Abstract
Background/Aim: Albumin is abundant in human plasma and has been widely studied in cancer mainly in the context of systemic nutrition or the tumor microenvironment; however, the clinicopathologic significance and intracellular role of tumor-cell albumin in gastric adenocarcinoma remain unclear.
Patients and Methods: We analyzed 187 patients who underwent gastrectomy for gastric adenocarcinoma between 2000 and 2010. Albumin expression was evaluated by immunohistochemistry on tissue microarrays and classified as high versus low based on intensity relative to intra-tumoral stromal cells. Associations with clinicopathologic variables were examined, and disease-free survival (DFS) and disease-specific survival (DSS) were assessed using Kaplan-Meier and Cox regression. Albumin mRNA/protein expression was examined in three metastatic gastric cancer cell lines, and functional assays (wound healing and proliferation) were performed after siRNA-mediated albumin knockdown in Hs746T cells.
Results: High albumin expression was significantly associated with larger tumor size and advanced T and N stages. Albumin expression was not significantly associated with DFS or DSS in univariate or multivariate analyses, whereas T stage and N stage remained independent prognostic factors. In vitro, albumin knockdown significantly impaired migration and reduced proliferative capacity, despite limited detectable reduction in protein levels.
Conclusion: Tumor-cell albumin correlates with gastric cancer progression and functionally contributes to motility and growth at the intracellular level, supporting its role as a marker of aggressive tumor biology rather than an independent prognostic biomarker.
Introduction
Interest in gastric cancer is increasing, given that it remains one of the most common malignancies worldwide and South Korea has one of the highest incidence rates, second only to Mongolia (1). In particular, growing attention is being directed toward metastatic gastric cancer because outcomes differ markedly by stage: early lesions confined to the mucosa or submucosa generally have an excellent prognosis, whereas advanced disease has an approximate 30% 5-year survival rate (2). Accordingly, early detection remains essential, and there is growing interest in biomarkers that can predict prognosis and metastatic potential. Among the many candidates, we focused on albumin because it is a practical and clinically accessible biomarker that may also reflect key aspects of tumor biology. Serum albumin is the most abundant protein in human circulation and has several properties that make it especially relevant in oncology. From a practical standpoint, it is readily available, biodegradable, nontoxic, and largely nonimmunogenic, which is why it has been widely considered an ideal carrier for drug delivery applications (3). Functionally, albumin’s interactions with albumin-binding partners can extend the in vivo half-life of proteins, helping to reduce clearance and improve pharmacokinetic stability (3). These characteristics have led to its extensive use as a pharmacological strategy to increase both bioavailability and biocompatibility of therapeutic agents across diverse settings (4-6).
Importantly, the relevance of albumin is not limited to drug delivery. Clinically, serum albumin has emerged as a meaningful prognostic indicator in multiple malignancies. Recent studies have shown that serum albumin can serve as an independent prognostic biomarker in ovarian cancer (7) and in diffuse large B-cell lymphoma (8). Taken together, these established roles–spanning clinical prognostication and therapeutic engineering–provide a strong rationale for using serum albumin as a practical and well-justified starting point for investigating its role in cancer. With that foundation, we then extend the discussion to what is more directly aligned with our aim: intracellular albumin. While serum albumin is the most studied and frequently cited form in literature, intracellular albumin may have distinct biology–such as cellular uptake, intracellular trafficking, metabolic adaptation, or stress responses–that could be particularly relevant to tumor progression and metastasis. Thus, our approach is to start from the well-established serum/endogenous albumin context (3-8) and then move into a focused examination of intracellular albumin, as detailed in the following section.
Patients and Methods
Patients and clinicopathological data. A total of 187 patients who underwent surgery for adenocarcinoma of the stomach between January 2000 and December 2010 at the Gyeongsang National University Hospital, Jinju, South Korea, were enrolled for the study. Representative hematoxylin and eosin (H&E)-stained slides from the 187 patients were reviewed by two pathologists. Medical records were reviewed, and the clinicopathological data, including age, sex, surgery history, T stage, N stage, pathologic differentiation, disease-free survival (DFS), and disease-specific survival (DSS), were obtained. To reduce selection bias related to loss to follow-up, we included consecutive eligible cases during the study period. The TNM stages of stomach cancer specimens were determined according to the eighth edition guidelines of the American Joint Committee on Cancer (AJCC). This study was approved by the institutional review board of the Gyeongsang National University Hospital (GNUH-2019-02-016).
