Diagnostic Efficacy of Serum PDCD4 and HSP70 Levels for Lymph Node Metastasis in Early Cervical Cancer

By Xiaohua Zhao, Jing Zhang, Yan Xia, Shuang Liu, Weiyan Li

Affiliations

1. Department of Gynaecology, Urumqi Maternal and Child Health Hospital, Xinjiang, China

doi: 10.29271/jcpsp.2025.12.1568

ABSTRACT
Objective: To investigate the diagnostic value of serum programmed cell death protein 4 (PDCD4) and heat shock protein 70 (HSP70) levels in detecting lymph node metastasis (LNM) in patients with early-stage cervical cancer (International Federation of Gynaecology and Obstetrics [FIGO] stages I to IIA).
Study Design: A comparative study.
Place and Duration of the Study: Department of Gynaecology, Urumqi Maternal and Child Health Hospital, Xinjiang, China, from January 2021 to December 2023.
Methodology: One hundred and thirty-two early-stage cervical cancer patients were divided into two subgroups: the LNM subgroup (25 cases) and the Non-LNM subgroup (107 cases). Additionally, 60 healthy women were included as the Control group. Serum PDCD4 and HSP70 levels were measured using enzyme-linked immunosorbent assay (ELISA). Multivariate logistic regression analysis was conducted to identify risk factors for LNM.
Results: Serum PDCD4 levels were significantly lower in the Cervical cancer group compared to the Control group (1.31 ng/mL vs. 3.27 ng/Ml; p <0.001), and HSP70 levels were significantly higher (85.20 ± 14.88 ng/mL vs. 39.22 ± 10.03 ng/Ml; p <0.001). The incidence of LNM among the 132 early-stage cervical cancer cases was 18.94% (25/132). The LNM subgroup exhibited lower serum PDCD4 levels (1.31 ng/mL, IQR 0.59-2.14) and higher HSP70 levels (85.20 ± 14.88 ng/mL) compared to the Non-LNM subgroup (PDCD4: 3.27 ng/mL, IQR 1.78-5.37; HSP70: 39.22 ± 10.03 ng/mL; both p <0.05). The multivariate logistic regression analysis identified advanced stromal infiltration depth (≥1/2 cervical muscle wall, OR 4.288, 95% CI: 1.155-15.922) and elevated serum HSP70 levels (OR 1.093, 95% CI 1.031-1.158) as independent risk factors for LNM, while elevated serum PDCD4 levels were found to be an independent protective factor (OR 0.245, 95% CI: 0.091-0.656). The combined detection of serum PDCD4 and HSP70 demonstrated a sensitivity of 88.00%, specificity of 84.11%, and a Youden index of 0.721 (AUC 0.926, 95% CI: 0.867-0.964).
Conclusion: Reduced serum PDCD4 levels and elevated HSP70 levels were significantly correlated with LNM in early-stage cervical cancer. The combination of serum PDCD4 and HSP70 levels demonstrated high diagnostic efficacy for LNM in early- stage cervical cancer.

Key Words: Early-stage cervical cancer, Programmed cell death protein 4, Heat shock protein 70, Lymph node metastasis, Diagnostic efficiency.

INTRODUCTION

Cervical cancer is the most common malignant tumour of the female reproductive system, with its incidence and mortality ranking fourth among global gynaecological cancer aetiologies.¹ In China, 111,820 new cases of cervical cancer and 61,579 related deaths were reported in 2022.²
 

Lymph node metastasis (LNM) typically plays a pivotal role in surgical pathological staging, therapeutic strategies, and the short- and long-term prognoses of patients with cervical cancer. Early diagnosis of LNM is crucial for guiding clinical treatments  and  improving  patient  outcomes.^3,4

