Screening of serum biomarkers using antibody microarray in diagnosis of papillary thyroid carcinoma

doi:10.21203/rs.3.rs-4829537/v1

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Screening of serum biomarkers using antibody microarray in diagnosis of papillary thyroid carcinoma

https://doi.org/10.21203/rs.3.rs-4829537/v1

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Objective

Papillary thyroid cancer (PTC) is one of the most common types of endocrine cancer. Given that a certain percentage of PTCs are very aggressive and prone to recurrence, early diagnosis of PTCs is of great clinical significance. However, it remains a diagnostic challenge because of lack of reliable serum biomarkers currently. This study aimed to find novel biomarkers with good diagnostic value for PTCs.

Methods

A total of 31PTC patients and 31healthy controls were included in this study. The Human Antibody Arrays were used to screen potential biomarkers and enzyme-linked immunosorbent assay analysis was performed to validate candidate proteins. The receiver operating characteristic curve was utilized to evaluate the diagnostic value of candidate.

Results

The mean levels of phosphatidylserine decarboxylase (PISD), prostaglandin E synthase 3 (PTGES3), prostaglandin D2 synthase (HPGDS), and proteasome 20S were 14.11±0.32 ng/mL, 14.09±7.01 ng/mL, 178.31±32.50 pg/mL, and 0.18±0.21 μg/mL in serum samples of PTC patients, and were 12.46±6.31 ng/mL, 11.27±4.23 ng/mL, 199.22±25.91 pg/mL, and 0.06±0.05 μg/mL in healthy control samples, respectively. Compared to the control group, the expression of PTGES3 and proteasome 20s were higher in the PTC group. Interestingly, the combination of HPGDS and proteasome 20S yields a better predictive value of PTC with a sensitivity and specificity of 80.56% and 75.00%, respectively.

Conclusion

The combination of HPGDS and proteasome 20S may serve as a potential predictive biomarker for PTC.

apillary thyroid carcinoma

proteasome 20S

prostaglandin E synthase 3

prostaglandin D2 synthase

biomarker

Thyroid cancer (TC) is responsible for 5.86/105 cases worldwide, ranking in 9th place in incidence in 2020 ¹. The global incidence rate in women is 10.1/105 which is 3-fold higher than that in men, and the age-standardized mortality rates are 0.5/105 women and 0.3/105 men ². In China, the age-standardized incidence rate was 3.21/105 in 2005 and increased to 9.61/105 in 2015 ³. Disability-adjusted life years cases increased from 1.03/105 in 1990 to 1.87/105 in 2019 ⁴. In the United States, female (75.6%) and white (81.0%) patients accounted for the majority of 1.97/105 patients⁵. However, the etiology of thyroid cancer is not well understood.

Papillary thyroid carcinoma (PTC), the vast majority of TC patients, had a rapid worldwide increase in the last thirty years ⁶. Early diagnosis and timely treatment are crucial for PTCs. High-resolution ultrasound is a primary tool for evaluating thyroid nodules and helps in determining the size, location, and characteristics of nodules. However, the disadvantages are equally obvious, including operator-dependent, limited depth, and lack of histological information^{7, 8}. Accurate diagnosis is crucial for identifying PTC patients who require aggressive treatment in histopathology ⁹. Fine needle aspiration (FNA) is a minimally invasive procedure in which a thin needle is used to obtain cells from thyroid nodules for cytological examination. This method helps distinguish between benign and malignant nodules. Unfortunately, FNA may yield indeterminate results and need additional tests^10–12.

Although molecular markers aid in diagnosis and prognosis, current research has few clear therapeutic implications, limiting their direct impact on treatment strategies¹³. Therefore, it is crucial to explore new biomarkers for accurate diagnosis and prognostication of PTC. The essential methods used in exploring cancer molecular diagnostic markers are genomic analysis^{14, 15}, transcriptomics (RNA sequencing and microarray analysis)¹⁶, proteomics (mass spectrometry and two-dimensional gel electrophoresis)^{17, 18}, and metabolomics. Antibody microarrays, also known as antibody chips, offer significant advantages for discovering molecular diagnostic markers in cancer research¹⁹. Biomarkers are currently widely used to improve diagnoses, predict disease, and monitor treatment effects. However, no specific antibody microarray-discovered molecular biomarkers of PTC were reported for routine clinical use²⁰. In this study, we used the antibody microarray technique to find serum biomarkers to enhance early diagnosis and prognoses of PTC.

Participants

All participants in the study were taken from the West China Hospital of Sichuan University in Chengdu, China. PTC (n = 31) was diagnosed as validated by biopsy specimen analysis and categorized using the Tumor Node Metastasis (TNM) system. At the time of recruitment, none of these patients had received radiation therapy or chemotherapy. Control subjects (n = 31) were randomly selected from cancer-free people who participated in health examinations in the same period at the same hospital.Patients with ages less than 20 years and more than 65 years were excluded from this study ,The age and gender variations between the two groups were negligible (Table 1). Each participant provided written informed permission before they participated in the study. Each participant had peripheral blood samples taken, and the serum was separated, frozen,Peripheral blood samples were collected from all participants and the serum was separated, frozen, and kept at − 80°C following established laboratory protocols.

