Abstract
Background/Aim: Non-small cell lung cancer (NSCLC) accounts for most lung cancer cases and has high mortality, especially in advanced stages. MicroRNAs (miRNAs) and immunoregulatory genes such as suppressor of cytokine signaling 3 (SOCS3) play critical roles in cancer progression and immune evasion. miR-30d-5p is known to act as a tumor suppressor by down-regulating oncogenic pathways, while SOCS3 modulates immune responses and tumor microenvironment interactions. This study aimed to evaluate the clinical relevance of circulating miR-30d-5p and serum SOCS3 protein levels in patients with NSCLC versus healthy controls and to assess their potential as diagnostic and prognostic biomarkers.
Materials and Methods: Serum samples were collected from 35 patients with NSCLC and 26 healthy individuals. miR-30d-5p expression was measured using RT-qPCR, and SOCS3 protein levels were determined using ELISA. Statistical comparisons were performed, and diagnostic performance was evaluated using Receiver Operating Characteristic (ROC) analysis. The correlation between SOCS3 and miR-30d-5p was assessed with Spearman’s rank test.
Results: SOCS3 levels were significantly elevated in patients with NSCLC (120.84±117.62 pg/ml) compared to controls (16.88±11.91 pg/ml, p<0.0001). Contrarily, miR-30d-5p expression was significantly decreased (fold change: 0.24, p<0.002). A moderate negative correlation was observed between SOCS3 and miR-30d-5p levels (ρ=−0.439, p=0.025). ROC analysis displays good diagnostic accuracy for both SOCS3 [area under curve (AUC)=0.821] and miR-30d-5p (AUC=0.878). SOCS3 levels increased significantly with clinical stage.
Conclusion: Increased SOCS3 and decreased miR-30d-5p expression were observed in patients with NSCLC, indicating their involvement in tumor progression and immune disruption. The inverse correlation between these biomarkers suggests a regulatory interaction that may influence the JAK/STAT signaling pathway. These findings highlight the diagnostic and therapeutic potential of targeting the miR-30d-5p/SOCS3 axis in NSCLC.
Introduction
Non-small cell lung cancer (NSCLC) represents the most prevalent type of lung cancer, constituting approximately 80-85% of all lung cancer cases (1, 2). This heterogeneous disease encompasses several histological subtypes, including adenocarcinoma, squamous cell carcinoma, and large cell carcinoma, each with distinct biological and clinical characteristics (3, 4). Accurate staging of NSCLC is critical for guiding therapeutic decisions and predicting patient outcomes. The tumor-node-metastasis (TNM) classification system, established by the International Association for the Study of Lung Cancer (IASLC), is the most widely adopted framework for staging NSCLC (5). The disease is categorized into stages ranging from Stage 0 to Stage IV. Stage 0, also referred to as carcinoma in situ, denotes localized cancer that has not infiltrated deeper lung tissues (6). In Stage I, the tumor is confined to the lung, whereas Stage II may involve larger tumors with potential regional lymph node involvement (7). Stage III is characterized by local invasion of adjacent structures and extensive lymph node involvement (7, 8). Stage IV, marked by distant metastasis to organs such as the brain, liver, or bones, is associated with a poor prognosis and significantly reduced survival rates (9, 10). Despite advancements in therapeutic strategies, the prognosis for NSCLC remains unfavorable, particularly in advanced stages, where the 5-year survival rate falls below 20% (11). These observations underscore the urgent need for continued research into the molecular mechanisms, prognostic determinants, and novel treatment modalities for NSCLC.
Recent studies have identified several key prognostic factors that significantly influence patient outcomes. For instance, Ran and Liu demonstrated that tailoring systemic therapies based on specific biomarkers improves survival in elderly patients with advanced NSCLC (12). Similarly, Arbour and Riely highlighted the critical role of genetic alterations in refining treatment strategies, aligning with the paradigm of precision medicine in NSCLC (13). While immune checkpoint inhibitors, such as pembrolizumab, have shown efficacy in metastatic NSCLC, their therapeutic benefits may be limited in cases harboring specific genetic mutations, including EGFR alterations (14).