Studies have reported that LNM in cervical cancer is closely associated with the dysregulated expression of multiple genes.⁵ Programmed cell death protein 4 (PDCD4), a protein translation inhibitor, is known to suppress tumourigenesis and tumour progression by inhibiting the transcription and translation of various proteins. Goldar reported that PDCD4 was underexpressed in cervical cancer cells and tissues,⁶ while Han found a correlation between serum PDCD4 levels and LNM in bladder cancer patients.^7,8 Heat shock protein 70 (HSP70), a protective protein, can promote tumour develop-ment by modulating immunity, apoptosis, and the activation of related signalling pathways. A study reported an over expression of HSP70 in cervical cancer tissues,⁹ and a link between serum HSP70 levels and LNM in patients with primary liver cancer.^10,11

However, the relationship between serum PDCD4, HSP70 levels, and LNM in early-stage cervical cancer has not been fully elucidated.¹² This study aimed to investigate the diagnostic efficacy of serum PDCD4 and HSP70 levels for LNM in early-stage cervical cancer, thereby providing additional evidence to facilitate the diagnosis of LNM in early-stage cervical cancer.

METHODOLOGY

This study employed a comparative design, involving 132 early-stage cervical cancer patients diagnosed in the Department of Gynaecology, Urumqi Maternal and Child Health Hospital, Xinjiang, China, from January 2021 to December 2023, with postoperative pathological confirmation. Ethical approval was obtained from the Ethics Committee of the Urumqi Maternal and Child Health Hospital, Xinjiang, China (Approval No. XJFYLL2020008). The sample size was calculated based on the primary objective of assessing LNM, with an expected proportion of 20% (p = 0.20), a desired precision of ± 5% (d = 0.05), and a 95% confidence level (Z = 1.96).

The patients, aged 40-80 years with an average body mass index (BMI) of 22.48 kg/m², were categorised by tumour type, pathological type, tumour size, stromal invasion depth, and International Federation of Gynaecology and Obstetrics (FIGO) staging. The study included patients aged 18 years or above, diagnosed with initial cervical cancer, FIGO stages I to IIA, and who provided voluntary informed consent. Exclusion criteria included other viral infections, severe organ dys-function, prior antitumour treatment, recurrent or other malignancies, and haematological disorders. A Control group of 60 healthy women matched for age and BMI was also selected.

Serum PDCD4 and HSP70 levels were measured using enzyme-linked immunosorbent assay (ELISA) kits from Wuhan Fein Biotechnology Co., Ltd. Demographic and clinical data of the patients were collected and analysed. LNM was diagnosed using sentinel lymph node biopsy, and patients were divided into LNM and Non-LNM subgroups.

Statistical analyses were performed using SPSS version 28.0. Categorical data were analysed with the Chi-square test, skewed metric data with the Mann-Whitney U test, and normally distributed data with the t-test. LNM in early-stage cervical cancer was evaluated using multivariable logistic regression. Variables were selected based on univariate analysis (p <0.2) and clinical relevance; these included tumour size, stromal invasion depth, FIGO stage, PDCD4, and HSP70. Stepwise regression identified stromal invasion depth ≥1/2, FIGO stage IIA, and elevated HSP70 as independent risk factors for LNM, while elevated PDCD4 was identified as a protective factor (p <0.05). Using a p <0.2 threshold, univariate analysis retained variables that may be significant after adjusting for confounders, reducing the risk of excluding relevant factors prematurely. Sensitivity, specificity, and the Youden index were used to evaluate the diagnostic efficacy of PDCD4 and HSP70 in detecting LNM in early-stage cervical cancer, with a significance level of α = 0.05.

RESULTS

Compared with the Control group, the  cervical cancer group had lower serum PDCD4 levels and  higher HSP70 levels (p <0.05, Table I).

Out of 132 early-stage cervical cancer patients, 25 (18.94%) had LNM. The LNM subgroup more frequently presented with tumours of ≥2cm in diameter and stromal invasion depth of ≥1/2, as well as higher FIGO stages, elevated HSP70 levels, and lower PDCD4 levels, compared to the non-LNM sub-group (p <0.05). No significant differences were observed between the two groups in terms of age, BMI, menopausal status, tumour type, pathological type, HPV status, diabetes, hypertension, parametrial, vaginal wall involvement, or vascular tumour thrombus (p >0.05, Table II).

