responsive element (CRE)-binding protein (CREB) [43] in hepatocellular carcinoma. Scaffold lncRNAs provide a platform for assembling molecular complexes, such as HOXA11-AS, which recruits chromatin modifiers to silence genes and drive tumor progression [44]. Guide lncRNAs direct ribonucleoprotein complexes to specific genomic loci, exemplified by HOTTIP, which guides the WDR5/MLL complex to the HOXA locus to promote histone methylation and gene activation [45]. SINEUPs represent a unique class of lncRNAs that enhance the translation of target mRNAs without affecting transcript levels; for instance, AS-Uchl1 increases protein synthesis by facilitating polysome association with Uchl1 mRNA, showcasing therapeutic potential for disorders caused by insufficient protein production [46].

PSMG3-AS1 in human cancers

PSMG3-AS1 acts as an oncogenic lncRNA and shows abnormal expression levels in a range of human cancers. It is involved in post-transcriptional regulation and has been linked to processes such as proliferation, migration, and invasion (Fig. 1) (Table 1). We conducted a comprehensive literature search to identify studies on PSMG3‑AS1 in cancer. We queried at least three major databases, including PubMed/MEDLINE, Embase, and Web of Science, using structured Boolean combinations of controlled vocabulary terms (e.g. MeSH or Emtree) and free-text keywords such as “PSMG3‑AS1”, “long non‑coding RNA”, “lncRNA”, and “cancer”. Studies were eligible if they (i) examined PSMG3‑AS1 expression, function, or mechanism in human cancers; (ii) reported original experimental data (in vitro, in vivo, or clinical); and (iii) were published in English. Reviews, editorials, conference abstracts without full data, and non-human-only studies were excluded. We restricted our search to publications from 2010 to 2025, as lncRNA research became robust during this period.

Fig. 1.

The functional roles of PSMG3-AS1 in different cancers

Table 1.

The biological roles of PSMG3-AS1 in different types of cancer

Cancer type	Property	Expression	Mechanism	Biological functions	References
Breast cancer	Oncogene	Upregulate	Sponging of miR‑143‑3p, leading to COL1A1 upregulation	Proliferation, migration, metastasis	[47]
Cervical squamous cell carcinoma	Oncogene	Upregulate	Sponging of miR‑4417, resulting in derepression of oncogenic targets	Migration, invasion	[48]
Endometrial cancer	Oncogene	Upregulate	Negative regulation of MEG3, modulating tumor suppressor pathways	Proliferation	[49]
Gastric cancer	Oncogene	Upregulate	Sponging of miR‑451a, upregulating CAV1; activation of oxidative stress and cell death pathways	Proliferation, apoptosis	[50]
Glioma	Oncogene	Upregulate	Downregulates miR‑34a via methylation; stabilizes c‑Myc protein	Chemoresistance, proliferation	[51]
Hepatocellular carcinoma	Oncogene	Upregulate	Sponging of miR‑143‑3p	Proliferation	[52]
Lung carcinoma	Oncogene	Upregulate	Sponging of miR‑449b‑5p; sponging of miR‑613 (activating SphK1); sponging of miR‑143‑3p	Proliferation, migration, invasion	[53] [54] [55]
Oral squamous cell carcinoma	Oncogene	Upregulate	Sponging of miR‑141, enhancing oncogenic signaling pathways	Proliferation	[56]
Prostate carcinoma	Oncogene	Upregulate	Sponging of miR‑106b, modulating proliferation-associated targets	Proliferation	[57]

Breast cancer

Breast cancer is the second most common cancer globally, with 2.3 million new cases in 2022, accounting for 11.6% of all cancer cases [4]. It is the most frequently diagnosed cancer among women and the leading cause of cancer deaths in 157 countries [58]. Despite higher incidence rates in transitioned regions such as Northern America and Europe (54.1 per 100,000), mortality is lower in these areas compared to transitioning regions like South-Central Asia, where limited access to early detection and treatment contributes to higher mortality rates (15.3 per 100,000) [59]. The highest mortality rates globally are reported in Melanesia, with Fiji having the world’s highest rate [4].

PSMG3-AS1 has been identified as an oncogenic lncRNA in breast cancer. Bioinformatics analysis and experimental validation revealed its upregulation in tumor tissues and cell lines [47]. Functional assays, including CCK-8, colony formation, Transwell, and wound-healing assays, demonstrated that knockdown of PSMG3-AS1 significantly suppressed cell proliferation and migration. Mechanistically, PSMG3-AS1 was found to act as a competitive endogenous RNA (ceRNA), sponging miR-143-3p, which itself inhibits tumor progression [47]. This interaction modulates the expression of COL1A1, a direct target of miR-143-3p, known to promote breast cancer metastasis. The PSMG3-AS1-miR-143-3p-COL1A1 axis highlights a lncRNA-miRNA-mRNA regulatory mechanism underlying breast cancer progression, offering a novel therapeutic target for treatment strategies. To address these gaps, future work should employ larger, subtype‑diverse cohorts and in vivo models to validate the PSMG3‑AS1‑miR‑143‑3p‑COL1A1 signaling axis—examining its impact on tumor growth, hormone receptor status, chemoresponsiveness, and metastatic potential.

Cervical squamous cell carcinoma (CSCC)

Cervical Squamous Cell Carcinoma (CSCC) ranks fourth among cancers affecting women, with 660,000 new cases and 350,000 deaths globally in 2022⁴. It remains the leading cause of cancer deaths in 37 countries, predominantly in sub-Saharan Africa, South America, and South-Eastern Asia [4]. The regional disparity is stark, with incidence and mortality rates being 10 times higher in sub-Saharan Africa and Melanesia compared to Northern America and Australia/New Zealand. Such variations highlight the impact of access to preventive measures like HPV vaccination and regular screening [60, 61].

In CSCC, PSMG3-AS1 was shown to play an oncogenic role by promoting cell invasion and migration. Expression analysis revealed upregulation of PSMG3-AS1 and downregulation of miR-4417 in cancer tissues [48]. Functional assays demonstrated that overexpression of miR-4417 suppressed cell migration and invasion, while its inhibition had the opposite effect. Mechanistically, miR-4417 was identified as a tumor suppressor that targets PSMG3-AS1. Their inverse correlation suggests that PSMG3-AS1 facilitates tumor progression by antagonizing the suppressive effects of miR-4417⁴⁸. High expression of PSMG3-AS1 was also associated with poor patient survival, indicating its potential as a prognostic biomarker in CSCC. However, these findings warrant further investigation with larger patient cohorts to validate their clinical relevance.

Endometrial cancer (EC)

Endometrial cancer, accounting for 90% of uterine cancers, is among the most common gynecological malignancies, with 417,000 new cases and nearly 97,000 deaths worldwide in 2020 [1, 62]. Rising rates of obesity and diabetes have driven an increase in cases, despite significant advances in early diagnosis and treatment [63, 64]. While most patients are diagnosed at early stages with high survival rates, around 20% present with extra-uterine disease, and only 15% of women with stage IV disease survive beyond five years. Mortality has doubled since 1990, although age-standardized rates have declined globally [65].

In EC, PSMG3-AS1 was found to regulate cell proliferation through a novel interaction with another lncRNA, MEG3 [49]. RT-qPCR analysis demonstrated that PSMG3-AS1 was upregulated, while MEG3 was downregulated in EC tissues. Pearson’s correlation revealed an inverse relationship between their expression levels. Functional studies showed that PSMG3-AS1 promoted, whereas MEG3 inhibited, cell proliferation. Co-transfection experiments revealed that these two lncRNAs negatively regulate each other, effectively neutralizing their individual effects on cell proliferation [49]. This reciprocal regulatory mechanism highlights the complexity of lncRNA interactions in cancer biology, presenting PSMG3-AS1 and MEG3 as potential therapeutic targets in EC.

Gastric cancer

Gastric cancer is the fifth most commonly diagnosed cancer and the fourth leading cause of cancer deaths worldwide, with a five-year survival rate of less than 10% [1, 66]. Surgery combined with chemotherapy is standard treatment, but about 60% of patients relapse after resection, often due to peritoneal metastasis, which affects one-third of patients at diagnosis [67, 68]. Limited treatment options and a high incidence of late-stage diagnoses contribute to the poor prognosis, emphasizing the urgent need for better therapeutic strategies and early detection [69].

