Correlation of serum cytokine-induced neutrophil chemoattractant levels with Helicobacter pylori infection and disease severity in gastric cancer patients

Abstract

BACKGROUND

Gastric cancer (GC) is a leading cause of cancer-related mortality worldwide, with Helicobacter pylori (H. pylori) infection recognized as a major risk factor. Chronic H. pylori-induced inflammation drives carcinogenesis through neutrophil-mediated pathways, in which cytokine-induced neutrophil chemoattractant (CINC) plays a pivotal role. However, the interplay among H. pylori virulence factors, systemic CINC levels, and GC progression remains poorly defined.

AIM

To investigate the correlation among serum CINC levels, H. pylori infection, and disease severity in patients with GC.

METHODS

This retrospective cohort study included 258 patients with GC diagnosed between April 2020 and November 2023. H. pylori infection was confirmed via histology, rapid urease test, and serology. Serum CINC levels were quantified using ELISA. Statistical analyses were performed with SPSS 26.0.

RESULTS

The H. pylori-positive patients exhibited significantly higher serum CINC levels (312.5 ± 120.3 pg/mL) than the H. pylori-negative patients (150.2 ± 95.4 pg/mL; P < 0.05). CINC levels were correlated positively with TNM stage in the H. pylori-positive patients (P < 0.05), with the highest levels recorded in stage IV (415.7 ± 150.6 pg/mL). The patients infected with cytotoxin-associated gene A/vacuolating cytotoxin-positive H. pylori strains had elevated CINC levels (P < 0.05). High CINC levels and H. pylori infection independently predicted poor survival (HR of 2.41 and 1.89, respectively; P < 0.05).

CONCLUSION

Elevated serum CINC levels are strongly associated with H. pylori infection, advanced TNM staging, and poor prognosis in GC. CINC serves as a novel prognostic biomarker, underscoring the role of neutrophil-driven inflammation in H. pylori-associated carcinogenesis.

Key Words: Gastric cancer; Helicobacter pylori; Cytokine-induced neutrophil chemoattractant; Inflammation; Prognosis

Core Tip: This study reveals that Helicobacter pylori (H. pylori) infection significantly elevates serum cytokine-induced neutrophil chemoattractant (CINC) levels in gastric cancer patients, particularly in those infected with cytotoxin-associated gene A/vacuolating cytotoxin-positive strains. CINC levels correlate with advanced TNM staging and independently predict poor survival, highlighting its role as a novel prognostic biomarker. Longitudinal monitoring demonstrates dynamic CINC changes aligned with disease progression, suggesting utility in treatment response assessment. These findings position CINC-driven neutrophilic inflammation as a therapeutic target and underscore the synergy between H. pylori virulence factors and systemic inflammation in accelerating gastric carcinogenesis.

INTRODUCTION

Gastric cancer (GC) is a leading cause of cancer-related mortality worldwide, with Helicobacter pylori (H. pylori) infection recognized as a significant risk factor for its onset[1]. H. pylori is a Gram-negative bacterium that resides the stomach and is associated with chronic inflammation, potentially lead to gastritis, peptic ulcer disease, and gastric malignancy[2]. Although multiple pro-inflammatory cytokines, such as IL-8 and TNF-α, have been implicated in H. pylori-associated carcinogenesis[3,4], cytokine-induced neutrophil chemoattractant (CINC) has emerged as a uniquely potent mediator of neutrophil-driven inflammation in the gastric tumor microenvironment. Different from IL-8 that broadly activates innate and adaptive immunity, CINC specifically orchestrates neutrophil chemotaxis and activation through its high-affinity binding to CXCR2 receptors, driving tissue damage and oxidative stress that directly promote epithelial carcinogenesis[5,6]. Furthermore, CINC exhibits dual roles in tumor progression: While amplifying anti-bacterial responses, it paradoxically enhances angiogenesis and suppresses antitumor immunity by polarizing neutrophils toward a pro-tumorigenic N2 phenotype[7,8].

Despite the extensive characterization of IL-8 and TNF-α in H. pylori pathogenesis, the unique role of CINC remains poorly defined[9]. Previous studies primarily focused on CINC’s chemotactic functions in acute inflammation; its interaction with H. pylori virulence factors or its prognostic value in GC subtypes are rarely explored. H. pylori strains expressing cytotoxin-associated gene A (CagA) and vacuolating cytotoxin (VacA) induce distinct cytokine profiles, but their specific effects on CINC regulation remain uncharacterized[10]. This gap is critical because CagA/VacA-mediated CINC overexpression could be a novel mechanism by which virulent H. pylori strains exacerbate tumor microenvironment remodeling. Although serum IL-8 levels correlate broadly with GC stage, CINC’s specificity for neutrophil-driven pathways may provide superior prognostic stratification, particularly in H. pylori-positive patients where neutrophil infiltration dominates the inflammatory landscape[11].