Using LNM occurrence as the dependent variable (1/0 for Yes/No), logistic regression analysis was performed with the significant variables from Table II, including maximum tumour diameter (1/0 for ≥2cm/<2cm), stromal invasion depth (1/0 for ≥1/2/<1/2), FIGO staging (1/2/3 for stages IA/IB/IIA), and continuous variables (PDCD4 and HSP70). The analysis identified stromal invasion depth of ≥1/2, FIGO stage IIA, and high HSP70 as independent risk factors for LNM in early-stage cervical cancer, while higher PDCD4 levels were found to be an independent protective factor (p <0.05).

The joint detection of PDCD4 and HSP70 for LNM in early-stage cervical cancer showed a sensitivity of 88.00%, specificity of 84.11%, and a Youden index of 0.721, suggesting optimal diagnostic performance (Table III).

Table I: Comparison of serum PDCD4 and HSP70 levels (ng/mL) between the two groups.
 

Groups	Number of cases	PDCD4 [M (P25, P75)]	HSP70 (x±s)
Cervical cancer group	132	1.31 (0.59, 2.14)	85.20 ± 14.88
Control group	60	3.27 (1.78, 5.37)	39.22 ± 10.03
Z/t-values	-	-7.106	25.101
p-valuesa	-	<0.001	<0.001
ap-values were determined using the Mann-Whitney U test (for comparing PDCD4 levels) and the t-test (for comparing HSP70 levels) between the two independent samples.

Table II: Comparison of general information and serum PDCD4 and HSP70 levels in the subgroups.

Variables	LNM subgroup (n = 25)	Non-LNM subgroup (n = 107)	χ2/t/Z-values	p-valuesb
Age (years, mean ± SD)	63.68 ± 8.20	60.67 ± 6.92	1.887	0.061
BMI (kg/m2, mean ± SD)	22.39 ± 1.87	22.50 ± 1.67	-0.298	0.766
Menopause [cases (%)]
Yes	15 (60.00)	58 (54.21)	0.275	0.600
No	10 (40.00)	49 (45.79)
Tumour type [cases (%)] Oestrogen-dependent	11 (44.00)	39 (36.45)	0.491	0.483
Non-oestrogen-dependent	14 (56.00)	68 (63.55)
Pathological type [cases (%)]
Squamous cell	20 (80.00)	89 (83.18)	0.278	0.870
Adenocarcinoma	4 (16.00)	13 (12.15)
Other	1 (4.00)	5 (4.67)
HPV [cases (%)]
Positive	23 (92.00)	104 (97.20)	-
Negative	2 (8.00)	3 (2.80)
Diabetes [cases (%)]
Present	8 (32.00)	30 (28.04)	0.155	0.694
Absent	17 (68.00)	77 (71.96)
Hypertension [cases (%)]
Yes	6 (24.00)	27 (25.23)	0.016	0.898
No	19 (76.00)	80 (74.77)
Parametrial and vaginal wall involvement [cases (%)]
Yes	3 (12.00)	9 (8.41)	0.316	0.574
No	22 (88.00)	98 (91.59)
Lymphovascular space invasion [cases (%)]
Yes	9 (36.00)	21 (19.63)	3.094	0.079
No	16 (64.00)	86 (80.37)
Maximum tumour diameter [cases (%)]
≥2 cm	7 (28.00)	16 (14.95)	3.959	0.047
<2 cm	18 (72.00)	91 (85.05)
Stromal invasion depth [cases (%)]
≥1/2	19 (76.00)	54 (50.47)	6.960	0.008
<12	6 (24.00)	53 (49.53)
FIGO staging [cases (%)]
Stage IA	2 (8.00)	46 (42.99)	-4.178	＜0.001
Stage IB	6 (24.00)	35 (32.71)
Stage IIA	17 (68.00)	27 (25.23)
PDCD4 [ng/mL, M (P25, P75)]	0.47 (0.21, 1.04)	1.47 (0.89, 2.36)	-4.835	<0.001
HSP70 (ng/Ml, x±s)	99.47 ± 14.77	81.86 ± 12.85	5.996	<0.00
bt-test and Mann-Whitney U test were used for continuous data, according to the distribution, while the Chi-square test was used for qualitative data.