PSMG3-AS1 has been found to exhibit significantly increased expression in gastric cancer patients compared to healthy controls, with its upregulation strongly associated with poor prognosis. Bioinformatics analyses demonstrated that PSMG3-AS1 correlates with high tumor mutation burden (TMB) and microsatellite instability (MSI) in gastric cancer [50]. To investigate its biological role, a disruption vector targeting PSMG3-AS1 was introduced into AGS and MKN-45 gastric cancer cell lines. The knockdown of PSMG3-AS1 using siRNA significantly reduced its expression at both the RNA and protein levels, leading to a marked decrease in cell proliferation capacity. Further correlation analysis revealed interactions between PSMG3-AS1, caveolin-1 (CAV1), and miR-451a, indicating a positive association between PSMG3-AS1 and CAV1 but an inverse relationship between PSMG3-AS1 and miR-451a [50]. Pathway enrichment analyses, including GSEA and GSVA, highlighted that PSMG3-AS1 and its associated pathways (e.g., ribosome, oxidative phosphorylation, and calcium signaling) are involved in oxidative stress and programmed cell death. This underscores its potential as a regulator of autophagy and other cellular stress responses in gastric cancer. However, given the sensitivity of in silico approaches to dataset heterogeneity, algorithmic biases, and multiple-testing artifacts, these findings warrant experimental validation, particularly functional assays to confirm PSMG3‑AS1’s roles in stress response and therapy sensitivity.

Glioma

Gliomas are the most common brain and spinal cord cancers, with glioblastoma (GBM) representing 57% of all gliomas and 48% of aggressive CNS tumors [70]. GBM, a grade IV glioma, is highly malignant and resistant to current treatments, including surgery, radiotherapy, and chemotherapy [71]. Despite advancements, the prognosis for GBM remains grim, with median survival often under two years, underscoring the need for innovative therapies to improve outcomes [72].

Shan et al. highlighted the upregulation of PSMG3-AS1 in plasma and tumor tissues of GBM patients [73]. ROC curve analysis demonstrated that elevated PSMG3-AS1 levels could effectively distinguish GBM patients from sarcoidosis patients and healthy controls, indicating its diagnostic potential [73]. Functional assays revealed that overexpression of PSMG3-AS1 in GBM cells downregulated miR-34a expression through increased methylation of the miR-34a gene, promoting tumor cell proliferation. Conversely, PSMG3-AS1 knockdown restored miR-34a levels, highlighting its role in modulating miR-34a-mediated anti-proliferative effects. While these findings establish PSMG3-AS1 as a diagnostic biomarker and therapeutic target in GBM, the specific methylation factors involved remain to be elucidated.

Another study explored the role of PSMG3-AS1 in mediating resistance to TMZ, a first-line chemotherapeutic drug for GBM [51]. PSMG3-AS1 expression was significantly higher in glioma tissues and increased progressively with glioma grade, peaking in GBM. Its overexpression was notably elevated in TMZ-resistant cells (T98G) compared to sensitive cells (U251). Mechanistically, PSMG3-AS1 was found to localize primarily in the nucleus, where it stabilized c-Myc, a key regulator of cell proliferation and survival. In vitro experiments demonstrated that PSMG3-AS1 knockdown abolished TMZ resistance, whereas overexpression enhanced it. These findings suggest that PSMG3-AS1 contributes to chemoresistance by stabilizing c-Myc, highlighting its potential as a therapeutic target to overcome TMZ resistance in GBM. Further studies should delineate the specific methyltransferases or chromatin modifiers that PSMG3‑AS1 recruits to silence miR‑34a, thereby completing the mechanistic map of its pro‑tumorigenic effects.

Hepatocellular carcinoma (HCC)

Hepatocellular carcinoma, the most common type of primary liver cancer, ranks as the sixth most prevalent cancer and the fourth leading cause of cancer deaths globally [74, 75]. Its five-year survival rate is only 12% due to late-stage detection and resistance to therapies such as sorafenib, with 70% of patients developing resistance within six months [76, 77]. The liver is also a frequent site for metastases from other cancers, complicating treatment further and highlighting the need for improved diagnostic tools and therapies [78].