Our study was the first to systematically investigate the interplay among H. pylori virulence factors, CINC dynamics, and GC severity across histological subtypes. We hypothesized that CagA/VacA-positive H. pylori strains selectively upregulate CINC, driving neutrophil-mediated inflammation that accelerates tumor progression and worsens survival. By analyzing longitudinal CINC levels in relation to TNM staging, virulence factors, and concurrent malignancies, we aimed to: (1) Establish CINC’s specificity compared with other cytokines in H. pylori-associated GC; (2) Elucidate how CagA/VacA modulate CINC production; and (3) Evaluate CINC’s potential as a stage-specific prognostic biomarker. These insights could redefine therapeutic strategies targeting neutrophil-mediated inflammation in H. pylori -positive GC.

MATERIALS AND METHODS

Study design and population

This retrospective cohort study was conducted at Shijiazhuang People's Hospital, involving 258 patients with GC diagnosed between April 2020 and November 2023. The inclusion criteria were as follows: (1) Patients with histologically confirmed GC; (2) Patients with pretreatment serum samples; and (3) Patients with complete clinical and demographic data. The exclusion criteria included prior treatment for GC, coexisting systemic inflammatory diseases, and incomplete medical records. This study was approved by the Ethics Committee of Shijiazhuang People's Hospital, and the Ethics Committee has exempted patients from providing an informed consent.

Data collection

Data on patient demographics [age, gender, body mass index (BMI)], clinical characteristics (TNM stage, smoking history, alcohol consumption, family history of GC, and previous gastric surgery), and H. pylori status were collected from medical records. H. pylori infection status was determined through a combination of histology, rapid urease test (RUT), and serology. All the patients underwent histopathological examination of gastric biopsy specimens (antrum and corpus) stained with Giemsa, and RUT (CLOtest^®, Kimberly-Clark) was performed during endoscopy. Serological testing for anti-H. pylori IgG antibodies (ELISA; Biohit, Finland) was conducted for cases where histology and RUT yielded discordant results. A patient was classified as H. pylori-positive if either: (1) Histology and RUT were both positive; or (2) Serology was positive and one result from histology/RUT was positive. Among the cohort, 92% of H. pylori-positive patients (127/138) showed concordant results across all three tests, with a Cohen’s kappa coefficient of 0.86 (95%CI: 0.79-0.93) indicating high intertest agreement. Serum samples were collected before treatment initiation and stored at −70 °C.

Serum CINC measurement

Serum CINC levels were quantified using a highly sensitive commercial ELISA kit (Abcam, Cat. No. ab21760) in accordance with the manufacturer’s protocol. Serum samples were diluted 1:50 to ensure they fell within the assay’s linear range. The assay was calibrated with a series of standards provided by the manufacturer, spanning from 0 to 2000 pg/mL. The intraassay and interassay coefficients of variation were found to be 7% and 12%, respectively, indicating high reproducibility. Known positive and negative controls were included to validate the assay’s accuracy.

Statistical analysis

Data were analyzed using SPSS 26.0 statistical software. Continuous variables were expressed as means ± SD or medians with interquartile ranges, and categorical variables were presented as frequencies and percentages. Student’s t-test or Mann-Whitney U test was used for continuous variables, and χ² test or Fisher’s exact test was applied for categorical variables. Correlations between serum CINC levels and TNM stage were assessed using ANOVA. Survival analysis was conducted using the Kaplan-Meier method with log-rank tests for univariate comparison. Multivariate Cox proportional hazards regression models were employed to adjust for potential confounders (age, gender, BMI, smoking status, alcohol consumption, TNM stage, and H. pylori virulence factors). Variables with P < 0.10 in the univariate analysis or established clinical relevance were included in the multivariate model. The proportional hazards assumption was verified using Schoenfeld residuals. HRs with 95% confidence intervals (CIs) were calculated to assess independent prognostic factors.

RESULTS

Demographic and clinical characteristics

In accordance with their H. pylori infection status, the 258 patients were categorized into two distinct groups: Those who were H. pylori-positive (n = 138) and those who were H. pylori-negative (n = 120). Significant statistical differences in terms of gender distribution, TNM staging, smoking history, alcohol consumption, family history of GC, and history of previous gastric surgery were found between the two groups (all P < 0.05, Table 1).