MicroRNAs (miRNAs), a class of small non-coding RNAs involved in the regulation of gene expression, have emerged as promising biomarkers and therapeutic targets in cancer biology (15). For example, miR-222-3p has been shown to promote cell proliferation and inhibit apoptosis in NSCLC by targeting the PUMA gene (16). Additionally, Liao and Peng reported that miR-206 may function as a metastasis suppressor by modulating the CORO1C gene, offering new insights into miRNA-based therapeutic strategies for NSCLC (17). Among the miRNAs gaining attention in recent years, miR-30d-5p, a member of the miR-30-5p family, has been implicated in the pathogenesis of various cancers (18-21). Evidence suggests that miR-30d-5p expression is significantly down-regulated in NSCLC tissues compared to normal lung tissues, which correlates with enhanced tumor cell proliferation and invasiveness (22, 23). Gao et al. demonstrated that restoring miR-30d-5p levels in NSCLC cells markedly reduces proliferation and viability, supporting its role as a tumor suppressor (22). Similarly, Zhang et al. revealed that miR-30d-5p inhibits tumor cell proliferation and motility by directly targeting cyclin E2 (CCNE2), a critical regulator of the cell cycle, thereby disrupting oncogenic signaling pathways that drive tumor progression (23). Over-expression of miR-30d-5p induces cell cycle arrest and promotes apoptosis in NSCLC cell lines, further emphasizing its potential as a therapeutic target for halting tumor growth (22). Moreover, miR-30d-5p has been linked to the modulation of the PI3K/AKT pathway, a key signaling cascade involved in cell survival and proliferation. Although studies directly exploring miR-30d-5p’s impact on this pathway in NSCLC are limited, it is suggested that down-regulation of miR-30d-5p enhances PI3K/AKT activity in some cancers, implying that restoring its levels could block survival signals and make tumor cells more sensitive to chemotherapy (24). Besides its local effects, miR-30d-5p may also influence the tumor microenvironment. For example, Shimada et al. identified circulating miR-30d-5p in extracellular vesicles as a potential biomarker for predicting lymphovascular invasion in lung adenocarcinoma (25). This indicates that miR-30d-5p not only acts within tumor cells but also interacts with systemic factors that affect cancer spread and progression.
Equally important, miR-30d-5p has been repeatedly reported to influence the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway, a key regulatory axis in cancer biology, by down-regulating the suppressor of cytokine signaling 3 (SOCS3) underlying their functional relevance to lung cancers, including NSCLC (26).
SOCS3 is a key negative feedback regulator of the JAK/STAT signaling pathway, which orchestrates numerous physiological processes including immune regulation, inflammation, and cellular proliferation. Dysregulation of this signaling axis, particularly through aberrant expression of SOCS3, has been increasingly implicated in the pathogenesis and progression of NSCLC. Accumulating evidence suggests that altered SOCS3 levels influence not only tumor development but also diagnostic and prognostic outcomes, positioning SOCS3 as a promising molecular target for therapeutic intervention. Notably, inadequate expression of SOCS3 has been consistently associated with the hyperactivation of its downstream effector, STAT3, a transcription factor with well-established oncogenic properties in lung cancer (27). The study has shown that SOCS3 secretion via microvesicles from alveolar macrophages is significantly diminished in patients with NSCLC, coinciding with enhanced epithelial cell transformation and tumor-promoting functions (27). Moreover, expression profiling of signaling-related genes has identified the IL-4/IL-13/STAT6 axis and SOCS3 as key discriminators among different histopathological NSCLC subtypes, further emphasizing the gene’s role in tumor biology (28).