PSMG3-AS1 has been identified as an oncogenic lncRNA in HCC, marking its first reported upregulation in this cancer type [52]. Functional assays demonstrated that PSMG3-AS1 overexpression promoted HCC cell proliferation, correlating with poor patient survival. Notably, high levels of PSMG3-AS1 expression were significantly associated with reduced survival rates in HCC patients, suggesting its potential as a prognostic biomarker. Mechanistically, PSMG3-AS1 was shown to interact with miR-143-3p, a tumor-suppressive miRNA [52]. This interaction was crucial as miR-143-3p—known for its suppressive roles in other malignancies [79]—targets lncRNAs like PSMG3-AS1 to inhibit cancer progression. These findings highlight PSMG3-AS1 as a promising therapeutic target for HCC. Additional investigations are needed to uncover alternative molecular partners and pathways through which PSMG3‑AS1 may regulate HCC cell behavior beyond the miR‑143‑3p axis.

Lung carcinoma

Lung cancer remains the leading cause of cancer-related deaths globally, with 1.8 million deaths in 2020 [1]. Non-small cell lung cancer (NSCLC) accounts for 85% of cases, with lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) being the most common subtypes [80, 81]. Although advances in targeted therapies have improved outcomes, only 24% of lung cancers are diagnosed at a localized stage, where the five-year survival rate is 60% [82, 83]. Continued progress in early detection and personalized treatment is critical to reducing mortality.

In vitro experiments demonstrated that LUAD cell proliferation was promoted by PSMG3-AS1, with higher expression levels being associated with poorer survival during a 5-year follow-up [53]. Additionally, an interaction between PSMG3-AS1 and miR-449b-5p, a tumor-suppressive miRNA targeting protein-coding genes such as CREPT and c-Met, was identified. The downregulation of miR-449b-5p in LUAD and its inhibitory effects on cell proliferation were confirmed [53]. These findings suggest that the interplay between PSMG3-AS1 and miR-449b-5p is critical in LUAD biology, underscoring the potential of PSMG3-AS1 as a prognostic and therapeutic target.

In another study the PSMG3-AS1/miR-613/SphK1 axis was investigated in NSCLC [54]. PSMG3-AS1 was upregulated and miR-613 downregulated, with their interplay promoting cancer cell proliferation through SphK1 upregulation. miR-613’s tumor-suppressive role was highlighted, as it targets SphK1 to inhibit cell proliferation. PSMG3-AS1 acted as a miRNA sponge, sequestering miR-613 and upregulating SphK1, which is associated with tumor progression and poor survival [54]. This novel regulatory axis offers potential diagnostic and therapeutic opportunities for NSCLC management.

Another study in LUSC, PSMG3-AS1 was upregulated and associated with poor prognosis [55]. Loss-of-function experiments demonstrated that silencing PSMG3-AS1 reduced cancer cell proliferation, migration, and invasion. PSMG3-AS1 was shown to bind miR-143-3p, negatively regulating its expression. miR-143-3p overexpression inhibited LUSC cell proliferation, while PSMG3-AS1 knockdown upregulated miR-143-3p [55]. These findings underscore PSMG3-AS1’s oncogenic role and its potential as a prognostic biomarker and therapeutic target in LUSC. To strengthen these observations, future work should expand patient sample numbers and incorporate in vivo lung cancer models to validate PSMG3‑AS1’s functional impact.

Oral squamous cell carcinoma (OSCC)

Oral squamous cell carcinoma (OSCC) accounted for 377,713 new cases and 177,757 deaths worldwide in 2020 [84]. It is often preceded by potentially malignant oral diseases and predominantly affects men, with a male-to-female ratio of 2.3:1 [85]. Key risk factors include tobacco and alcohol use, alongside hormonal changes, chronic injuries, and UV radiation for lip cancers [86, 87]. Early differentiation from benign conditions is essential for timely diagnosis and management, particularly in regions with high prevalence rates.