Serum profiling on Human Antibody Array

Five PTC samples and 5 healthy control (HC) samples were randomly selected for screening analysis by using the RayBio Label-based (L-Series) Human Antibody Array L2000 kit (AAH-BLM-2000-2) according to the manufacturer's instructions (RayBiotech, USA). Four slides were provided: L-3, L-4, L-493, and L-507 coated with indicated numbers of capture antibodies. Signals can be detected directly from the membrane using Axon GenePix laser scanner and analyzed using RayBio Analysis Tool software. Protein intensity was obtained by averaging two spots specific for each protein, and the positive, negative, blank, and internal controls were used in all antibody microarray assays.

Enzyme-linked immunosorbent assay (ELISA)

The expression of human PISD (abx538949, Abbexa), PTGDS (abx351066, Abbexa), proteasome 20S (NBP2-62173, Novus), PTGES3 (Abbexa, abx250407), and EphB3 immunoassay (ELH-EPHB3, RayBio) was detected by using ELISA kits according to the manufacturer’s directions and optical density was determined using a microplate reader set to 450 nm (Thermo Fisher Scientific, USA). Analyte concentrations within each sample were calculated from a standard curve generated simultaneously on the same plate.

Statistical analysis

The levels of PISD, PTGDS, proteasome 20S, PTGES3 (p23), and EphB3 were expressed as means ± standard deviations (SD) and compared by Student’ t-test. SPSS version 20 was used for all statistical analyses, and P ≤ 0.05 was considered to indicate statistical significance. The PISD, PTGDS, proteasome 20S, PTGES3, and EphB3 threshold that gave the maximal sensitivity and specificity for the diagnosis of PTC was determined by using receiver-operating characteristics (ROC) curves.

Patient characteristics

The characteristics of the recruited participants of the two groups are listed in Table 1. No significant difference between the PTC and controls based on age and gender.

Screening of serum biomarkers

The human antibody array used in this study could simultaneously detect 2000 human proteins in the given sample. The density of each analyte spot was semi-quantitative by the human antibody array. The signals of PISD, HPGDS, PTGES3, proteasome 20S, and EphB3 were more interesting.

PISD, HPGDS, PTGES3, and proteasome 20S levels in PTC and HC samples

After further verification by ELISA (n = 36), we focused only on PISD, HPGDS, PTGES3, and proteasome 20S, because the serum level of EphB3 was lower than the detection limit. The mean levels of PISD, PTGES3, HPGDS, and proteasome 20S were 14.11 ± 0.32 ng/mL, 14.09 ± 7.01 ng/mL, 178.31 ± 32.50 pg/mL, and 0.18 ± 0.21 µg/mL in PTC samples, and were 12.46 ± 6.31 ng/mL, 11.27 ± 4.23 ng/mL, 199.22 ± 25.91 pg/mL, and 0.06 ± 0.05 µg/mL in controls, respectively. The mean levels of PTGES3 and proteasome 20s were much higher in the PTC samples than in the control group. However, the expression of PISD and HPGDS was not statistically significant different between the PTC patients and the control group.(Fig. 1).

Diagnostic value of proteasome 20S and PTGES3

ROC curve analysis of a single parameter with significant difference was performed between the groups. With a cut-off value of 0.09, the area under the receiver operating characteristic curve (AUC) of proteasome 20S, sensitivity, and specificity were 0.75 (95% CI: 0.64–0.86), 80.56%, and 63.89%, respectively. With a cut-off value of 11.87, the AUC of PTGES3, sensitivity, and specificity were 0.61 (95% CI: 0.43–0.70), 58.33%, and 52.78%, respectively (Table 2 Fig. 2).

The diagnostic performance using a single protein was not good enough for clinical use. Therefore, we combined the two proteins to determine whether the diagnostic performance can be improved. As shown in Table 2 and Fig. 3, after combining PTGDS and proteasome 20S, the sensitivity and specificity were 80.56% and 75.00%, respectively, when the cut-off was set at -0.17 (Fig. 3).

The number of new TC cases in China was 0.10/105 in 1990, and 0.39/105 in 2019, and it is expected to be 0.47/105 in 2039⁴, which is equivalent to 3,320, 7,240, and 4,160 deaths, respectively. The incidence of thyroid cancer in China is projected to increase over the next two decades, combined with slightly declining mortality, especially in males and adolescents ²¹. Although the long-term survival prognosis of thyroid cancer is good, PTC still has a high recurrence rate. The rising incidence of PTC also suggests that the diagnosis and treatment of PTC is very important ²². The diagnosis and treatment of metastatic recurrence for advanced PTC are still a challenge.

Although research based on molecular mechanisms is more effective for the diagnosis and treatment of PTC, the systematic detection method is not perfect ²³. We applied a strategy using antibody microarrays to quantify a total of 2000 serum proteins, which resulted in an improved depth of the serum proteome to find serum biomarkers and help screen early diagnosis of PTC. Four candidate proteins, i.e., PISD, HPGDS, PTGES3, and proteasome 20S were validated by ELISA following screening. We found that proteasome 20S and PTGES3 might be used as a potential predictive biomarker in PTC.

