Overexpression of Angiogenic Factors and Matrix Metalloproteinases in the Saliva of Oral Squamous Cell Carcinoma Patients: Potential Non-Invasive Diagnostic and Therapeutic Biomarkers

Abstract Backgound: Salivary biomarkers hold huge potential for the non-invasive diagnosis of oral squamous cell carcinoma. Angiogenic factors and matrix-metalloproteinases (MMPs) are highly expressed in OSCC tissue, but their expression in the saliva is unknown. This study aimed to analyze the levels of angiogenic factors and MMPS in tumor-tissue and saliva of OSCC patients. Methods: OSCC-tissue, adjacent normal tissue (ANT), saliva from OSCC patients, and healthy controls were obtained. The expression patterns of angiogenic factors and MMPs were analyzed by immunohistochemistry, protein chip array, and RT-qPCR. Results: Results showed higher expression of ANG, ANG-2, HGF, PIGF, VEGF, MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, MMP-10, MMP-13, TIMP-1, and TIMP-2 in OSCC-tissues compared to the ANT. Among the overexpressed markers in OSCC-tissues, HGF, VEGF, PIGF, PDGF-BB, MMP-1, MMP-3, MMP-8, MMP-9, MMP-10, MMP-13, and TIMP-2 were significantly upregulated in the saliva of OSCC patients compared to healthy controls. Conclusions: The levels of HGF, VEGF, PIGF, PDGF-BB, MMP-1, MMP-3, MMP-8, MMP-9, MMP-10, MMP-13, and TIMP-2 were upregulated both in OSCC tissue and saliva of OSCC patients. Bioinformatic analysis revealed the correlation of these factors with patient survival and cancer functional states in head and neck cancer, indicating these factors as possible saliva-based non-invasive diagnostic/prognostic markers and therapeutic targets of OSCC.

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Epithelial and fibroblast SPARC expression patterns in oral leukoplakia and oral squamous cell carcinoma

Oral Surgery Oral Medicine Oral Pathology and Oral Radiology ◽

10.1016/j.oooo.2021.10.019 ◽

2021 ◽

Author(s):

Sopee Poomsawat ◽

Theerachai Kosanwat ◽

Ounruean Meesakul ◽

Sirima Sanguansin

Keyword(s):

Squamous Cell Carcinoma ◽

Oral Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Expression Patterns ◽

Oral Leukoplakia ◽

Sparc Expression

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Saliva protein biomarkers to detect oral squamous cell carcinoma in a high-risk population in Taiwan

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1612368113 ◽

2016 ◽

Vol 113 (41) ◽

pp. 11549-11554 ◽

Cited By ~ 43

Author(s):

Jau-Song Yu ◽

Yi-Ting Chen ◽

Wei-Fan Chiang ◽

Yung-Chin Hsiao ◽

Lichieh Julie Chu ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

High Risk ◽

Oral Cancer ◽

Oral Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Risk Score ◽

Squamous Cell ◽

Low Risk ◽

Healthy Controls ◽

Protein Biomarkers

Most cases of oral squamous cell carcinoma (OSCC) develop from visible oral potentially malignant disorders (OPMDs). The latter exhibit heterogeneous subtypes with different transformation potentials, complicating the early detection of OSCC during routine visual oral cancer screenings. To develop clinically applicable biomarkers, we collected saliva samples from 96 healthy controls, 103 low-risk OPMDs, 130 high-risk OPMDs, and 131 OSCC subjects. These individuals were enrolled in Taiwan’s Oral Cancer Screening Program. We identified 302 protein biomarkers reported in the literature and/or through in-house studies and prioritized 49 proteins for quantification in the saliva samples using multiple reaction monitoring-MS. Twenty-eight proteins were successfully quantified with high confidence. The quantification data from non-OSCC subjects (healthy controls + low-risk OPMDs) and OSCC subjects in the training set were subjected to classification and regression tree analyses, through which we generated a four-protein panel consisting of MMP1, KNG1, ANXA2, and HSPA5. A risk-score scheme was established, and the panel showed high sensitivity (87.5%) and specificity (80.5%) in the test set to distinguish OSCC samples from non-OSCC samples. The risk score >0.4 detected 84% (42/50) of the stage I OSCCs and a significant portion (42%) of the high-risk OPMDs. Moreover, among 88 high-risk OPMD patients with available follow-up results, 18 developed OSCC within 5 y; of them, 77.8% (14/18) had risk scores >0.4. Our four-protein panel may therefore offer a clinically effective tool for detecting OSCC and monitoring high-risk OPMDs through a readily available biofluid.

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Immunoexpression of matrix metalloproteinases and their inhibitors in different areas of oral squamous cell carcinoma

Australian Dental Journal ◽

10.1111/j.1834-7819.2012.01705.x ◽

2012 ◽

Vol 57 (3) ◽

pp. 300-307 ◽

Cited By ~ 3

Author(s):

ML Suarez-Roa ◽

J Asbun-Bojalil ◽

LM Ruiz-Godoy ◽

AA Meneses-García

Keyword(s):

Squamous Cell Carcinoma ◽

Matrix Metalloproteinases ◽

Oral Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell

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Salivary Circular RNAs Hsa_Circ_0001874 and Hsa_Circ_0001971 as Novel Biomarkers for the Diagnosis of Oral Squamous Cell Carcinoma

Cellular Physiology and Biochemistry ◽

10.1159/000491624 ◽

2018 ◽

Vol 47 (6) ◽

pp. 2511-2521 ◽

Cited By ~ 31

Author(s):

Si-Yu Zhao ◽

Jun Wang ◽

Shao-Bo Ouyang ◽

Zi-Kun Huang ◽

Lan Liao

Keyword(s):

Squamous Cell Carcinoma ◽

Oral Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Roc Curve ◽

Tnm Stage ◽

Differentially Expressed ◽

Circular Rnas ◽

Healthy Controls ◽

Novel Biomarkers

Background/Aims: Recent studies have demonstrated that circular RNAs (circRNAs) can serve as potential molecular markers for disease diagnosis. However, little is known about their diagnostic potential for oral squamous cell carcinoma (OSCC). This study aimed to determine the expression of circRNAs in the saliva of OSCC patients to identify novel biomarkers for OSCC screening. Methods: Microarray screening of circRNA was performed to identify differentially expressed circRNAs in saliva from 3 OSCC patients compared with 3 healthy controls. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to validate the results, and the association between these confirmed salivary circRNAs and clinicopathological features was analyzed using the chi-squared test. A receiver operating characteristic (ROC) curve was constructed to evaluate the diagnostic value of the circRNAs identified. Preoperative expression and postoperative expression (1 month after the surgery) of hsa_circ_0001874 and hsa_circ_0001971 was also determined. Results: Our results indicated 12 upregulated and 20 downregulated circRNAs in the saliva from the OSCC patients compared with that from the healthy controls. