Blood MALT1 expression levels reflect the lymph node stage and disease‑free survival in patients with non‑small cell lung cancer
- Authors:
- Published online on: June 3, 2025 https://doi.org/10.3892/ol.2025.15127
- Article Number: 381
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Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Lung cancer, a common fatal malignancy, contributes to 2.21 million new cancer cases and 1.80 million new cancer-related deaths annually worldwide (1). In China, 0.83 million new lung cancer cases and 0.66 million new lung cancer-related deaths are recorded every year (2), thus causing heavy burdens to the patients and society (3,4). Non-small cell lung cancer (NSCLC) accounts for ~85% of lung cancer cases in China, thus giving an opportunity for research and development (5). Along with the advances in molecular detection technology and big-data gathering and analysis, biomarker-based precision therapy is considered an effective approach to improve prognosis and reduce disease burden in patients with NSCLC (6–8). However, the detection of a large proportion of predictive biomarkers requires the isolation of tissue lesions, which is not always feasible, particularly in patients who cannot undergo surgery.
Mucosa-associated lymphoid tissue lymphoma translocation protein-1 (MALT1), acting as a scaffolding gene/protein that triggers the activation of NF-κB transcription factors and as a protease to modify immune activation-related signaling via diversified substrate cleavage, was recently discovered to facilitate cancer development via both cancer cell-intrinsic and -extrinsic mechanisms (9,10). MALT1 has been reported to promote cancer cell viability, migration, invasion and drug resistance, and particularly resistance to immune checkpoint inhibitors, in several malignancies, such as breast cancer, prostate cancer, hepatocellular carcinoma and lymphomas (11–15). Previous studies have also demonstrated that MALT1 was upregulated and associated with poor prognosis in patients with colorectal cancer, malignant melanoma and lymphomas (16–18). In terms of lung cancer, MALT1 could promote cancer progression via interacting with caspase recruitment domain-coiled-coil complexes and NF-κB activation (19,20). Apart from the aforementioned direct regulation of cancer by MALT1, other studies indicated that MALT1 could regulate cancer immunity to promote cancer progression (15,21). These findings supported the potential of MALT1 expression levels as a prognostic biomarker in patients with NSCLC.
Therefore, the present study aimed to investigate the utility of the expression levels of MALT1 in blood samples from patients with NSCLC and their association with the clinical features, treatment options and survival outcomes for these patients.
Patients and methods
Subjects
In the present study, a total of 125 patients with NSCLC who underwent tumor resection surgery between April 2019 and January 2022 at North Sichuan Medical University affiliated Nanchong Central Hospital (Nanchong, China) were enrolled. The inclusion criteria were as follows: i) Patients diagnosed with NSCLC by pathological examination; ii) aged ≥18 years; iii) received tumor resection surgery; and iv) followed the normal follow-up requirements. In addition, the exclusion criteria were as follows: i) Patients whose NSCLC was accompanied by other primary types of cancer; ii) suffering from hematological malignancies; iii) with needle or blood phobia; and iv) pregnant women or lactating mothers. Additionally, a total of 20 healthy individuals undergoing physical examination between February and March 2024 were enrolled as the control group. The recruitment criteria for individuals into the control group were as follows: i) Subjects without any abnormalities in recent physical examinations; ii) aged >18 years; and iii) those who were willing to cooperate with blood collection. The exclusion criteria of patients with NSCLC were also applied to individuals in the healthy control group. The present study was approved by the Ethics Committee of North Sichuan Medical University affiliated Nanchong Central Hospital (approval no. 2024018; Nanchong, China), and most patients with NSCLC and the controls had provided written informed consent, while a waiver was obtained for certain patients with NSCLC who had not provided informed consent.
