Verification of Saliva Matrix Metalloproteinase-1 as a Strong Diagnostic Marker of Oral Cavity Cancer

Ya-Ting Chang, Lichieh Julie Chu, Yen-Chun Liu, Chih-Jou Chen, Shu-Fang Wu, Chien-Hua Chen, Ian Yi-Feng Chang, Jun-Sheng Wang, Tzong-Yuan Wu, Srinivas Dash, Wei-Fan Chiang, Sheng-Fu Chiu, Shin-Bin Gou, Chih-Yen Chien, Kai-Ping Chang, Jau-Song Yu, Ya-Ting Chang, Lichieh Julie Chu, Yen-Chun Liu, Chih-Jou Chen, Shu-Fang Wu, Chien-Hua Chen, Ian Yi-Feng Chang, Jun-Sheng Wang, Tzong-Yuan Wu, Srinivas Dash, Wei-Fan Chiang, Sheng-Fu Chiu, Shin-Bin Gou, Chih-Yen Chien, Kai-Ping Chang, Jau-Song Yu

Abstract

Oral squamous cell carcinoma (OSCC) accounts for >90% of cases of oral cancer, including cancer at the lip and oral cavity and cancer at the oropharynx. Most OSCCs develop from oral potentially malignant disorders (OPMDs), which consist of heterogeneous lesions with different malignant transformation potentials that make early detection of OSCC a challenge. Using a targeted mass spectrometry-based assay to compare multiple candidate proteins, we previously identified matrix metalloproteinase-1 (MMP-1) as one of the most promising salivary OSCC biomarkers. To explore the clinical utility of MMP-1 in OSCC detection, we developed an in-house, sensitive enzyme-linked immunosorbent assay (ELISA) for measuring MMP-1 content, and tested it on saliva samples from 1160 subjects (313 healthy controls, and 578 OPMD and 269 OSCC patients) collected at two medical centers. Salivary MMP-1 levels measured by our in-house ELISA significantly discriminated OSCC patients from non-cancerous groups. A receiver operating characteristic curve analysis showed that MMP-1 was effective in separating non-cancer groups from patients with OSCCs at the oral cavity. Additionally, salivary MMP-1 levels in oral cavity cancer patients were highly correlated with tumor progression (tumor size, lymph node metastasis, and overall stage). Collectively, our results indicate that salivary MMP-1 is an effective biomarker for OSCC that can be sensitively detected using our newly developed ELISA. The newly developed MMP-1 ELISA may be used as a new adjunctive tool to aid in detecting and monitoring OSCC.

Keywords: ELISA; MMP-1; biomarker; oral cancer; saliva.

Conflict of interest statement

This work was supported in part by a grant (SCRPD1G0071) from an industry–university collaboration between Chang Gung University and See & Treatment Biomed Co. Ltd. Y.-T. Chang and C.-J. Chen are currently Chief Technology Officer and R&D specialist, respectively, of See & Treatment Biomed Co. Ltd.

Figures

Figure 1
Figure 1
Matrix metalloproteinase-1 (MMP-1) levels in saliva from 1160 clinical specimens. (A,B) Salivary levels of MMP-1 in healthy controls, oral potentially malignant disorders (OPMD) I, OPMD II, and oral squamous cell carcinoma (OSCC) patients were determined using two pairs of enzyme-linked immunosorbent assays (ELISAs), pair A (A) and B (B), as described in Section 2. ** p < 0.01. *** p < 0.001. (C,D) Receiver operating characteristic (ROC) curve showing the diagnostic efficacy of salivary MMP-1, determined using pair-A ELISA (C) and pair-B ELISA (D) for OSCC versus non-cancerous groups (healthy controls (HC) and OPMD). (E) Correlation between levels of salivary MMP-1 in HC, OPMD I, OPMD II, and OSCC patients, determined using pair A- and pair B-ELISA, as described in Section 2 (Pearson correlation, r = 0.957, p < 0.001). The boxed image in the right panel is enlarged and shown on the left.
Figure 2
Figure 2
Differential expression levels of salivary MMP-1 in OSCC and non-cancerous groups. (A) Clinical information and subgroups of OSCC (n = 269) in this study. (B) Associations between salivary MMP-1 content in HC, OPMD, and OSCC with different tumor sites. *** p < 0.001. The median level of salivary MMP-1 (pg/mL) in each subgroup is shown for comparison.
Figure 3
Figure 3
Differential expression levels of salivary MMP-1 in OPMD I and OPMD II. (A) Diagnostic types of OPMD I and OPMD II cases in this study. (B) Associations between salivary MMP-1 content in HC, different types (case no. > 10) of non-cancerous OPMD I and OPMD II, and OSCC. * p < 0.05, ** p < 0.01. *** p < 0.001.
Figure 4
Figure 4
Differential expression levels of salivary MMP-1 in oral cavity cancer patients with advanced stages and grades. (A) Associations between salivary MMP-1 content in HC, OPMD, and different stages (0, I, II, III, and IV) of oral cavity cancer. * p < 0.05, ** p < 0.01, *** p < 0.001. (B) ROC curve showing the diagnostic efficacy of salivary MMP-1 for different stages (I–IV) of oral cavity cancer versus non-cancerous groups (HC and OPMD). (C–E) Associations between salivary MMP-1 content in oral cavity cancer specimens with tumor size (pT status, T0–T4) (C), neck lymph node metastasis (pN status, N0–N3) (D), and grade (G0–G3) (E).

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