Table III: Diagnostic efficacy of serum PDCD4 and HSP70 levels for LNM in early-stage cervical cancer.

Markers	95% CI	p-valuesd	Cut-off values	Sensitivities (%)	Specificities (%)	Youden index
PDCD4	0.733~	<0.001	1.52	60.00	91.59	0.516
HSP70	0.873 0.741~	<0.001	98.08 ng/mL	64.00	89.72	0.537
Combined detection	0.879 0.867~	<0.001	0.18 ng/mL	88.00	84.11	0.721
	0.964	0.001
dp-values were determined by ROC analysis.

DISCUSSION

Cervical cancer is the second most common and deadly gynaecological malignancy worldwide, with persistent high-risk HPV infections—particularly HPV16 and HPV18—being the leading cause. Advances in high-risk HPV screening and imaging technologies have significantly improved the early detection rate of cervical cancer.¹³ Radical surgery, including systematic pelvic lymph node dissection, is the most effective treatment for early-stage cervical cancer. However, the incidence of LNM in early-stage disease is relatively low, and performing systematic lymph node dissection in patients without LNM can lead to unnecessary morbidities and postoperative complications.¹⁴ Therefore, accurate diagnosis of LNM in early-stage cervical cancer is crucial for minimising surgical damage and avoiding complications. Current clinical assessments of LNM in cervical cancer patients rely heavily on imaging modalities, such as magnetic resonance imaging, computed tomo-graphy, and ultrasound, which are subject to equipment limitations and physician subjectivity.¹⁵ Consequently, there is a clear need for additional reliable indicators.

Programmed cell death is a genetically regulated process that is often disrupted in tumourigenesis, allowing tumour cells to evade apoptosis and continue to proliferate, thereby promoting tumour development and spread.⁶ PDCD4, a key member of the programmed cell death protein family, inhibits tumour cell growth, differentiation, and proliferation by suppressing translation. It can induce apoptosis in tumour cells through programmed cell death pathways and exert antitumour effects by regulating other tumour- associated proteins.¹⁶ Han et al. demonstrated that increased PDCD4 protein expression could inhibit the proliferation of HPV16- and HPV18-positive cervical cancer HeLa cells.⁷ Yao et al. reported that upregulating PDCD4 expression could suppress the proliferation and invasiveness of cervical cancer HeLa cells.¹⁷ Raniolo et al. showed that upregulating PDCD4 expression could enhance doxorubicin-induced reduction in proliferation and migration and increase apoptosis in cervical cancer cells.¹⁸ These studies collectively suggest that PDCD4 plays a role in the pathogenesis and progression of cervical cancer. Some researchers have indicated that serum PDCD4 levels may assist in diagnosing LNM in bladder cancer.⁸

However, the relationship between serum PDCD4 and LNM in early-stage cervical cancer remains to be elucidated. The present study reveals that serum PDCD4 levels are low in early-stage cervical cancer, with elevated HSP70 emerging as an independent protective factor against LNM, suggesting that elevated serum PDCD4 levels may inhibit LNM in early-stage cervical cancer. The mechanisms underlying this observation include: increased PDCD4 promoting programmed cell death and inducing apoptosis in cervical cancer cells, thereby reducing the risk of LNM; PDCD4 directly binding to Y-box binding protein 1 through a nuclear localisation signal sequence,¹⁶ preventing its nuclear translocation and subsequent binding to the promoter of multidrug resistance protein 1, thus inhibiting the growth, proliferation, and metastasis of cervical cancer cells and reducing the risk of LNM;¹⁹ PDCD4 blocking the Wnt/β-catenin signalling pathway, suppressing the malignant progression of cervical cancer cells by reducing the expression of downstream oncogenes, and lowering the risk of LNM.²⁰