Tissue microarray construction and immunohistochemistry. Representative H&E-stained glass slides containing tumorous lesions were examined. A core (3 mm in size) was collected from the invasive tumor front of each representative paraffin block and transplanted into recipient tumor microarray (TMA) blocks. Immunohistochemical staining was carried out using an automated immunostainer (Benchmark Ultra, Ventana Medical Systems Inc., Tucson, AZ, USA) with an anti-albumin monoclonal antibody at a dilution of 1:200 (sc-271605; Santa Cruz Biotechnology, Dallas, TX, USA). Intra-tumoral stromal cells were used as the positive control for albumin.
Albumin expression. Albumin expression was evaluated in the cytoplasm and membrane of the tumor cells. The intensity of tumor cell expression was graded as either high or low expression. Tumor cells that stained stronger than intratumoral stromal cells were classified as high expression, and others were classified as low expression. If the tumor cells showed heterogeneous expression in the same core, the representative value was determined according to the majority of tumor cells. To confirm the reproducibility, all samples were individually reviewed by two independent pathologists.
Cell culture. The human stomach cell lines MKN-45 (adenocarcinoma, intestinal type), Hs746T (carcinoma, metastasis to lung), and NCI-N87 (carcinoma, metastasis to liver) were purchased from the Korean Cell Line Bank (Seoul, Republic of Korea). HS746T cells were cultured in Dulbecco’s modified Eagle’s medium (Gibco, Grand Island, NY, USA), and the MKN-45 and NCI-N87 cell lines were cultured in RPMI 1640 (Gibco). Both media were supplemented with 10% fetal bovine serum (Gibco) and 1% penicillin-streptomycin (Corning, Corning, NY, USA), and cell lines were incubated at 37°C under an atmosphere containing 5% CO2.
Semi-qPCR. When the cells reached 70% confluence, RNA was extracted from stomach cell lines using TRIzol (Qiagen, Germantown, MD, USA). Total RNA was quantified using a NanoDrop 2000 (Thermo Fisher Scientific, Wilmington, DE, USA) The prepared RNA (1 μg) was reverse transcribed to cDNA using the Maxime RT PreMix Kit (iNtRON, Burlington, MA, USA). Equal amounts of synthesized cDNA (1 μg) were used to carry out semi-qPCR using Maxime PCR PreMix kit (iNtRON). Albumin primers (P197016; Bioneer, Daejeon, Republic of Korea) were added. PCR was performed in 20 μl using a thermocycler (Biometra, Uberlingen, Germany) with the following PCR program: pre-denaturation for 2 min at 94°C, denaturation for 20 s at 94°C, annealing for 10 s at 58°C, extension for 20 s at 72°C, and a final elongation for 2 min at 72°C. PCR was performed for 40 cycles. PCR products were analyzed using electrophoresis on a 1.5% agarose gel, and band intensity was measured directly on a gel documentation system (Bio-Rad, Hercules, CA, USA) and quantified relative to that of glyceraldehyde 3-phosphate dehydrogenase.
Western blotting. When the cells reached 70% confluence, proteins were extracted from the harvested cells using RIPA lysis buffer (Thermo Fisher Scientific) containing protease inhibitor cocktail (Thermo Fisher Scientific). The total protein concentration of each cell lysate was measured by the Bradford method using bovine serum albumin as a standard. Equal amounts of protein lysates (45 μg) were loaded onto denaturing polyacrylamide gels and then transferred to a nitrocellulose membrane. The primary antibodies used for immunoblotting were anti-albumin (diluted 1:100; sc-271605; Santa Cruz Biotechnology) followed by horseradish peroxidase-conjugated secondary antibodies. Immunoreactive bands were detected by enhanced chemiluminescence reaction (Thermo Fisher Scientific). Digital chemiluminescence images were captured and quantitatively analyzed by Fusion solo (Vilber, Marne-la-Vallee, France).
Albumin knockdown. Cells were cultured to 70-80% confluence in 60 mm dishes. The cells assigned to the knockdown group were transfected using Lipofectamine 3000 (Invitrogen, Carlsbad, CA, USA, #L3000015) with human albumin siRNA (#231-1; Bioneer,), while cells in the negative control group were transfected with scrambled siRNA (#SN-1002; Bioneer) at a final concentration of 25 nM. After a 24 h incubation, cells were re-transfected using the same protocol. The cells were then incubated for 72 h before harvesting.