Data collection and sample detection
The clinical characteristics of patients with NSCLC, including demographic, and disease- and therapy-related data, were collected. The tumor-node-metastasis (TNM) stage was defined according to the guidelines provided by the International Association for the Study of Lung Cancer (22). Prior to treatment initiation, neoadjuvant therapy or tumor resection surgery, 2 ml peripheral blood (PB) was collected from all patients with NSCLC. In addition, PB from healthy controls was collected immediately after enrollment. For MALT1 detection, PB mononuclear cells (PBMCs) were separated from PB, and MALT1 levels were detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) assay. For qPCR, the thermocycling was as follows: 95°C for 60 sec, 1 cycle; 95°C for 15 sec and 61°C for 60 sec, 40 cycles. GAPDH was used as the internal reference and MALT1 levels were quantified using the 2−ΔΔCq method (23). The primer sequences were as follows: MALT1 forward (F), 5′-TCTTGGCTGGACAGTTTGTGA-3′ and reverse (R), 5′-GCTCTCTGGGATGTCGCAA-3′; GAPDH F, 5′-TGACCACAGTCCATGCCATCAC-3′ and R, 5′-GCCTGCTTCACCACCTTCTTGA-3′. The corresponding kits used for RT-qPCR are listed in Table SI and the kits were used according to the manufacturer's instructions.
Grading of MALT1 levels
MALT1 expression levels in patients with NSCLC were divided into four different grades. The quartile (Q) values for each grade were as follows: i) Q1, MALT1 ranged from the minimum value, 0.690, to the 1st quartile value, 2.190 (Q1, 0.690–2.190); ii) Q2, MALT1 ranged from the 1st quartile value to the 2nd quartile value, 3.600 (2.190–3.600); iii) Q3, MALT1 ranged from the 2nd quartile value to the 3rd quartile value, 5.945 (Q3, 3.600–5.945); and iv) Q4, MALT1 ranged from the 3rd quartile value to the maximum value, 12.770 (Q4, 5.945–12.770).
Follow-up and evaluation
Routine follow-up was conducted, with a median follow-up time of 18.1 months (range, 2.8–39.1 months). In the first year after surgery, follow-up was conducted once every 3 months and once every 3–6 months thereafter. If the patients experienced disease recurrence, a follow-up was performed once every 2 months. During the follow-up, the disease progression status, death and the corresponding periods were recorded. The accumulating disease-free survival (DFS) and overall survival (OS) rates were calculated.
Bioinformatics
The association of MALT1 gene expression levels with TNM stage, DFS and OS in patients with NSCLC using publicly data was performed as well, which was based on the Gene Expression Profiling Interactive Analysis (GEPIA) database (http://gepia.cancer-pku.cn/). Correlation analysis of MALT1 gene expression with immune infiltrates in various types of cancer and NSCLC specifically using publicly available data was performed using the TIMER database (http://timer.comp-genomics.org/).
Statistical analyses
Data analyses were performed using SPSS (version 26.0; IBM Corp.). Categorical data were expressed as number (percentage), normally distributed continuous data were expressed as the mean ± standard deviation and skewedly distributed continuous data were expressed as the median [interquartile range (IQR)]. To compare the clinical characteristics between different grades of MALT1, the Mann-Whitney U-test, χ2 test or Fisher's exact test was carried out. In addition, to compare accumulating DFS/OS rates between patients with NSCLC with different grades of MALT1, a log-rank test was performed. The results were displayed by Kaplan-Meier curves. Enter-method Cox regression models were used to identify the factors that were independently associated with DFS or OS. P<0.05 was considered to indicate a statistically significant difference.
Results
Characteristics of patients with NSCLC
A total of 125 patients with NSCLC were included in the present study. The mean age of the patients with NSCLC was 57.1±12.3 years. Among them, 27.2 and 72.8% were ≥65 and <65 years old, respectively. A total of 54.4% of patients were males and 45.6% were females (Table I), while 61.6, 28.8 and 9.6% of the patients were categorized as lung adenocarcinoma, lung squamous cell carcinoma and others, respectively. In addition, 36.0% of the cases had poor differentiation, and 8.0, 8.8, 20.0, 39.2, 21.6 and 2.4% of patients were of TNM stage of IA, IB, IIA, IIB, IIIA and IIIB, respectively. The mean age of the healthy control subjects was 55.5±5.2 years, consisting of 50% females and 50% males. Age (P=0.384) and sex (P=0.714) were not significantly different between the healthy controls and patients with NSCLC (Table SII).