HSP70, a highly conserved member of the HSP family, is produced in response to cellular stress and is involved in stress response and protection. However, during tumour progression, HSP70 aids cancer cells in coping with external stress, enhancing their survival and protecting them from damage caused by therapies, such as chemotherapy and radiotherapy. It can also interact with other proteins, influencing cellular signalling pathways to promote tumour cell proliferation, invasion, and metastasis.²¹ Zhang et al. reported that downregulating HSP70 expression could inhibit the vitality and invasiveness of cisplatin-resistant cervical cancer HeLa/DDP cells.²² Wang et al. demonstrated that HPV16 could induce high expression of HSP70, thereby promoting the proliferation, migration, and invasion of cervical cancer C33A-E6 cells.²³ These studies indicate that HSP70 is implicated in the development of cervical cancer. Some researchers have suggested that elevated serum HSP70 levels are associated with LNM in patients with primary liver and gastric cancers.^11,23 It is hypothesised that serum HSP70 may also be related to LNM in early-stage cervical cancer.

This study shows that increased serum HSP70 levels in early-stage cervical cancer patients are an independent risk factor for LNM, indicating that higher serum HSP70 levels may elevate the risk of LNM. The reasons for this asso-ciation include: HSP70 aiding cervical cancer cells in coping with environmental stress and enhancing their survival, thereby promoting LNM; HSP70 inhibiting programmed cell death, promoting the survival and proliferation of cervical cancer cells, and thus promoting LNM; HSP70 interacting with other proteins, affecting cellular adhesion, migration, and invasion, thereby facilitating LNM; HSP70 promoting the secretion of inflammatory cytokines by macrophages, inhibiting the killing effects of immune system on cervical cancer cells, thereby promoting LNM.²⁴

This study, although highlighting the diagnostic potential of PDCD4 and HSP70 for LNM in patients with early-stage cervical cancer, has several limitations. The small sample size may reduce statistical power and limit generalisability, necessitating validation in larger cohorts. Additionally, the single-centre design may introduce bias, and multi-centre studies are required for broader validation. The study focused on preoperative indicators without long-term outcomes; future research should include long-term follow-up to assess the impact on survival and recurrence. While PDCD4 and HSP70 showed high diagnostic efficacy, their clinical application requires optimisation through combination with other diagnostic tools (such as, imaging or tumour markers) to improve accuracy. The study primarily used clinical data and did not fully elucidate the molecular mechanisms of PDCD4 and HSP70 in LNM; further exploration through in vitro and in vivo experiments is warranted. Finally, logistic regression analysis was conducted; however, the risks of model overfitting and assumptions about variable distributions (such as PDCD4 and HSP70 levels) may affect the interpretation of the results. While this study offers new insights into the diagnosis of LNM in early-stage cervical cancer, further large-scale, multi-centre validation is needed to confirm these findings and explore their clinical application.

CONCLUSION

Lower serum PDCD4 levels and elevated HSP70 levels in patients with early-stage cervical cancer are independent factors for LNM, and the combined assessment of these two markers shows high efficacy for diagnosing LNM in early-stage cervical cancer. However, given the limited sample size of this study, further validation with a larger cohort is warranted.

ETHICAL APPROVAL:
Ethical approval was obtained from the Ethics Committee of the Urumqi Maternal and Child Healthcare Hospital, Xinjiang, China (Approval No. XJFYLL2020008).

PATIENTS’ CONSENT:
Written informed consent was obtained from all the parti-cipants included in the study.

COMPETING INTEREST:
The authors declared no conflict of interest.

AUTHORS’ CONTRIBUTION:
XZ: Designed the study, performed statistical analysis, and wrote the initial draft of the manuscript.
JZ, YX, : Assisted in data collection, contributed to the literature review, and helped in manuscript preparation.
SL: Conducted laboratory experiments, contributed to data interpretation, and reviewed the manuscript.
WL: Supervised the study, provided critical feedback, and revised the manuscript.
All authors approved the final version of the manuscript to be published.

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