Wound healing assay. Cells were transfected with albumin siRNA as described above. Once the cells reached 100% confluence, 25 Culture-Inserts 2 Well for Self-Insertion (#80209; Ibidi, Planegg, Germany) were used for the wound-healing assays. The cells were washed twice with phosphate-buffered saline to remove detached cells. Then the cells were incubated at 37°C in an atmosphere containing 5% CO2, and the wounded area was monitored for 48 h using JuLI Br (NanoEntek, Seoul, Republic of Korea). Images were transferred to and analyzed by image-processing software ImageJ (National Institutes of Health, Bethesda, MD, USA).
Proliferation assay. Cells were seeded in 60-mm culture dishes and maintained under standard culture conditions until they reached approximately 70-80% confluence. After albumin knockdown, the culture medium was replaced with serum-free medium and cells were incubated for 24 h to minimize the influence of serum-driven proliferation. Following starvation, cell proliferation was monitored for the subsequent 48 h using a live-cell imaging system (JuLI™ Br; NanoEntek). For each dish, two predefined fields of view were selected, and images were captured repeatedly at the same coordinates throughout the monitoring period. Proliferation was quantified by counting cells in sequential images acquired from each fixed field over time.
Statistical analysis. The correlation of albumin expression with pathological and clinical data was evaluated using Pearson’s chi-square test and Fisher’s exact test. Differences in DFS and DSS among groups were evaluated using the Kaplan-Meier method with the log-rank test and the Cox proportional hazard regression model. p-values less than 0.05 were considered statistically significant. The analyses were performed using IBM SPSS ver. 24.0 (IBM Corp., Armonk, NY, USA).
Results
Clinicopathological data of the patients. The clinicopathological data of the 187 patients with gastric tubular carcinoma are summarized in Table I. The median age of the cohort is 65 years, with a range of 24 to 85 years. 123 patients are male. The median tumor size is 4.2 cm, varying from 0.5 to 17 cm. Pathologic differentiation of the tumors is categorized into well differentiated (W/D), moderately differentiated (M/D), and poorly differentiated (P/D), accounting for 19.3%, 41.7%, and 39.0% of the cases, respectively. Tumor staging is based on T stage, with 43.9% of patients at T1, 12.3% at T2, 43.3% at T3, and 0.5% at T4. Nodal involvement is classified into N0 (56.7%), N1 (10.7%), N2 (13.9%), and N3 (18.7%). Finally, albumin expression is evaluated as either low (47.6%) or high (52.4%), indicating its potential role as a biomarker in gastric adenocarcinoma.
Clinicopathological characteristics of 187 patients with gastric tubular carcinoma.
Correlation between albumin expression and clinicopathological data. The correlation between albumin expression and various clinicopathological factors in 187 patients with gastric tubular carcinoma is shown in Table II. Age is bifurcated at 65 years, with similar proportions of low and high albumin expression in both age groups (p=0.508). Sex distribution shows a non-significant trend towards higher albumin expression in men (p=0.161). A significant association is observed in tumor size; smaller tumors (<4.2 cm) are more likely to have low albumin expression (p=0.004). Pathologic differentiation, categorized into well/moderately differentiated (W/D, M/D) and poorly differentiated (P/D), shows no significant correlation with albumin expression (p=0.823). Smaller tumors (<4.2 cm) had more often low albumin expression, whereas larger tumors (≥4.2 cm) had more often high albumin expression (p=0.004). Early T stage (T1) tumors predominantly exhibit low albumin expression, while advanced stages (T2, T3, T4) are associated with high expression (p<0.001). Nodal involvement (N stage) also demonstrates a significant association, with N0 stage more likely to have low albumin expression, and advanced nodal stages (N1, N2, N3) showing high expression (p=0.012).
Correlation between expression of albumin in gastric tubular carcinoma and clinicopathological factors (N=187).
The immunohistochemical staining patterns of albumin. High albumin expression showed a strong and diffuse cytoplasmic and membranous staining pattern. Positive tumor cells were stained more strongly than or equal to the surrounding stromal fibroblasts (Figure 1A). Low albumin expression showed a negative or weaker cytoplasmic or membranous staining pattern. Tumor cells were stained weaker than the surrounding stromal fibroblasts (Figure 1B).