Table 1 Demographic and clinical characteristics of study population, n (%).

Characteristic	H. pylori positive (n = 138)	H. pylori negative (n = 120)	P value
Age (years)	60.1 ± 11.5	57.8 ± 10.9	0.423
Gender			0.035
Male	38 (27.5)	22 (18.3)
Female	100 (72.5)	98 (81.7)
TNM stage			0.007
Stage I	6 (4.3)	4 (3.3)
Stage II	22 (15.9)	8 (6.7)
Stage III	30 (21.7)	10 (8.3)
Stage IV	80 (57.9)	98 (81.7)
Smoking history			0.021
Never smoked	28 (20.3)	12 (10)
Former smoker	22 (15.9)	8 (6.7)
Current smoker	88 (63.8)	100 (83.3)
Alcohol consumption			0.034
Never drank	42 (30.4)	18 (15)
Former drinker	14 (10.1)	6 (5)
Current drinker	82 (59.4)	96 (80)
BMI (kg/m²)	25.3 ± 4.1	24.9 ± 3.2	0.567
Family history of cancer			0.008
Yes	16 (11.6)	4 (3.3)
No	122 (88.4)	116 (96.7)
Previous gastric surgery			0.009
Yes	8 (5.8)	2 (1.7)
No	130 (94.2)	118 (98.3)

BMI: Body mass index; H. pylori: Helicobacter pylori.

Serum CINC levels

The serum CINC levels were significantly higher in the H. pylori-positive patients than in the H. pylori-negative patients (P < 0.05, Figure 1). The increased serum levels of CINC in the H. pylori-positive patients suggested that their immune system was actively trying to fight the infection by attracting immune cells to the site of inflammation in the stomach.

Figure 1 Comparison of serum cytokine-induced neutrophil chemoattractant levels between Helicobacter pylori-positive and Helicobacter pylori-negative patients with gastric cancer. ^aP < 0.05, Helicobacter pylori (H. pylori)-positive group vs H. pylori-negative group. CINC: Cytokine-induced neutrophil chemoattractant; H. pylori: Helicobacter pylori.

Association between serum CINC levels and TNM stage

Analysis of serum CINC concentration in the cohort of H. pylori-positive patients (n = 138) demonstrated its notable correlation with TNM staging. As the TNM stage increased, the average serum CINC levels markedly increased (P < 0.05, Figure 2).

Figure 2 Association between serum cytokine-induced neutrophil chemoattractant levels and TNM staging in Helicobacter pylori-positive patients with gastric cancer. ^aP < 0.05, stage IV group vs stage I group; ^n.s.P > 0.05, stage II group vs stage I group; ^n.s.P > 0.05, stage III group vs stage I group. CINC: Cytokine-induced neutrophil chemoattractant.

Serum CINC levels and H. pylori virulence factors

Substantially elevated serum CINC levels were found in the H. pylori-positive patients possessing recognized virulence factors. Compared with the H. pylori-positive patients without such factors, those infected with H. pylori strains harboring CagA/VacA exhibited a significant increase in serum CINC levels (all P < 0.05, Figure 3). This finding underscored the crucial role of these virulence factors in activating an inflammatory response.

Figure 3 Cytotoxin-associated gene A/vacuolating cytotoxin -positive Helicobacter pylori strains enhance cytokine-induced neutrophil chemoattractant production via NF-κB activation in gastric epithelial cells, promoting neutrophilic inflammation. ^aP < 0.05, CagA+/VacA+ vs nontoxic control; ^bP < 0.01, CagA+/VacA−/Tox1+ vs nontoxic control; ^cP < 0.001, CagA+/VacA−/Tox2+ vs nontoxic control; ^dP < 0.0001, CagA−/VacA+/Tox1+ vs nontoxic control; ^eP < 0.00001, CagA−/VacA−/Tox1+/Tox2+ vs nontoxic control. CagA: Cytotoxin-associated gene A; VacA: Vacuolating cytotoxin; CINC: Cytokine-induced neutrophil chemoattractant.

Correlation of serum CINC levels with GC subtype and H. pylori status

Among those with intestinal-type and diffuse-type GC, the H. pylori-positive patients had significantly higher serum CINC levels than the H. pylori-negative patients (all P < 0.05, Figure 4). These results indicated that serum CINC levels might vary depending on the presence of H. pylori infection and the histological subtype of GC.