Beyond its biological role, SOCS3 has demonstrated therapeutic potential. Adenovirus-mediated over-expression of SOCS3 has been shown to inhibit NSCLC cell growth and increase radiosensitivity, thereby supporting its utility as a tumor suppressor and potential adjuvant therapy (29). Experimental strategies aiming to restore SOCS3 expression have also yielded promising results in mitigating tumor progression (30). Paradoxically, elevated SOCS3 expression within the tumor microenvironment has been correlated with poor clinical outcomes and increased metastatic potential, particularly in cases of colon cancer with lung metastases (31). This duality underscores the complex role of SOCS3 in cancer progression, where its influence appears highly context-dependent. SOCS3 also regulates inflammatory cytokines such as IL-6 and TNF-α, which are key components of the tumor microenvironment. Ren et al. observed that SOCS3-mediated regulation of inflammatory responses might allow NSCLC cells to evade immune surveillance, thereby promoting tumor growth (32). This interplay between miR-30d-5p, SOCS3, and inflammatory pathways may represent an essential mechanism through which NSCLC progresses, particularly via immune evasion strategies.
The immunological dimension of SOCS3’s function is further highlighted by its involvement in modulating tumor-associated inflammation. High SOCS3 expression has been linked to increased immune cell infiltration, which may facilitate tumor-promoting inflammation (33). Conversely, SOCS3 depletion exacerbates pulmonary inflammation, underscoring its essential role in maintaining immune homeostasis (34). These findings illustrate the fine balance SOCS3 maintains between protective immunoregulation and tumor-supportive mechanisms.
At the molecular level, SOCS3 is subject to various regulatory influences. Epigenetic silencing via promoter hypermethylation has been identified as a mechanism contributing to its down-regulation in NSCLC and other malignancies (29, 35). Researchers like Fukui et al. have suggested that SOCS3 silencing can result from epigenetic modifications, such as methylation, adding another layer of regulation between miR-30d-5p and SOCS3 (36). Given SOCS3’s role in regulating the JAK/STAT pathway and inflammation, targeting the miR-30d-5p/SOCS3 axis has been proposed as a promising therapeutic strategy. This approach could be especially beneficial for patients with NSCLC with low SOCS3 expression, potentially slowing tumor progression and improving patient outcomes. Furthermore, miRDB, a miRNA-mRNA target prediction database, predicts miRNA targets using machine learning algorithms and assigns confidence scores to each predicted interaction. The confidence score for the interaction between miR-30d-5p and the SOCS3 gene is very high (94.9), indicating a strong likelihood of miR-30d-5p binding to the 3′-UTR of SOCS3 (37, 38). By binding to the 3′-UTR of SOCS3, miR-30d-5p is expected to regulate its expression. Given this strong target prediction and the direct relevance of SOCS3 to the JAK/STAT3 signaling pathway, miR-30d-5p was selected as the most promising candidate for this study.
Recent studies have demonstrated that miR-30d-5p plays a functional role in various oncogenic processes, including promoting proliferation and inhibiting apoptosis, primarily by targeting SOCS3 and lifting its suppressive effects on STAT3 activation (39). Given this mechanistic relationship, the miR-30d-5p/SOCS3 axis has been proposed as a promising therapeutic target, particularly in NSCLC cases exhibiting low SOCS3 expression. Therapeutic modulation of this axis may offer novel avenues to restore SOCS3 function, attenuate tumor progression, and overcome resistance to conventional treatments.
Considering this information, this study investigated the regulatory interaction between miR-30d-5p and SOCS3 in NSCLC by quantifying the serum expression levels of miR-30d-5p and the serum protein levels of SOCS3 in patients compared to healthy controls. Our analysis elucidated the mechanistic interplay between these molecules and evaluated their potential utility as diagnostic and prognostic biomarkers. By characterizing the dynamics of the miR-30d-5p/SOCS3 axis, this research contributes straightforward evidence that may guide future development of targeted therapeutic strategies aimed at modulating this pathway to improve clinical outcomes in NSCLC.
Materials and Methods
Study design and participants. The study population consisted of 35 patients diagnosed with NSCLC and 26 healthy control individuals with no prior history of NSCLC, all recruited from Süreyyapaşa Chest Diseases and Thoracic Surgery Training and Research Hospital. Ethical approval for the study was obtained from the Yeditepe University Clinical Research Ethics Committee.
