Decreased CSTA expression promotes lymphatic metastasis and predicts poor survival in oral squamous cell carcinoma

Yupu Wang; Lin Wang; Xing Li; Xingzhou Qu; Nannan Han; Min Ruan; Chenping Zhang

doi:10.1016/j.archoralbio.2021.105116

Decreased CSTA expression promotes lymphatic metastasis and predicts poor survival in oral squamous cell carcinoma

Arch Oral Biol. 2021 Jun:126:105116. doi: 10.1016/j.archoralbio.2021.105116. Epub 2021 Mar 31.

Authors

Yupu Wang¹, Lin Wang¹, Xing Li², Xingzhou Qu¹, Nannan Han³, Min Ruan⁴, Chenping Zhang¹

Affiliations

¹ Department of Oral & Maxillofacial-Head & Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China; College of Stomatology, Shanghai Jiao Tong University, Shanghai, 200011, China; National Center for Stomatology, Shanghai, 200011, China; National Clinical Research Center for Oral Diseases, Shanghai, 200011, China; Shanghai Key Laboratory of Stomatology, Shanghai, 200011, China.
² Department of Oral & Maxillofacial-Head & Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China; College of Stomatology, Shanghai Jiao Tong University, Shanghai, 200011, China; National Center for Stomatology, Shanghai, 200011, China; National Clinical Research Center for Oral Diseases, Shanghai, 200011, China; Shanghai Key Laboratory of Stomatology, Shanghai, 200011, China; School of Stomatology, Weifang Medical University, Weifang, 261031, Shandong, China.
³ Department of Oral & Maxillofacial-Head & Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China; College of Stomatology, Shanghai Jiao Tong University, Shanghai, 200011, China; National Center for Stomatology, Shanghai, 200011, China; National Clinical Research Center for Oral Diseases, Shanghai, 200011, China; Shanghai Key Laboratory of Stomatology, Shanghai, 200011, China. Electronic address: hannannan111@126.com.
⁴ Department of Oral & Maxillofacial-Head & Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China; College of Stomatology, Shanghai Jiao Tong University, Shanghai, 200011, China; National Center for Stomatology, Shanghai, 200011, China; National Clinical Research Center for Oral Diseases, Shanghai, 200011, China; Shanghai Key Laboratory of Stomatology, Shanghai, 200011, China. Electronic address: doctorruanmin@sjtu.edu.cn.

PMID: 33831734
DOI: 10.1016/j.archoralbio.2021.105116

Abstract

Objective: Herein, we aimed to identify biomarkers that affect lymphatic metastasis of oral squamous cell carcinoma (OSCC) through bioinformatic analysis, and clinicopathological and in vitro verifications.

Design: The OSCC-related gene expression dataset was retrieved from The Cancer Genome Atlas (TCGA) and analyzed to identify differentially expressed genes (DEGs), which were subjected to pathway analysis. Weighted gene co-expression network analysis (WGCNA) and protein-protein interaction (PPI) network analysis were performed to identify hub genes. Expression of potential biomarkers was examined using quantitative real-time polymerase chain reaction, immunohistochemistry, and western blotting. Statistical analyses were performed to determine the association between biomarker expression and clinicopathological characteristics of patients with OSCC. Effects of selected biomarkers on proliferation, migration, and invasion were evaluated using in vitro assays.

Results: For DEGs, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed potential lymphatic metastasis-related biological processes and signaling pathways. Eight hub genes - ALOXE3, CSTA, PLA2G4E, PPL, SPRR1A, SPRR2A, SPRR2D, and SPRR2E, were identified via WGCNA and PPI analyses. CSTA expression was markedly downregulated in primary OSCC tissues, and low CSTA expression significantly correlated with high tumor grade (P = 0.001), nodal metastasis (P = 0.028), and poor overall survival (P < 0.001). CTSA overexpression inhibited OSCC cell migration and invasion in vitro, with little effect on OSCC cell proliferation.

Conclusions: Our study revealed that CSTA is a promising biomarker and therapeutic target with prognostic implications in patients with OSCC. CSTA may play an essential role in OSCC lymphatic metastasis and tumor differentiation.

Keywords: Bioinformatics; Biomarker; Cystatin A; Lymphatic metastasis; Oral squamous cell carcinoma.

MeSH terms

Biomarkers, Tumor / genetics
Carcinoma, Squamous Cell* / genetics
Cornified Envelope Proline-Rich Proteins
Cystatin A
Gene Expression Regulation, Neoplastic
Head and Neck Neoplasms*
Humans
Lymphatic Metastasis
Mouth Neoplasms* / genetics
Squamous Cell Carcinoma of Head and Neck / genetics

Substances

Biomarkers, Tumor
Cornified Envelope Proline-Rich Proteins
Cystatin A
SPRR2A protein, human
CSTA protein, human