Clinical significance of urinary SPP1 as a potential new diagnostic marker for oesophageal squamous cell carcinoma

Abstract

Background: Urinary proteins could be useful as noninvasive biomarkers for the detection of oesophageal squamous cell carcinoma (ESCC). We assessed the levels of secreted phosphoprotein 1 (SPP1) in urine samples from patients with ESCC and evaluated its potential as a diagnostic biomarker.

Methods: Urinary SPP1 levels were measured in 29 ESCC patients and 30 healthy controls using an enzyme-linked immunosorbent assay. SPP1 expression was subsequently examined in tumour tissues and paired peritumoural normal tissue from the patients via immunohistochemistry. The diagnostic performance of SPP1 for ESCC was evaluated using receiver operating characteristic curve analysis.

Results: Urinary SPP1 levels were significantly higher in the ESCC group than in the control group. This parameter demonstrated discriminatory power between the groups, with an area under the curve of 0.7. Furthermore, immunohistochemical analysis confirmed that SPP1 expression was markedly upregulated in ESCC tissues compared with that in paired normal tissues. Moreover, subgroup analysis revealed that urinary SPP1 also effectively identified patients with stage III ESCC.

Conclusion: Our study suggests that urinary SPP1 may serve as a novel biomarker for the detection of ESCC.

Keywords

oesophageal squamous cell carcinoma / SPP1 / urinary biomarker

References

[1] Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229-263.

[2] Liu CQ, Ma YL, Qin Q, et al. Epidemiology of esophageal cancer in 2020 and projections to 2030 and 2040. Thorac Cancer. 2023;14(1):3-11.

[3] Ismail M, Mondlane L, Loforte M, et al. Demographic, endoscopic and histological profile of esophageal cancer at the Gastroenterology Department of Maputo Central Hospital from January 2016 to December 2018. Pan Afr Med J. 2022;41:100.

[4] Grille VJ, Campbell S, Gibbs JF, Bauer TL. Esophageal cancer: the rise of adenocarcinoma over squamous cell carcinoma in the Asian belt. J Gastrointest Oncol. 2021;12(suppl 2):S339-S349.

[5] Fang YJ, Huang CW, Karmakar R, et al. Assessment of narrow-band imaging algorithm for video capsule endoscopy based on decorrelated color space for esophageal cancer: part II, detection and classification of esophageal cancer. Cancers (Basel). 2024;16(3):572.

[6] Rai V, Abdo J, Agrawal DK. Biomarkers for early detection, prognosis, and therapeutics of esophageal cancers. Int J Mol Sci. 2023;24(4):3316.

[7] Wei WQ, Chen ZF, He YT, et al. Long-term follow-up of a community assignment, one-time endoscopic screening study of esophageal cancer in China. J Clin Oncol. 2015;33(17):1951-1957.

[8] Waters JK, Reznik SI. Update on management of squamous cell esophageal cancer. Curr Oncol Rep. 2022;24(3):375-385.

[9] Qiu XO, Jiang X, Chen YZ, et al. New US capsule endoscopy for superficial and submucosal imaging of the esophagus: the first-in-human study. Gastrointest Endosc. 2023;98(4):642-652.

[10] Jing Z, Chen K, Gong L. The significance of exosomes in pathogenesis, diagnosis, and treatment of esophageal cancer. Int J Nanomed. 2021;16:6115-6127.

[11] Ma S, Zhou M, Xu Y, et al. Clinical application and detection techniques of liquid biopsy in gastric cancer. Mol Cancer. 2023;22(1):7.

[12] Zheng Q, Zhang L, Tu M, et al. Development of a panel of autoantibody against NSG1 with CEA, CYFRA21-1, and SCC-Ag for the diagnosis of esophageal squamous cell carcinoma. Clin Chim Acta. 2021;520:126-132.

[13] Iacob R, Mandea M, Iacob S, et al. Liquid biopsy in squamous cell carcinoma of the esophagus and of the head and neck. Front Med (Lausanne). 2022;9:827297.

[14] De Matteis S, Bonafè M, Giudetti AM. Urinary metabolic biomarkers in cancer patients: an overview. Methods Mol Biol. 2021;2292:203-212.

[15] Okuda Y, Shimura T, Iwasaki H, et al. Urinary microRNA biomarkers for detecting the presence of esophageal cancer. Sci Rep. 2021;11(1):8508.

[16] Shimura T, Dayde D, Wang H, et al. Novel urinary protein biomarker panel for early diagnosis of gastric cancer. Br J Cancer. 2020;123(11):1656-1664.

[17] Ji L, Wang J, Yang B, et al. Urinary protein biomarker panel predicts esophageal squamous carcinoma from control cases and other tumors. Esophagus. 2022;19(4):604-616.

[18] Inada M, Nishimura Y, Ishikawa K, et al. Comparing the 7th and 8th editions of the American Joint Committee on Cancer/Union for International Cancer Control TNM staging system for esophageal squamous cell carcinoma treated by definitive radiotherapy. Esophagus. 2019;16(4):371-376.

[19] Ouyang T, Ma C, Zhao Y, et al. (1)H NMR-based metabolomics of paired tissue, serum and urine samples reveals an optimized panel of biofluids metabolic biomarkers for esophageal cancer. Front Oncol. 2023;13:1082841.

[20] Joshi N, Bhat F, Bellad A, et al. Urinary proteomics for discovery of gastric cancer biomarkers to enable precision clinical oncology. Omics. 2023;27(8):361-371.

[21] Lin SY, Chang CH, Wu HC, et al. Proteome profiling of urinary exosomes identifies alpha 1-antitrypsin and H2B1K as diagnostic and prognostic biomarkers for urothelial carcinoma. Sci Rep. 2016;6:34446.