Pathological investigations of patients were performed according to the World Health Organization Classification of Lung Tumors. The NSCLC patient cohort was stratified into three clinical stages according to the 2015 World Health Organization (WHO) classification of lung tumors, which integrates genetic, clinical, and radiologic advancements to refine tumor categorization and staging. This classification considers tumor size and the extent of regional spread. Stage I patients presented with tumors smaller than 4 cm, confined to the lung with no evidence of metastasis. Stage II patients had tumors also less than 4 cm but with metastasis to ipsilateral peribronchial or hilar lymph nodes. Stage III patients exhibited larger tumors with more extensive locoregional spread, including involvement of mediastinal or contralateral lymph nodes (40). Detailed demographic and clinical characteristics of the study population are presented in Table I.
Demographic characteristics of the study population.
Sample collection and storage. Peripheral blood samples were collected from both patients and control subjects. The samples were then centrifuged at 1,520×g for 15 min to separate the serum. Following centrifugation, the serum was carefully collected and stored at −80°C until analysis. On the day of analysis, the serum samples were thawed and equilibrated to room temperature to ensure optimal conditions for accurate assessment.
miRNA extraction and real-time polymerase chain reaction (PCR) analysis. Serum samples were processed to isolate miRNA using the miRNeasy Serum/Plasma Kit (Cat. No. 217184, Qiagen, Germantown, MD, USA), following the manufacturer’s protocol. The optical density of isolated miRNAs was measured utilizing NanoDrop 2000 spectrophotometer (Thermo Scientific, Waltham, MA, USA). miRNAs were reverse-transcribed into cDNA using the miRCURY LNA RT Kit (Cat. No: 339340, Qiagen). The cDNA concentration was measured with the NanoDrop 2000, and the samples were then diluted for PCR analysis. For the analysis of miR-30d-5p (miRCURY hsa-miRNA-30d-5p PCR assay, Qiagen,) expression levels, polymerase chain reaction (PCR) was conducted using the miRCURY LNA SYBR green PCR kit (Cat. No./ID: 339346, Qiagen). PCR amplification was performed on a Rotor-Gene Q system (Rotor-Gene Q; Qiagen). The expression levels of miR-30d-5p were calculated using td by fold change analysis using 2−ΔΔCT methods (41) from Ct values. RNU6 served as the internal control for normalization.
Enzyme-linked immunosorbent assay (ELISA). The thawed serum samples were centrifuged at 850×g for 20 min. SOCS3 levels were then measured using a sandwich ELISA method with a commercial kit (CAT: KTE62844, LOT: ATRMR1101, Abbkine, Atlanta, GA, USA), following the manufacturer’s protocol precisely. Optical density was recorded at 450 nm with an ELISA plate reader (Model WHYM201, Poweam Medical Co., Ltd., Nanjing, PR China). SOCS3 concentrations were calculated from a standard curve based on known concentrations and reported in pg/ml.
Statistical analysis. For the statistical analyses, the IBM SPSS Statistics software, version 22 (IBM Corp., Armonk, NY, USA) was used. The normality of data distribution was tested with the Shapiro-Wilk test and graphical inspections for suitability of quantitative data. Normally distributed values were evaluated with Student’s t-test and Mann-Whitney U-test was used to compare two groups of quantitative variables that did not show normal distribution. Receiver operating characteristic (ROC) curve analysis was conducted with MedCalc software (MedCalc Software Ltd, Ostend, Belgium). Statistical significance was accepted at values of p<0.05.
Results
Demographic and clinical characteristics. The demographic and clinical characteristics of the study population, comprising 35 patients with NSCLC and 26 healthy controls, are summarized in Table I. There was no statistically significant difference between the NSCLC and control groups in terms of sex distribution (p=0.531) or mean age (60.55±8.37 vs. 58.75±10.26 years, p=0.547). Age stratification (<60 vs. ≥60 years) also did not differ significantly between the groups (p=0.391).