Proteasome 20S is a catalytic domain for proteolysis²⁴. The proteasome 20S and 19S-RP from the 26S proteasome an unusually large complexes, which are crucial for cellular signaling and protein turnover ²⁴. Inhibiting the function of proteasome, especially the selective suppression of proteasome chymotrypsin-like subunits, can induce cell cycle arrest, apoptosis, and cell death to substantiate proteasome as an optimal chemotherapeutic target²⁵. In colorectal cancer²⁶, breast cancer²⁷, lung cancer²⁸, and acute myeloid leukemia²⁹, the inhibition of multiple catalytic subunits of the 20S proteasome can promote cell cycle arrest, and trigger cell death. Nitazoxanide and related thiazoles induce cell death in cancer cells by targeting the 20S proteasome and provide new insights into the design of novel small molecular proteasome inhibitors as anti-tumor agents³⁰. Our results showed that the expression levels of proteome 20S in PTC were significantly higher than those in the healthy control by human antibody array and Elisa test. Zong et al. reported that proteasome inhibition induces ORP150 expression via Nrf2 in thyroid cancer cells³¹. In addition, the NRF3-POMP-20S proteasome assembly axis is important for cancer development through ubiquitin-independent proteolysis of tumor suppressor protein ³². Taken together, we may conclude that proteasome 20S is associated with tumorigenesis and development in PTC.

HPGDS, a member of the lipocalin superfamily, has dual functions of catalyzing prostaglandin metabolism and lipid transport. PTGDS is a secreted protein, which can be secreted out of cells and into body fluids such as blood, urine, and cerebrospinal fluid. PTGDS also plays an important role in suppressing cancer cell proliferation³³, migration, and invasion in different cancers ³⁴. Some authors reported that the expression level of HPGDS in various solid tumors was increased, and its expression level was correlated with tumor stages, metastasis, and poor prognosis, such as melanoma, ovarian cancer³⁵, and liver cancer³⁶. Nevertheless, some authors found that HPGDS was low-expressed in tumors and inhibited the occurrence and development of tumors, such as prostate cancer, gastric cancer ³⁷, ovarian cancer³⁸, endometrial cancer³⁹, and lung cancer. The expression level and biological function of PTGDS in different tumors are still controversial. In addition, the concentration level of HPGDS in body fluids can reflect the state of the body with tissue-specificity.

In our study, the serum level of HPGDS was not statistically significant different between the PTC patients and the control group. Using PISD, HPGDS, PTGES3, and proteasome 20S as a single protein, the diagnostic performance was not good enough for clinical use. We then combined the HPGDS and proteasome 20s proteins together and found that the sensitivity and specificity were improved to 80.56% and 75.00%, respectively at the cut-off − 0.17, indicating the reference for clinical diagnosis of PTC through serum HPGDS and proteasome 20S examination. To better predict their potential diagnosis and treatment effects at PTC, it will be necessary in the future to investigate the HPGDS and proteasome 20S molecular mechanisms of different signaling pathways in cell experiments, animal experiments, and human studies.

Ethics approval and consent to participate

1. The experimental protocol was established, according to the ethical guidelines of the Helsinki Declaration and was approved by the Human Ethics Committee ofWest China Hospital of Sichuan University. Written informed consent was obtained from individual or guardian participants(2019No.514).

2. All participants signed the consent form.

3. In this study, we used protein array to identify differential proteins between PTC patients and healthy controls, which is not related to the sequences and structure of DNA, RNA, and protein. Therefore, data deposition is not required.

4. This is a case-control study without any intervention, rather than a cinical trial.

Consent for publication

Not applicable.

Availability of data and materials

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Competing interests

The authors declare no conflict of interest.

Funding

This work was supported by Scientific and technological project in Henan Province (No. 222102310398).

Authors' contributions

Xinmin Pan and designed the study.Caiyuan Liu and Yichan Wang performed the experiments and analyzed the data. Wei Feng And Tiantian Feng contributed substantially to the data interpretation and participated in critical manuscript revision. Caiyuan Liu wrote the manuscript. Haojie Qin and Liya Ma searched the literature and revised the manuscript. All authors read and approved the final manuscript. Xinmin Pan and Zheng Zhe confirm the authenticity of all the raw data.

Acknowledgements

We thank of all participate in this study.

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You are reading this latest preprint version

Screening of serum biomarkers using antibody microarray in diagnosis of papillary thyroid carcinoma

Status:

Version 1

Abstract

Figures

Introduction

MATERIALS AND METHODS

Participants

Serum profiling on Human Antibody Array

Enzyme-linked immunosorbent assay (ELISA)

Statistical analysis

RESULTS

Patient characteristics

Screening of serum biomarkers

PISD, HPGDS, PTGES3, and proteasome 20S levels in PTC and HC samples

Diagnostic value of proteasome 20S and PTGES3

DISCUSSION

Declarations

References

Tables

Additional Declarations

Supplementary Files

Status:

Version 1