Figure 4 Serum cytokine-induced neutrophil chemoattractant levels classified according to gastric cancer subtype. ^aP < 0.05, ^bP < 0.01 for Helicobacter pylori (H. pylori)-positive vs H. pylori-negative within each subtype; CINC: Cytokine-induced neutrophil chemoattractant; H. pylori: Helicobacter pylori.

Survival analysis

Survival analysis revealed that the patients with high serum CINC levels and H. pylori infection had significantly worse 3- and 5-year overall survival rates than those with low CINC levels (P = 0.035, Figure 5). These results suggested that CINC levels could serve as a prognostic marker for survival in H. pylori-positive patients with GC. Multivariate Cox regression analysis adjusting for age, gender, TNM stage, smoking, alcohol use, and H. pylori virulence factors revealed that elevated serum CINC levels (HR = 2.41, 95%CI: 1.58-3.68; P < 0.001) and H. pylori infection (HR = 1.89, 95%CI: 1.23-2.90; P = 0.004) were independent predictors of poor overall survival (Table 2). Other significant prognostic factors included advanced TNM stage (HR = 3.02, 95%CI: 1.95-4.68; P < 0.001) and current smoking (HR = 1.65, 95%CI: 1.10-2.47; P = 0.015).

Figure 5 Kaplan-Meier curves demonstrating the correlation of 3- and 5-year overall survival with serum cytokine-induced neutrophil chemoattractant level and Helicobacter pylori status in patients with gastric cancer. CINC: Cytokine-induced neutrophil chemoattractant.

Table 2 Multivariate cox regression analysis of prognostic factors for overall survival.

Variable	HR (95%CI)	P value
CINC (high vs low)	2.41 (1.58-3.68)	< 0.001
H. pylori infection	1.89 (1.23-2.90)	0.004
TNM stage (IV vs I)	3.02 (1.95-4.68)	< 0.001
Current smoking	1.65 (1.10-2.47)	0.015
Age (> 60 vs ≤ 60)	1.32 (0.88-1.98)	0.182
Male gender	1.24 (0.82-1.87)	0.305

H. pylori: Helicobacter pylori; HR: Hazard ratio; CI: Confidence interval; CINC: Cytokine-induced neutrophil chemoattractant.

Serum CINC levels and concurrent malignancies

The findings indicated that patients with GC who also had concurrent malignancies demonstrated markedly elevated serum CINC levels. Additionally, these individuals were more likely to be infected with H. pylori and to have a family history of cancer, when compared to patients without concurrent malignancies (all P < 0.05, Table 3). These observations highlight the potential interplay between serum CINC levels, H. pylori infection, and a genetic predisposition in the context of multiple primary cancers.

Table 3 Serum cytokine-induced neutrophil chemoattractant levels in patients with gastric cancer with or without concurrent malignancies, n (%).

Characteristic	Concurrent malignancies (n = 32)	No concurrent malignancies (n = 226)	P value
CINC (pg/mL)	395.2 ± 142.6	250.1 ± 110.3	< 0.001
H. pylori			0.005
H. pylori-positive	24 (75)	114 (50.44)
H. pylori-negative	8 (25)	112 (49.56)
Age (years)	62.4 ± 11.7	59.9 ± 10.5	0.214
Male gender	18 (56.3)	76 (33.6)	0.058
TNM stage			0.064
Stage I	8 (3.5)	2 (6.3)
Stage II	6 (18.8)	26 (11.5)
Stage III	10 (31.3)	44 (19.5)
Stage IV	14 (43.8)	148 (65.5)
Smoking history			0.179
Never	4 (12.5)	38 (16.9)
Former	6 (18.8)	22 (9.7)
Current	22 (68.8)	166 (73.5)
Alcohol consumption			0.165
Never	8 (25.0)	42 (18.6)
Former	3 (9.4)	14 (6.2)
Current	21 (65.6)	170 (75.2)
Family history of cancer			0.031
Yes	6 (18.8)	16 (7.1)
No	26 (81.3)	210 (92.9)
Previous gastric surgery			0.162
Yes	2 (6.3)	6 (2.7)
No	30 (93.8)	220 (97.3)

BMI: Body mass index; H. pylori: Helicobacter pylori; CINC: Cytokine-induced neutrophil chemoattractant.

Longitudinal changes in serum CINC levels

A 12-month longitudinal follow-up of patients demonstrated that fluctuations in serum CINC levels were linked to disease progression. The patients who suffered from tumor progression exhibited an upward trend in their CINC levels, and those who experienced disease regression had a decline in their CINC levels (all P < 0.05, Table 4).