However, smoking status was significantly different between groups (p<0.0001). Most NSCLC patients were ex-smokers (90.9%), whereas among controls, active smokers (61.5%) and non-smokers (23.1%) were more common. This distribution reflects a potentially critical role of smoking history in NSCLC pathogenesis. Regarding disease severity among patients with NSCLC, clinical staging was distributed as follows: 34.2% were stage I, 40% were stage II, and 25.8% were stage III.
Expression of miR-30d-5p and SOCS3 serum levels in NSCLC and controls. A comparison of serum SOCS3 protein levels and miR-30d-5p expression levels between patients with NSCLC and healthy controls revealed statistically significant differences. The mean serum SOCS3 concentration in the NSCLC group was significantly elevated (120.84±117.62 pg/ml) compared to the control group (16.88±11.91 pg/ml) (p<0.0001).
Similarly, miR-30d-5p expression was significantly up-regulated in patients with NSCLC, showing a fold change of 1.40 relative to controls (p<0.002). These findings suggest both SOCS3 and miR-30d-5p may serve as potential biomarkers for NSCLC (Table II). The miR-30d-5p levels in the NSCLC group were markedly higher than in the control group (p<0.001) (Figure 1). Figure 2 illustrates an elevation in SOCS3 levels among patients with NSCLC, suggesting its potential as a biomarker for this condition.
Comparison of serum SOCS3 and miR-30d-5p expression levels among non-small cell lung cancer (NSCLC) clinical stages.
miR-30d-5p expression in patients with non-small cell lung carcinoma (NSCLC) and healthy controls. The expression of miR-30d-5p was significantly up-regulated in the NSCLC group (p<0.001; Mann-Whitney U test). The boxplots show the median (line), interquartile range (box) and minimum-maximum (whiskers) values.
Comparison of serum SOCS3 levels between control and non-small cell lung carcinoma (NSCLC) patient groups (*p<0.05). p-Values are derived from the Mann-Whitney U-test. The boxplots display the median (line), interquartile range (box) and minimum-maximum (whiskers) values.
Correlation analysis between serum SOCS3 levels and miR-30d-5p expression revealed a statistically significant moderate negative correlation. Spearman’s rho was calculated as −0.439, with a p-value of 0.025, indicating that as SOCS3 levels increase, miR-30d-5p expression tends to decrease (Table III). This inverse relationship suggests a potential regulatory interaction between SOCS3 and miR-30d-5p in NSCLC pathogenesis.
Correlation analysis between serum SOCS3 and miR-30d-5p expression levels.
To evaluate the diagnostic performance of SOCS3 and miR-30d-5p expression levels in distinguishing patients with NSCLC from healthy controls, ROC curve analysis was conducted using MedCalc software, as shown in Figure 3.
Diagnostic potential of serum SOCS3 (A) and miR-30d-5p (B) levels for distinguishing non-small cell lung cancer (NSCLC) patients from healthy controls assessed using ROC curve analysis. (A) ROC analysis graph of SOCS3 levels in the control and non-small cell lung carcinoma groups. *p-value <0.05. (B) ROC analysis graph of miR-30d-5p expression levels in the control and NSCLC groups. *p-value <0.05. ROC: Receiver Operating Characteristic; miR: MicroRNA; AUC: Area Under the Curve; 95%CI: 95% confidence interval.
The ROC analysis for SOCS3 levels revealed a strong discriminatory capacity between patients with NSCLC and controls (Figure 3A). The area under the ROC curve (AUC) was 0.821 [95% confidence interval (CI)=0.70-0.98], indicating good accuracy. The optimal cut-off point for SOCS3 was >37.61, which yielded a sensitivity of 67.6% and a specificity of 100%. The result was statistically significant with a p-value of 0.0001, suggesting SOCS3 is a potentially robust biomarker for NSCLC diagnosis.
For miR-30d-5p, ROC analysis also indicated good diagnostic potential (Figure 3B). The AUC was 0.802 (95%CI=0.60-0.93). A cut-off value of ≤0.41 provided 94.4% sensitivity and 75.0% specificity. The analysis indicated a statistically significant p-value of 0.0035, supporting the use of miR-30d-5p as a diagnostic marker for NSCLC.