[22] Swensen AC, He J, Fang AC, et al. A comprehensive urine proteome database generated from patients with various renal conditions and prostate cancer. Front Med (Lausanne). 2021;8:548212.

[23] Zhang C, Leng W, Sun C, et al. Urine proteome profiling predicts lung cancer from control cases and other tumors. EBioMedicine. 2018;30:120-128.

[24] Joshi N, Garapati K, Ghose V, Kandasamy RK, Pandey A. Recent progress in mass spectrometry-based urinary proteomics. Clin Proteomics. 2024;21(1):14.

[25] Zhang Y, Du W, Chen Z, Xiang C. Upregulation of PD-L1 by SPP1 mediates macrophage polarization and facilitates immune escape in lung adenocarcinoma. Exp Cell Res. 2017;359(2):449-457.

[26] Tan Y, Zhao L, Yang YG, Liu W. The role of osteopontin in tumor progression through tumor-associated macrophages. Front Oncol. 2022;12:953283.

[27] Nallasamy P, Nimmakayala RK, Karmakar S, et al. Pancreatic tumor microenvironment factor promotes cancer stemness via SPP1‒CD44 axis. Gastroenterology. 2021;161(6):1998-2013.e7.

[28] Dongre A, Rashidian M, Eaton EN, et al. Direct and indirect regulators of epithelial‒mesenchymal transition-mediated immunosuppression in breast carcinomas. Cancer Discov. 2021;11(5):1286-1305.

[29] Zhang X, Zhang L, Tan X, et al. Systematic analysis of genes involved in oral cancer metastasis to lymph nodes. Cell Mol Biol Lett. 2018;23:53.

[30] Wang GQ, Jiao GG, Chang FB, et al. Long-term results of operation for 420 patients with early squamous cell esophageal carcinoma discovered by screening. Ann Thorac Surg. 2004;77(5):1740-1744.

[31] Kita Y, Natsugoe S, Okumura H, et al. Expression of osteopontin in oesophageal squamous cell carcinoma. Br J Cancer. 2006;95(5):634-638.

[32] Zou Y, Tan X, Yuan G, et al. SPP1 is associated with adverse prognosis and predicts immunotherapy efficacy in penile cancer. Hum Genomics. 2023;17(1):116.

[33] Bui TM, Yalom LK, Ning E, et al. Tissue-specific reprogramming leads to angiogenic neutrophil specialization and tumor vascularization in colorectal cancer. J Clin Invest. 2024;134(7):e174545.

[34] Gao S, Gang J, Yu M, Xin G, Tan H. Computational analysis for identification of early diagnostic biomarkers and prognostic biomarkers of liver cancer based on GEO and TCGA databases and studies on pathways and biological functions affecting the survival time of liver cancer. BMC Cancer. 2021;21(1):791.

[35] Samant RS, Clark DW, Fillmore RA, et al. Breast cancer metastasis suppressor 1 (BRMS1) inhibits osteopontin transcription by abrogating NF-kappaB activation. Mol Cancer. 2007;6:6.

[36] Jan HJ, Lee CC, Shih YL, et al. Osteopontin regulates human glioma cell invasiveness and tumor growth in mice. Neuro Oncol. 2010;12(1):58-70.

[37] Li K, Lin Y, Zhou Y, et al. Salivary extracellular microRNAs for early detection and prognostication of esophageal cancer: a clinical study. Gastroenterology. 2023;165(4):932-945.e9.

[38] Liu J, Dai L, Wang Q, et al. Multimodal analysis of cfDNA methylomes for early detecting esophageal squamous cell carcinoma and precancerous lesions. Nat Commun. 2024;15(1):3700.

[39] Hayano K, Ohira G, Hirata A, et al. Imaging biomarkers for the treatment of esophageal cancer. World J Gastroenterol. 2019;25(24):3021-3029.

[40] Xu L, Chen Y, Liu L, et al. Tumor-associated macrophage subtypes on cancer immunity along with prognostic analysis and SPP1-mediated interactions between tumor cells and macrophages. PLoS Genet. 2024;20(4):e1011235.

[41] Zhang Z, Liu B, Lin Z, Mei L, Chen R, Li Z. SPP1 could be an immunological and prognostic biomarker: from pan-cancer comprehensive analysis to osteosarcoma validation. FASEB J. 2024;38(14):e23783.

[42] Gao W, Liu D, Sun H, et al. SPP1 is a prognostic related biomarker and correlated with tumor-infiltrating immune cells in ovarian cancer. BMC Cancer. 2022;22(1):1367.

[43] Liu L, Zhang R, Deng J, et al. Construction of TME and identification of crosstalk between malignant cells and macrophages by SPP1 in hepatocellular carcinoma. Cancer Immunol Immunother. 2022;71(1):121-136.

[44] Wang C, Sun G, Wang H, Dai L, Zhang J, Du R. Serum anti-SPP1 autoantibody as a potential novel biomarker in detection of esophageal squamous cell carcinoma. BMC Cancer. 2022;22(1):932.

[45] Wang C, Li Y, Wang L, et al. SPP1 represents a therapeutic target that promotes the progression of oesophageal squamous cell carcinoma by driving M2 macrophage infiltration. Br J Cancer. 2024;130(11):1770-1782.

[46] Standal T, Borset M, Sundan A. Role of osteopontin in adhesion, migration, cell survival and bone remodeling. Exp Oncol. 2004;26(3):179-184.

[47] Inoue M, Shinohara ML. Intracellular osteopontin (iOPN) and immunity. Immunol Res. 2011;49(1-3):160-172.

RIGHTS & PERMISSIONS

2026 The Author(s). Clinical and Translational Discovery published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.