A study showed that PSMG3-AS1 was highly expressed in OSCC tissues, promoting cell proliferation [56]. Its interaction with miR-141 revealed a novel mechanism where PSMG3-AS1 reduced mature miR-141 levels by binding to its precursor, thereby inhibiting miRNA maturation. This regulatory mechanism mirrors similar findings in other lncRNAs and highlights PSMG3-AS1’s role in OSCC progression [56]. These results suggest that PSMG3-AS1 could serve as a diagnostic biomarker and therapeutic target for OSCC.

Prostate carcinoma (PCa)

Prostate cancer (PCa) is the second most common cancer in men, with 1.5 million new cases and 397,000 deaths globally in 2022 [4]. Incidence is three times higher in transitioned countries (35.5 per 100,000) compared to transitioning countries (12.6 per 100,000), although mortality rates show less disparity due to advances in detection and treatment [4]. PCa is the leading cancer diagnosis in men across 118 countries, emphasizing its global health impact and the need for effective screening and management strategies [4].

Qiang Xia et al. revealed the upregulation of PSMG3-AS1 in PCa and its interaction with miR-106b in their study [57]. PSMG3-AS1 decreased miR-106b expression via DNA methylation, enhancing cancer cell proliferation. Functional assays confirmed miR-106b’s tumor-suppressive role, as its overexpression reduced PCa cell proliferation. Interestingly, the correlation between PSMG3-AS1 and miR-106b was specific to tumor tissues, suggesting a pathological context for this interaction [57]. These findings position PSMG3-AS1 as an oncogenic regulator in PCa and a potential therapeutic target for combating tumor growth.

Integrative analysis and translational perspective on PSMG3-AS1 in cancer

Comparative mechanistic roles of PSMG3-AS1 across cancer types

Across diverse malignancies, PSMG3‑AS1 consistently orchestrates tumorigenic processes via common regulatory pathways. Most prominently, it functions as a ceRNA, sequestering tumor‑suppressive microRNAs (e.g. miR‑143‑3p, miR‑613, miR‑451a) across breast, lung, gastric, hepatocellular, and other cancers, thereby derepressing downstream oncogenic effectors (e.g. COL1A1, SphK1, CAV1). For instance, in breast cancer and lung squamous cell carcinoma [47, 54] PSMG3-AS1 acts as a sponge for miR-143-3p, thereby derepressing downstream targets such as COL1A1 that contribute to extracellular matrix remodeling and metastasis. Similarly, in non-small cell lung cancer (NSCLC), PSMG3-AS1 regulates the expression of SphK1 through miR-613 sponging, thereby promoting sphingolipid-mediated proliferative signaling (Fig. 2).

Fig. 2.

The ceRNA network of PSMG3-AS1 lncRNA

However, this ceRNA model does not universally explain the behavior of PSMG3-AS1 in all cancer types. In glioma [51] for example, PSMG3-AS1 exerts its oncogenic effects through epigenetic silencing of the tumor suppressor miR-34a via DNA methylation of its promoter region, and also by stabilizing c-Myc protein in the nucleus. The latter represents a shift from cytoplasmic RNA sponging activity to nuclear protein interaction and transcriptional regulation, suggesting context-specific functional adaptations. In prostate cancer [57] a similar pattern is observed wherein PSMG3-AS1 promotes DNA methylation to silence miR-106b, reinforcing its role as an epigenetic modulator rather than a canonical ceRNA.

Furthermore, the nature of downstream targets regulated by PSMG3-AS1 is highly variable. In gastric cancer [50] the PSMG3-AS1/miR-451a axis controls the expression of CAV1, a protein implicated in signal transduction and cellular trafficking, whereas in hepatocellular carcinoma [52] the primary axis involves miR-143-3p, with less clarity on direct effector molecules. In endometrial cancer [49] PSMG3-AS1 does not regulate a miRNA but interacts reciprocally with another lncRNA, MEG3, highlighting lncRNA-lncRNA regulatory dynamics that are largely absent in other cancer contexts. These differences underscore the need to consider cellular context and tissue-specific regulatory environments when interpreting PSMG3-AS1 function.