Table 4 Longitudinal changes in serum cytokine-induced neutrophil chemoattractant levels in patients with gastric cancer.

Disease status	Patients (n)	CINC level at baseline (pg/mL)	CINC level at 12 months (pg/mL)	Change in CINC level (pg/mL)	P value
Tumor progression	56	352.4 ± 130.1	415.7 ± 150.6	+63.3 ± 30.5	< 0.05
Disease regression	24	298.6 ± 139.8	224.3 ± 104.7	-74.3 ± 35.2	< 0.05

CINC: Cytokine-induced neutrophil chemoattractant.

DISCUSSION

In this study, we examined the relationship of serum CINC levels with H. pylori infection and disease severity in patients with GC. Our findings indicated a significant correlation between H. pylori infection and elevated CINC levels. This result agrees with earlier studies that correlated H. pylori infection with heightened inflammation and immune system activation in the gastric mucosa[12-14]. Moreover, our analysis showed a direct correlation between serum CINC levels and TNM stage in patients positive for H. pylori. As the TNM stage advanced, the average serum CINC levels noticeably increased. This trend implies that CINC levels could be used as a biomarker for disease severity and progression in H. pylori-positive patients with GC. Extensive studies were conducted on the role of CINC in fostering neutrophil infiltration and tissue damage, providing valuable insights into the inflammatory processes that accompany various diseases[15]. In the context of GC, Kinoshita et al[16] highlighted that the relationship between CINC and advanced disease stages is well-documented and closely tied to the complex pathophysiology of GC progression.

Furthermore, we noted that H. pylori-positive patients who were infected with strains possessing known virulence factors, specifically CagA and VacA, exhibited significantly elevated serum levels of CINC compared with those lacking these factors. This observation highlights the critical role of H. pylori virulence factors in initiating inflammatory responses and contributing to the development and progression of GC. The CagA protein stimulates the production of pro-inflammatory cytokines and promotes inflammation within the gastric mucosa[17,18]. In addition to CagA, VacA significantly exacerbates the inflammatory response in patients positive for H. pylori[19]. VacA is a pore-forming toxin that plays a pivotal role in H. pylori pathogenicity[20]. Connolly et al[21] emphasized the critical role of these virulence factors in the pathogenesis of H. pylori-related diseases, underscoring the need for targeted therapeutic interventions that could mitigate the effects of these toxins and reduce the risk of GC.

We also investigated the relationship between serum CINC levels and different GC subtypes. Our findings revealed that H. pylori-positive patients with either intestinal-type or diffuse-type GC had notably higher CINC levels than H. pylori-negative patients. This observation suggests that H. pylori infection and the resultant inflammation may contribute to the pathogenesis of both GC subtypes through distinct yet interrelated pathways. The role of H. pylori -induced changes in the tumor microenvironment is crucial in both GC subtypes. H. pylori infection can lead to alterations in the extracellular matrix, immune cell composition, and expression of angiogenic factors[22]. These changes facilitate enhanced angiogenesis, the formation of new blood vessels supplying nutrients to the tumor, and metastasis, the spread of cancer cells to other parts of the body[23]. The elevated CINC levels observed in our study might be indicative of this pro-angiogenic and pro-metastatic tumor microenvironment. Furthermore, H. pylori infection can influence the balance between regulatory T cells (Tregs) and effector T cells, which is important for immune surveillance and tumor progression[24]. H. pylori infection promotes the expansion of Tregs, which can suppress the immune response against cancer cells, thus contributing to immune escape and cancer progression[25]. The high CINC levels in H. pylori-positive patients reflect this altered immune balance and the subsequent impact on tumor growth and spread.