Figure 4 illustrates the relationship between SOCS3 serum levels and the relative expression of circulating miR-30d-5p among patients with NSCLC and control subjects. Statistical significance, indicated by *p<0.05, underscores the association between increased SOCS3 levels and miR-30d-5p expression in the NSCLC group, potentially indicating a link between SOCS3 and miRNA regulation in the context of NSCLC.
Association between SOCS3 levels and relative expression of circulating miR-30d-5p in non-small cell lung cancer (NSCLC) patient and control groups (*p<0.05).
SOCS3 levels according to clinical stage. An evaluation of serum SOCS3 concentrations across different clinical stages of NSCLC demonstrated a progressive increase in SOCS3 levels with advancing disease stage. The mean serum SOCS3 concentrations were 67.11±66.93 pg/ml in stage I, 80.88±102.84 pg/ml in stage II, and 179.56±128.13 pg/ml in stage III. In comparison, the control group exhibited significantly lower SOCS3 levels, with a mean of 16.88±11.91 pg/ml. The differences observed between groups were statistically significant (p<0.0001, Kruskal-Wallis test) (Figure 5). The 95%CI further supported the observed upward trend in SOCS3 expression correlating with disease advancement. These results indicate that elevated serum SOCS3 levels are associated with the progression of NSCLC and may hold potential as a biomarker for clinical staging of the disease (Table IV).
Serum SOCS3 concentrations across clinical stages of non-small cell lung cancer (NSCLC).
Comparison of SOCS3 serum levels among non-small cell lung cancer clinical stages.
Discussion
This study highlights the significant roles of miR-30d-5p and SOCS3 in the pathophysiology of NSCLC. Our results demonstrated elevated serum SOCS3 levels and reduced expression of circulating miR-30d-5p in patients with NSCLC compared to healthy controls, suggesting their potential utility as complementary diagnostic and prognostic biomarkers.
Elevated levels of SOCS3 have significant implications in the etiology and progression of NSCLC. SOCS3 plays a critical role in regulating the JAK/STAT signaling pathway, which governs various cancer-related cellular mechanisms, including proliferation, apoptosis, and inflammation (36). Dysregulation of SOCS3 in NSCLC often results in enhanced activation of oncogenic pathways, especially STAT3, thereby promoting tumor progression (29, 42). Indeed, restoration of SOCS3 expression in NSCLC cells has been shown to inhibit tumor growth and increase radiosensitivity, suggesting a promising therapeutic avenue (29). Furthermore, SOCS3 down-regulation due to promoter hypermethylation has been associated with poor prognosis in several cancers, indicating its pivotal tumor-suppressive function (35).
In our study, serum SOCS3 levels progressively increased across clinical stages, with the highest concentrations observed in stage III patients. This rising trend suggests that SOCS3 may serve not only as a diagnostic marker but also as a staging biomarker reflecting disease advancement. Although previous studies largely reported SOCS3 suppression in tumor tissue due to epigenetic silencing (35), our serum findings may reflect tumor-microenvironmental activity or systemic immune feedback rather than direct tumor cell expression alone.
The prognostic value of SOCS3 has been further substantiated by its association with the tumor microenvironment and immune responses. Elevated SOCS3 levels have been linked with increased infiltration of immune cells, which may facilitate tumor progression through tumor-promoting inflammation (33). SOCS3 also regulates inflammatory cytokines like IL-6 and TNF-α, playing a role in the tumor microenvironment and immune modulation, which may enable NSCLC cells to evade immune surveillance (32). This finding suggests that SOCS3 may function not only as a negative regulator of intracellular signaling but also as a modulator of the inflammatory tumor niche, potentially contributing to immune evasion mechanisms in NSCLC.
The complexity of SOCS3 regulation, including its epigenetic modulation, underscores the need to assess it across different biological compartments. Meanwhile, miR-30d-5p expression was significantly down-regulated in patients with NSCLC. This finding is consistent with studies implicating miR-30d-5p in tumor suppression, such as inhibiting cell cycle regulators like cyclin E2 (CCNE2) and reducing tumor cell proliferation (23, 43). Our ROC curve analysis demonstrated high diagnostic value for miR-30d-5p (AUC=0.878; sensitivity 85.7%; specificity 87.5%), suggesting it may serve as a reliable, non-invasive biomarker for early detection of NSCLC.