Mechanistic integration into oncogenic signaling pathways

The diversity of PSMG3-AS1’s molecular interactions suggests that it integrates into several key oncogenic signaling pathways, modulating their activity in a cancer-type-specific manner. In NSCLC [54] the upregulation of SphK1 mediated by PSMG3-AS1 implicates the PI3K/AKT/mTOR signaling cascade, as SphK1 is known to activate AKT signaling through sphingosine-1-phosphate, thereby promoting cell proliferation and survival. In breast cancer [47] derepression of COL1A1 through miR-143-3p sponging has indirect consequences on the Wnt/β-catenin pathway, given COL1A1’s role in extracellular matrix dynamics and its capacity to facilitate β-catenin nuclear localization and transcriptional activation.

In glioma [51] the stabilization of c-Myc by PSMG3-AS1 not only enhances proliferative capacity but also suggests activation of transcriptional networks downstream of STAT3 and NF-κB, both of which are commonly upregulated in glioblastoma and associated with chemoresistance and immune evasion. The epigenetic silencing of miR-34a in the same context further connects PSMG3-AS1 to p53-regulated apoptotic signaling pathways, as miR-34a is a well-characterized effector of p53. Collectively, these interactions position PSMG3-AS1 as a multi-level regulator capable of intersecting with a broad range of signaling axes central to cancer development and progression.

Tissue-specific regulation and functional divergence

Although PSMG3-AS1 is reported to be upregulated across a wide spectrum of solid tumors, the determinants of its tissue-specific functions remain poorly understood. It is plausible that these differences arise from variations in miRNA expression profiles, chromatin accessibility, and the relative abundance of nuclear versus cytoplasmic localization machinery. For example, the ceRNA mechanism is more prominent in cancers with high cytoplasmic localization of PSMG3-AS1 and active miRNA turnover, such as gastric or lung cancer. In contrast, nuclear retention of PSMG3-AS1 in glioma [51] and prostate cancer [57] favors interactions with DNA methyltransferases or transcription factors, leading to gene expression modulation through epigenetic pathways.

The differential availability of miRNA targets and RNA-binding proteins across tissues may also account for variability in downstream effectors. For instance, while miR-143-3p is functionally repressed in breast, lung squamous carcinoma, and hepatocellular carcinoma, its targets and the resulting phenotypic effects differ markedly. These observations underscore the importance of performing tissue-specific interactome mapping, using techniques such as RNA immunoprecipitation (RIP), crosslinking immunoprecipitation (CLIP), and subcellular RNA-seq profiling to uncover context-dependent regulatory architectures.

Translational perspectives

PSMG3‑AS1 may be targeted using several emerging modalities. Antisense oligonucleotides (ASOs) or siRNAs could be designed to degrade PSMG3‑AS1 transcripts, as has been demonstrated for other oncogenic lncRNAs [88, 89]. Small molecules might disrupt its interaction with partners such as c‑Myc or CAV1, while CRISPR–Cas systems could specifically edit its promoter or binding domains. Such approaches, singly or in combination, represent promising experimental therapies that merit preclinical validation.

Given its frequent dysregulation and mechanistic diversity across cancers, PSMG3‑AS1 expression, alone or integrated with miRNA‑based signatures (e.g., miR‑143‑3p, miR‑34a, miR‑613), may enhance diagnostic sensitivity or prognostic stratification, as seen in glioma. Clinical assays could detect its levels in tumor tissue or circulating fluid, informing both risk assessment and treatment decisions.

Several unresolved challenges hinder clinical translation of lncRNA-targeted therapies. The poor cross-species conservation and differing isoforms, stability, and subcellular localization in mice versus humans limit model relevance, requiring humanized systems or organoids for validation [13, 90]. Only ~ 35–38% of human lncRNAs have orthologs in rodents, and transcript stability (for example, MALAT1) is notably lower in mice [91, 92]. Extensive alternative splicing and post-transcriptional modifications further complicate mechanistic studies. Additionally, lncRNAs’ multi-target nature raises off-target concerns, and therapeutic toxicity may not be predicted in rodent models. Ultimately, reliable causal inference using methods like TWAS will be essential to prioritize therapeutically actionable lncRNAs [93].