In our survival analysis, we found that the patients with high serum CINC levels and H. pylori infection had a significantly worse 3- and 5-year overall survival rates than those with low CINC levels. Multivariate Cox regression adjusting for age, gender, TNM stage, smoking, alcohol use, and H. pylori virulence factors confirmed that elevated CINC levels (HR = 2.41, 95%CI: 1.58-3.68; P < 0.001) and H. pylori infection (HR = 1.89, 95%CI: 1.23-2.90; P = 0.004) were independent predictors of poor survival. This finding suggests that CINC levels could serve as a prognostic marker for survival in H. pylori-positive patients with GC. The association between high CINC levels and poor prognosis may be attributed to chronic neutrophilic inflammation, which promotes tumor progression through immune suppression and angiogenesis[26]. The synergistic effect of CINC and H. pylori infection (HR = 3.12, 95%CI: 1.92-5.06; P < 0.001 for interaction) highlights their combined oncogenic impact, potentially via H. pylori-driven NF-κB activation that amplifies CINC production. Patients with concurrent malignancies exhibited significantly higher serum CINC levels (P < 0.05), a higher prevalence of H. pylori infection, and an increased likelihood of a family history of cancer than those without additional malignancies. This result suggests that systemic inflammation driven by H. pylori infection may act as a shared carcinogenic mechanism across cancer types. Longitudinal monitoring further revealed dynamic changes in CINC levels: Increasing during tumor progression and decreasing with treatment response, highlighting its potential to reflect real-time tumor microenvironment remodeling. This finding suggests that H. pylori infection and chronic inflammation may play a role in the development of multiple cancers, highlighting the systemic effects of H. pylori-induced inflammation on carcinogenesis. In the context of longitudinal changes in serum CINC levels, our study showed an increasing trend in CINC levels among the patients with tumor progression. By contrast, those with disease regression exhibited decreasing levels. This result suggests that CINC levels may reflect the dynamic changes in the tumor microenvironment and the response to treatment. Monitoring CINC levels over time could provide valuable information on disease progression and treatment response in patients with GC.

The potential mechanisms underlying the association among H. pylori infection, CINC levels, and GC severity are multifaceted. H. pylori infection can lead to chronic inflammation in the gastric mucosa, which promotes the recruitment and activation of neutrophils and other immune cells[27]. Characterized by the release of pro-inflammatory cytokines such as CINC, this immune response can contribute to the development and progression of GC[28]. Furthermore, H. pylori virulence factors can directly interact with host cells and disrupt cellular signaling pathways, leading to increased inflammation and immune activation[29]. They also promote the formation of biofilms on the gastric mucosa, creating a favorable niche for H. pylori survival and colonization and further exacerbating the inflammatory response and cancer progression[30]. The role of CINC in GC pathogenesis may involve its ability to promote neutrophil infiltration into the tumor microenvironment. In turn, neutrophils release reactive oxygen species and proteases, contributing to tissue damage and tumor progression[31]. CINC also promotes angiogenesis and tumor growth by recruiting endothelial cells and inducing the formation of new blood vessels[32].

Our study has several limitations that warrant consideration. First, the retrospective single-center design may introduce selection bias, particularly in the representation of rare H. pylori strains or advanced-stage cancers, and information bias due to the incomplete documentation of H. pylori virulence factors (e.g., CagA/VacA status) or inconsistent follow-up intervals. Second, although we employed histology, RUT, and serology for H. pylori diagnosis, the consistency among these methods was not formally assessed, and the criteria for defining H. pylori positivity (e.g., single vs multiple positive tests) were not explicitly stated. Third, although we identified correlations between CINC levels and clinical outcomes, the absence of multivariate adjustments for TNM stage, age, sex, and lifestyle factors (e.g., smoking and alcohol use) limited the interpretation of CINC as an independent prognostic marker. Fourth, the longitudinal analysis had limited follow-up duration and sample size, which may reduce the generalizability of CINC’s dynamic role in tracking disease progression. Finally, the lack of mechanistic experiments (e.g., in vitro neutrophil migration assays or murine H. pylori infection models) precluded the definitive conclusions about CINC’s causal role in tumor progression, such as immune evasion via PD-L1 upregulation or metastasis through CXCR2-mediated angiogenesis.

CONCLUSION

Our study demonstrates a significant correlation among serum CINC levels, H. pylori infection, and disease severity in patients with GC. The H. pylori-positive patients exhibited elevated CINC levels, particularly when infected with strains harboring CagA/VacA virulence factors. The progressive increase in CINC levels with advanced TNM staging underscores the potential of CINC as a biomarker for disease severity and progression in H. pylori-associated GC. Furthermore, high CINC levels were linked to poor prognosis and concurrent malignancies, emphasizing the systemic oncogenic effects of chronic H. pylori-induced inflammation. Longitudinal monitoring revealed dynamic CINC changes correlated with disease trajectory, supporting its utility in tracking therapeutic response. These findings advocate for clinical strategies targeting the CINC/CXCR2 axis-such as CXCR2 antagonists or neutrophil-depleting therapies-to mitigate systemic inflammation and potentially reduce multicancer risk in H. pylori-infected populations. Our work provides mechanistic insights into H. pylori-driven carcinogenesis with actionable therapeutic opportunities, advancing personalized management for patients with GC.