High albumin expression shows a strong and diffuse cytoplasmic and membranous staining pattern. Cancer cells are stained more strongly than or equal to the surrounding stromal fibroblasts (A). Low albumin expression shows a negative or weaker cytoplasmic or membranous staining pattern. Cancer cells show weaker staining than the surrounding stromal fibroblasts (B). Scale bar=200 μm
Albumin expression and survival analysis. Table III presents the results of Cox proportional hazards regression models assessing DFS and DSS in 187 patients with gastric tubular adenocarcinoma. In univariate analysis, significant predictors of worse DFS include larger tumor size [>4.2 cm; hazard ratio (HR)=5.285, p<0.001], advanced T stage (T2-4; HR=6.509, p<0.001), and higher N stage (N1-3; HR=18.275, p<0.001). Multivariate analysis confirms the independent prognostic significance of tumor size (HR=2.372 for DFS, HR=2.832 for DSS) and N stage (HR=6.106 for DFS, HR=4.571 for DSS), and for T stage (HR=3.094 for DFS). Age, sex, and pathologic differentiation (W/D, M/D vs. P/D) show no significant association with survival outcomes in either univariate or multivariate analyses. Additionally, albumin expression (low vs. high) does not demonstrate a significant impact on survival in this patient cohort.
Cox proportional hazards regression model of survival for patients with gastric tubular adenocarcinoma (n=187).
mRNA and protein expression. Albumin expression was assessed in human gastric cancer cell lines. Albumin mRNA levels were measured by semi-quantitative PCR using total RNA extracted from MKN-45, Hs746T, and NCI-N87 cells (Figure 2A and B). Among the three cell lines, Hs746T showed the highest relative albumin mRNA expression. Consistently, western blotting demonstrated that albumin protein levels were also highest in Hs746T cells (Figure 2C and D). Based on these findings, Hs746T cells were selected for albumin knockdown experiments. Albumin knockdown significantly reduced albumin mRNA levels compared with the control group (Figure 3A and B); however, the relative albumin protein level was not significantly different between the two groups (Figure 3C and D).
Albumin expression identified in stomach cancer cell lines. Among the three stomach cancer cell lines, including MKN-45, HS746T, and NCI-N87, Hs746T exhibit the highest relative mRNA density for albumin (A, B). The highest relative protein levels of albumin are observed in the Hs746T cell line (C, D).
Knockdown (KD) of albumin in HS746T cells decreased the relative albumin (ALB) mRNA density compared to the control (NC) cells (A, B); however, relative albumin protein density is not significantly different between these groups (C, D). *p<0.05. M: Molecular weight marker.
Migration activity. During the 48-h wound-healing assay, migratory activity differed significantly between the albumin knockdown and control groups, as quantified using ImageJ (Figure 4A and B). Albumin knockdown markedly attenuated gastric cancer cell migration, resulting in delayed wound closure. Consistent with this, the migrated distance (or remaining wound gap) at 24 h and 48 h was significantly different between the albumin knockdown and control cells (Figure 4B), indicating that albumin contributes to cell migratory capacity.
During the 48 h of the wound-healing assay, there was significant difference in migration between the albumin knockdown (ALB KD) and the control (N.Con) group (A, B), as measured using ImageJ. The wound gap measured at 24 and 48 h differed significantly between the albumin-knockdown (KD) cells and the control (NC) cells (B), indicating that albumin activity is involved in cell migration (*p<0.05).
Proliferation activity. Based on cell count-based proliferation analysis, the albumin knockdown group showed a significantly smaller increase in confluence than the control group at 6 h, 24 h, and 48 h (p<0.005, p<0.0001, and p<0.0001, respectively) (Figure 5A and B). Consistently, the number of proliferating cells in the albumin knockdown group was 85 at 6 h, 70 at 24 h, and 60 at 48 h. In contrast, the corresponding counts in the control group were 110, 142, and 169, respectively (Figure 5B), indicating that albumin knockdown suppresses cell proliferation over time.
The albumin knockdown (ALB KD) group showed a significantly smaller increase in confluency at 6, 24, and 48 h than the control (N.Con) group (A, B) (p<0.005, p<0.0001, and p<0.0001, respectively). Consistent with this, fewer proliferating cells were observed in the albumin-knockdown (KD) group at each time point (85 at 6 h, 70 at 24 h, and 60 at 48 h) compared to the control (NC) group (110, 142, and 169, respectively) (B) (**p<0.005, ***p<0.0001).