MALT1 is aberrantly expressed in the blood and is associated with the clinical characteristics of patients with NSCLC
The blood MALT1 mRNA expression levels were quantified in the 20 healthy subjects and patients with NSCLC. The relative expression levels of MALT1 mRNA were increased in the blood samples of patients with NSCLC (median, 3.60; IQR, 2.19–5.95) compared with the healthy controls (median, 1.06; IQR, 0.66–2.29; P<0.001; Fig. 1), suggesting MALT1 was aberrantly expressed in the blood of patients with NSCLC. Subsequently, to analyze the association between blood MALT1 levels and clinical features, treatment options and prognosis in patients with NSCLC, the mRNA expression levels of MALT1 were divided into four groups, according to the quartiles (Q1, Q2, Q3 and Q4). The results demonstrated that the blood MALT1 quartile was markedly positively associated with the N (P=0.026) and TNM (P=0.036) stages in patients with NSCLC. Additionally, MALT1 expression levels displayed a tendency to be positively associated with poor differentiation (P=0.091) and T stage (P=0.058; Table I), but this did not reach statistical significance. By contrast, the blood MALT1 quartile was not associated with other clinical characteristics or with neoadjuvant therapy, surgical type or adjuvant therapy.
Prognostic value of blood MALT1 levels in patients with NSCLC
The blood MALT1 quartile was associated with shorter DFS (P=0.009), with 3-year accumulating DFS rates of 92.9, 68.8, 41.4 and 28.2% in patients with MALT1 levels at Q1, Q2, Q3 and Q4, respectively (Fig. 2A). However, the blood MALT1 quartile only showed a tendency to be associated with poor OS in these patients (P=0.118), but it did not reach statistical significance; 3-year accumulating OS rates of 100.0, 84.4, 65.7 and 44.5% were recorded in patients with MALT1 levels at Q1, Q2, Q3 and Q4, respectively (Fig. 2B). The aforementioned data suggested that blood MALT1expression levels may potentially predict DFS; however, they lacked efficiency in OS estimations of patients with NSCLC. Furthermore, multivariate Cox analysis was performed to identify the factors that could affect DFS and OS in patients with NSCLC. Increased MALT1 quartile [P=0.016; hazard ratio (HR), 1.712], age (P=0.026; HR, 1.043) and TNM stage (P=0.001; HR, 10.734) had a negative impact on DFS independently, while adjuvant tyrosine kinase inhibitor therapy (P=0.038; HR, 0.244) was independently associated with satisfied DFS (Fig. 3). In terms of OS, a higher MALT1 quartile (P=0.293; HR, 1.477) was not significantly associated with OS. However, a higher TNM stage (P=0.009; HR, 21.113) was significantly associated with lower OS rates (Fig. 4).
Bioinformatic analyses based on public database
GEPIA is a developed interactive web server for analyzing the RNA sequencing expression data from the The Cancer Genome Atlas and the Genotype-Tissue Expression projects, using a standard processing pipeline (24). With the use of GEPIA, it was observed that MALT1 was not related to TNM stage, DFS or OS in patients with lung adenocarcinoma (Fig. S1A), nor in patients with lung squamous cell carcinoma (Fig. S1B). MALT1 showed a notable association with DFS in lung squamous cell carcinoma but this was not of statistical significance.
The TIMER database is a comprehensive resource for the systematic analysis of immune infiltrates across diverse types of cancer (25). The TIMER database was used for immune analysis and demonstrated that MALT1 expression levels were correlated with macrophages and CD8+ T cells in various types of cancer (Fig. S1C and D). Regarding NSCLC, MALT1 was closely correlated with macrophages (particularly the M1 type) and CD8+ T cells in lung adenocarcinoma, but the correlation was lower in lung squamous cell carcinoma.
Discussion
It has been suggested that MATL1 is a significant carcinogenetic factor that promotes the initiation and progression of several types of cancer (11–21). More specifically, the role of MALT1 inhibitor as a candidate treatment option for hepatocellular carcinoma, colorectal cancer, chronic lymphocytic leukemia and glioblastoma both in vivo and in vitro, has been recently investigated (13,26–28). Due to these functions, MALT1 has attracted increasing attention as a biomarker in different types of cancer. Previous studies demonstrated that MALT1 was upregulated in colorectal cancer, melanoma and lymphomas (16–18). However, the aforementioned studies detected the expression levels of MALT1 in cancerous tissues. Therefore, data on the expression levels of MALT1 in blood samples are lacking. The present study demonstrated that MALT1 was upregulated in blood samples from patients with NSCLC compared with the control group (~3.4-fold). This finding could be due to the possible promoting role of MALT1 in lung cancer (19,20) and its effects on CD8+ T-cell functions, immune escape and anticancer immunity (29–31).