Emerging literature identifies an important regulatory interaction between SOCS3 and miRNAs, particularly miR-30d-5p. miRNAs are central modulators of gene expression, and miR-30d-5p has been shown to down-regulate SOCS3, leading to enhanced JAK/STAT signaling activation, which contributes to tumor progression (39). Although we observed a negative correlation between miR-30d-5p expression and SOCS3 serum levels (Spearman’s ρ=−0.439, p=0.025), the decreased levels of miR-30d-5p may contribute to the up-regulation of SOCS3 in serum, representing a feedback or compensatory mechanism.
This miR-30d-5p/SOCS3 axis is gaining interest not only for its biological relevance but also for its clinical implications. Recent studies suggest that elevated serum SOCS3 may serve as a prognostic biomarker in NSCLC, aligning with the regulatory influence of miR-30d-5p (31). Understanding this interplay could provide deeper insights into tumor microenvironment dynamics, immune modulation, and cancer progression. Therapeutically, restoring SOCS3 function–either by demethylation or targeting miRNAs like miR-30d-5p–could help reinstate its tumor-suppressive role and inhibit tumor progression (44).
Additionally, targeting the miR-30d-5p/SOCS3 pathway may offer innovative therapeutic strategies to recalibrate JAK/STAT signaling in NSCLC. Combined modulation of this axis may enhance treatment responsiveness, slow progression, and potentially synergize with existing therapies. Prior work has shown that SOCS3 reactivation can suppress STAT3-mediated oncogenic processes and improve therapeutic efficacy in NSCLC cells (26, 31, 45).
Our findings further support the dual biomarker potential of SOCS3 and miR-30d-5p. SOCS3 exhibited excellent specificity (100%) and good sensitivity (67.6%) at an optimal diagnostic cut-off, while miR-30d-5p showed higher sensitivity and specificity overall. These complementary profiles suggest that a combined diagnostic approach could improve early detection and risk stratification in patients with NSCLC.
In conclusion, this study demonstrates that reduced miR-30d-5p expression alongside elevated serum SOCS3 levels are distinctive features of NSCLC and may represent a key regulatory mechanism with potential diagnostic and therapeutic implications. The confluence of these molecular pathways heralds a promising avenue for future research, with the potential to develop targeted therapeutic interventions that more effectively address the complex biology of NSCLC (46, 47). Future research should focus on validating these findings in larger cohorts, exploring the dynamic regulation of miR-30d-5p and SOCS3 in different disease stages, and investigating the potential of targeting this axis to enhance treatment efficacy.
Footnotes
Authors’ Contributions
Seha Akduman, Sibel Arinç: Organized and coordinated the research. Seda Güleç Yilmaz, Müge Kopuz Álvarez Noval: Led the article writing. Seda Güleç Yilmaz, Müge Kopuz Álvarez Noval, Selvi Duman Bakirezer: Carried out the laboratory work. Seha Akduman, Seda Güleç Yilmaz: Contributed to the design and implementation of the research methodology. Huseyin Kilili: Assisted in bioinformatics analysis. Seda Güleç Yilmaz: Supervised the study and contributed to data analysis.
Conflicts of Interest
The Authors declare no conflicts of interest in relation to this study.
Funding
This study received no specific grant from any funding agency.
Artificial Intelligence (AI) Disclosure
During the preparation of this manuscript, a large language model (ChatGPT, OpenAI; Grammarly) was used solely for language editing and stylistic improvements in select paragraphs. No sections involving the generation, analysis, or interpretation of research data were produced by generative AI. All scientific content was created and verified by the authors. Furthermore, no figures or visual data were generated or modified using generative AI or machine learning-based image enhancement tools.
- Received June 26, 2025.
- Revision received July 23, 2025.
- Accepted July 28, 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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