Discussion
Albumin is a highly abundant plasma protein in human blood, with a molecular weight of approximately 65-70 kDa. It is notably stable, biocompatible, readily purified by ~40% ethanol fractionation, and tolerant of prolonged heating (up to 10 h), characteristics that have supported its long-standing use in biomedical applications. Beyond these physicochemical properties, albumin is particularly useful for investigating cancer-associated microenvironments because it can preferentially accumulate in tumors or inflamed tissues and may be efficiently internalized by cells within these microenvironments
Its broad availability, biodegradability, low toxicity, and minimal immunogenicity position albumin as a practical and versatile drug carrier (3). Moreover, albumin-mediated binding interactions can prolong the in vivo half-life of conjugated proteins and improve overall drug biocompatibility, thereby enhancing therapeutic performance in circulation and at target sites. Consistent with these advantages, prior work has incorporated serum albumin into a wide range of biotherapeutic strategies. Representative examples include albumin-based nanoformulations designed to deliver natural compounds such as curcumin, Rosmarinic acid (RosA), or Ursolic acid (UrsA) (6), paclitaxel-loaded biodegradable bovine serum albumin nanoparticles (3), curcumin-loaded albumin nanoparticles (9), and albumin nanovectors developed for broader anticancer delivery platforms (5). In parallel with its role as a delivery scaffold, serum albumin has also been studied as a prognostic indicator across malignancies. Specifically, serum albumin has been reported as an independent prognostic biomarker in ovarian cancer (7) and diffuse large B-cell lymphoma (8). In ovarian cancer, survival has been shown to correlate inversely with serum albumin level, with lower albumin associated with poorer outcomes (7). Similarly, in patients with diffuse large B-cell lymphoma treated with standard R-CHOP chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), serum albumin levels below 3.7 g/dl have been associated with worse overall survival and progression-free survival than levels above 3.7 g/dl (8). Together, these observations suggest that albumin is more than a passive carrier protein and underscore its relevance both as a functional platform for therapeutic design and as a clinically informative biomarker (3, 5-9).
Building on our unpublished lung cancer data, we observed strong diffuse cytoplasmic-membranous albumin staining in tumor cells, with accentuation at the invasive front in squamous cell carcinoma. In multivariable Cox models, this pattern–particularly when combined with poor differentiation–was associated with worse disease-free survival (DFS) and disease-specific survival (DSS). Together with our previous report on RAB27A/RAB27B in gastric cancer (10), these findings led us to hypothesize that albumin may play a biologically relevant role in gastric cancer. Accordingly, we investigated the expression pattern and biological significance of albumin in human gastric cancer tissues. Given that albumin is the most abundant protein in the human body, the mechanisms of albumin in gastric cancer cells which contribute to invasion and metastasis remain poorly understood and are likely to differ among cancer types because of tumor cell heterogeneity and distinct tumor microenvironments. Although drug delivery and therapeutic response of endogenous albumin within the tumor microenvironment have been actively investigated, there is still limited information on how intracellular albumin expression in cancer cells themselves relates to the behavior of gastric cancer. In this context, we hypothesized that albumin expression in gastric cancer tissue might serve not only as a prognostic or biological marker but also as a potential therapeutic target, particularly in tumors with high albumin expression. To the best of our knowledge, albumin has not previously been systematically evaluated using immunohistochemistry in human gastric cancer specimens, and the present study therefore examined albumin protein expression and its functional impact with the aim of contributing to future diagnostic and therapeutic strategies in gastric cancer.
In this study, in our cohort of 187 patients, high albumin expression in gastric cancer tissue was significantly associated with larger tumor size and more advanced T and N stages. However, albumin expression did not affect statistically significantly DFS or DSS in univariate or multivariate analyses, whereas T stage and N stage remained independent prognostic factors. These findings suggest that albumin expression correlates with tumor progression but does not function as an independent prognostic biomarker in gastric cancer. Thus, albumin expression may reflect certain aspects of tumor biology without serving as a reliable predictor of long-term patient outcome. To validate the biological relevance of these clinical observations at the intracellular level, we examined albumin expression across three metastatic gastric cancer cell lines and selected Hs746T, which exhibited the highest expression, for functional assays following albumin knockdown. Although mRNA levels were efficiently reduced, the corresponding protein levels did not show a marked decrease. This discrepancy is likely attributable to the complex nature of albumin biology, including the presence of multiple post-translationally modified or truncated forms, uptake of extracellular albumin from serum components, and the broad binding specificity of commercially available antibodies. Despite this limitation in detecting protein-level reduction, albumin knockdown resulted in significantly impaired migration and proliferation, with albumin knockdown cells demonstrating delayed wound closure and increased cell detachment compared to controls. These findings support the notion that albumin contributes functionally to tumor cell motility and growth, consistent with its association with more advanced tumor features in patient tissues. When considered together with the clinical association between high tissue albumin expression and more advanced T and N stages, these functional data support the interpretation that albumin contributes to the aggressive phenotype of gastric cancer cells. Importantly, the combined clinical-experimental findings indicate that high albumin expression in gastric cancer may not simply reflect intrinsic over-expression by tumor cells. Importantly, our data primarily support an intracellular, cell-autonomous role of albumin in gastric cancer cells. Although intracellular albumin expression has often been discussed in the context of the tumor microenvironment as an abundant extracellular protein, our findings indicate that once albumin is present within tumor cells–whether produced endogenously or internalized from the surrounding milieu–it can promote malignant behaviors, as evidenced by reduced migration and proliferation after albumin knockdown. Therefore, the clinical association between high tissue albumin expression and advanced T and N stages may reflect not only a progression-linked expression pattern in tissues, but also the biological advantage conferred by intracellular albumin-associated functions that facilitate invasion and nodal spread.