Subsequently, the present study also demonstrated that blood MALT1 expression levels were positively associated with N and TNM stages in patients with NSCLC, and showed a notable positive association with poor differentiation and T stage, thus supporting the possible role of MALT1 in predicting tumor progression or disease burden in patients with NSCLC. These findings could be for the following reasons: i) Previous studies demonstrated that MALT1 could directly activate NF-κB to promote NSCLC progression, while blood MALT1 levels could also reflect the expression levels of MALT1 in tumor tissues, to a certain extent (32,33); ii) in addition to the NF-κB signaling pathway, bioinformatics analysis in the Kyoto Encyclopedia of Genes and Genomes predicted that MALT1 could also regulate the C-type lectin, T-cell and B-cell receptor signaling pathways, thus promoting NSCLC progression (34,35); and ii) other studies also suggested that the T-cell receptor signaling pathway, a notable downstream pathway of MALT1, could affect tumor immunity and immune escape to promote NSCLC progression (36–38).
The present study also suggested that blood MALT1 levels may predict the prognosis of patients with NSCLC. Kaplan-Meier curves predicted that the expression levels of MALT1 in the blood of patients with NSCLC were associated with a shorter DFS, while they showed a notable association with worse OS. Further adjustment by multivariate Cox analysis demonstrated that the expression levels of MALT1 could independently predict unsatisfied DFS. The prognostic value of blood MALT1 levels could be due to the following: i) Correlation analysis revealed that MALT1 was associated with advanced tumor conditions, such as N and TNM stages, thus possibly affecting the prognosis of patients with NSCLC; and ii) a large proportion of patients with NSCLC were treated with adjuvant therapies. It has been reported that MALT1 regulates the sensitivity of patients to adjuvant therapies (19,21,39). Therefore, the aforementioned findings could affect the prognosis of patients with NSCLC. Furthermore, the lack of significance regarding the association between MALT1 levels and OS could be due to the fact that OS could be affected by several factors, such as treatment after tumor recurrence, comorbidity and supportive treatment. These factors may weaken the predictive value of MALT1 regarding the prognosis of patients with NSCLC. Furthermore, GEPIA database analysis revealed that MALT1 was not correlated with DFS or OS in lung cancer and the difference between the aforementioned GEPIA data and the present findings may have been due to the fact that tumor tissue was used in GEPIA, while blood samples were used in the present study.
However, the present study had certain limitations. First, the present study only included surgical patients with NSCLC to avoid interference, since the prognosis of advanced cases was far from surgical ones, which limited the generalizability of the study findings. More patients with different types of lung cancer would have been needed to be included to obtain more comprehensive conclusions. Second, the sample size of the present study was relatively small, which may limit the reliability and generalizability of the results. Therefore, more large population-based validation studies are needed to verify the results of the present study. Third, the follow-up time of the present study was relatively short and it was difficult to assess the correlation between blood MALT1 and long-term prognosis. Therefore, longer follow-up studies are needed to verify the long-term prognostic value of blood MALT1 expression levels. Finally, no investigation into the mechanistic relationship between blood MALT1 levels and the development and prognosis of NSCLC was performed, which could be further evaluated in future studies.
In conclusion, the results of the present study suggested that blood MALT1 levels could potentially reflect the stage of lymph node metastasis and predict DFS in patients with NSCLC. This suggests the potential of blood MALT1 to be a prognostic biomarker in patients with NSCLC, which could help facilitate personalized treatment via early identifying prognostic risk stratification. However, future large-scale studies with a longer follow-up duration are needed to further validate the results of the present study.
Supplementary Material
Supporting Data
Supporting Data
Acknowledgements
Not applicable.
Funding
The present study was supported by Nanchong City School Cooperation Special Project (grant no. 19SXH0353).
Availability of data and materials
The data generated in the present study may be requested from the corresponding author.
Authors' contributions
XZ contributed to the study conception and design. Data collection and analysis were performed by FZ and BW. XP was responsible for the interpretation of data for the present study. XZ and FZ confirm the authenticity of all the raw data. All authors contributed to drafting of article and revising it critically for important intellectual content. All authors read and approved the final manuscript.
Ethics approval and consent to participate
The Ethics Committee of North Sichuan Medical University (Nanchong, China) approved the present study (approval no. 2024018). Most NSCLC patients and the controls had provided written informed consent, while a waiver was obtained for certain patients with NSCLC who had not provided informed consent.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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