Subcellular localization of PSMG3‑AS1

PSMG3‑AS1 exhibits dynamic subcellular distribution that varies by cancer type, which likely influences its mechanism of action. In oral squamous cell carcinoma, nuclear fractionation assays demonstrated that PSMG3‑AS1 is present in both the nucleus and cytoplasm, where it interacts with premature miR‑141 to inhibit its maturation [56]. In gastric cancer, subcellular localization profiling in MKN‑45 cells revealed that PSMG3‑AS1 is predominantly nuclear with a smaller cytoplasmic pool, indicating potential dual roles in epigenetic regulation and cytoplasmic miRNA sponging [50]. In glioma, PSMG3‑AS1 functions within the nucleus to stabilize c‑Myc, consistent with a nuclear localization pattern in brain tumor cells [51]. Bioinformatic predictions and experimental confirm ations also support a predominantly cytosolic localization in cancers, aligning with its described role as a ceRNA. Taken together, these findings suggest that PSMG3‑AS1’s subcellular localization (nuclear versus cytoplasmic) dictates its functional modality, from epigenetic and protein stabilization in the nucleus to microRNA sponging in the cytoplasm, and should therefore be considered carefully in functional studies and therapeutic targeting strategies.

Conclusion and future perspectives

PSMG3‑AS1 has emerged as a pivotal oncogenic lncRNA, and this comprehensive review has consolidated fragmented evidence, demonstrating its upregulation, clinical relevance, and mechanistic versatility across multiple malignancies. Mechanistically, PSMG3‑AS1 exerts its effects primarily through ceRNA activity, but also via epigenetic modifications and protein stabilization, influencing a spectrum of oncogenic pathways and cellular processes. Functionally, it promotes proliferation, migration, invasion, chemoresistance, and immune evasion, consistently linked with poor prognosis in diverse tumor contexts.

While current findings underscore the oncogenic potential of PSMG3-AS1, several gaps remain. Most studies are limited to in vitro or small-scale clinical settings, highlighting the need for larger, tissue- and subtype-specific clinical validation. The precise molecular mechanisms (such as the recruitment of DNA methyltransferases, interaction with transcription factors, and subcellular localization dynamics) merit deeper investigation. Additionally, the impact of PSMG3‑AS1 dysregulation within tumor microenvironments (such as hypoxia or immune infiltration) is largely unexplored.

Future research should focus on leveraging advanced techniques like single-cell sequencing and CRISPR-based gene editing to dissect the role of PSMG3-AS1 in cancer heterogeneity and progression. Moreover, its therapeutic potential as a target for RNA-based therapies warrants further exploration, particularly through preclinical and clinical trials. The development of specific inhibitors, antisense oligonucleotides, or small molecules targeting PSMG3-AS1 could pave the way for novel, personalized cancer treatments. Integrating PSMG3-AS1 into diagnostic panels could also enhance early detection and prognosis in multiple cancer types. To date, there are no published studies addressing PSMG3-AS1’s role in the tumor microenvironment or immune modulation, representing an important and timely area for future investigation.

In conclusion, PSMG3‑AS1 represents a compelling candidate for both biomarker development and therapeutic innovation. Its multifaceted roles in tumorigenesis demand continued rigorous investigation to fully harness its potential, ultimately laying the groundwork for more accurate diagnostics and more effective, personalized treatments that improve outcomes for cancer patients.

Abbreviations

miRNAs

MicroRNAs

lncRNAs

Long non-coding RNAs

ceRNA

Competitive endogenous RNA

OSCC

Oral squamous cell carcinoma

CSCC

Cervical squamous cell carcinoma

GBM

Glioblastoma

TMZ

Temozolomide

HCC

Hepatocellular carcinoma

EMT

Epithelial–mesenchymal transition

EC

Endometrial carcinoma

NSCLC

Non-small cell lung cancer

LUAD

Lung adenocarcinoma

LUSC

Lung squamous cell carcinoma

LNM

Lymph node metastasis

Author contributions

H.Z. is the Main writer, contributed to all sections of the paper, X.W. is Corresponding author; involved in project planning and supervision. All authors discussed the results and contributed to the final manuscript.

Funding

No funding was received for this research.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable. This study is a literature review and did not involve new experiments with human participants or animals.

Consent for publication

Not applicable. No individual person’s data are included in any form.

Competing interests

The authors declare no competing interests.