The biological meaning of high albumin expression in gastric cancer is likely multifactorial and context-dependent, but our findings support an interpretation centered on tumor-cell-intrinsic, intracellular function. Clinically, high tissue albumin expression was associated with larger tumors and more advanced T and N stages, suggesting a link to tumor progression rather than an independent predictor of long-term outcome. Experimentally, albumin knockdown impaired migration and proliferation in metastatic gastric cancer cells, indicating that intracellular albumin-associated activity can contribute directly to aggressive tumor behavior. In this framework, prior reports can be viewed as complementary mechanisms that may increase the availability and functional impact of albumin in tumors: albumin can act as a nutrient reservoir and carrier of growth-promoting ligands in the tumor milieu, a concept supported by its use in tumor-targeted drug delivery systems (11); gastric cancer cells may internalize extracellular albumin or engage albumin-related signaling through surface interactions, thereby influencing survival, proliferation, and invasion (12); and albumin may also shape stromal responses such as angiogenesis or extracellular matrix remodeling that facilitate invasion and nodal spread. In addition, although direct evidence in gastric cancer remains limited, albumin-related changes in the local nutrient/ligand landscape could affect immune surveillance (13), and high intra-tumoral albumin may reflect heightened metabolic demand in aggressive tumors rather than simple host nutritional status. Finally, albumin biology has plausible links to therapeutic response and resistance, warranting further study. Taken together, these observations support our conclusion that high albumin expression in gastric adenocarcinoma is associated with tumor progression and an aggressive phenotype–likely mediated in part by intracellular albumin-related functions–even though albumin does not emerge as an independent prognostic marker for survival in our cohort.
In conclusion, our clinical and experimental findings indicate that high albumin expression in gastric adenocarcinoma is closely associated with tumor progression and reflects an aggressive phenotype, driven in part by functionally relevant intracellular albumin activity rather than intrinsic over-expression alone. Although albumin expression did not independently predict long-term survival in our cohort, it may serve as a practical biological indicator of tumor aggressiveness, particularly useful in small biopsy specimens to anticipate invasive potential and nodal involvement before surgery or advanced therapeutic decision-making. From a therapeutic perspective, our findings warrant further study of albumin-related vulnerabilities in gastric cancer, including targeting albumin-linked intracellular pathways and exploring albumin-based drug delivery to better treat albumin-high tumors.
Acknowledgements
This work was supported by biomedical research institute fund (GNUCHBRIF-2025-0002) from the Gyeongsang National University Changwon Hospital.
Footnotes
Authors’ Contributions
Conceptualization: Dae Hyun Song; Data curation: Hyo Jung An, Min Hye Kim; Funding acquisition: none; Methodology: Dae Hyun Song, Hyo Jung An; Project administration: Dae Hyun song; Resources: Hyo Jung An, Min Hye Kim; Supervision: Dae Hyun Song; Validation: Dae Hyun Song; Visualization: Hyo Jung An; Writing-original draft: Hyo Jung An; Writing-review and editing: Dae Hyun Song.
Conflicts of Interest
No potential conflicts of interest relevant to this article are reported.
Artificial Intelligence (AI) Disclosure
No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.
- Received February 2, 2026.
- Revision received February 27, 2026.
- Accepted March 6, 2026.
- Copyright © 2026 The Author(s). Published by the International Institute of Anticancer Research.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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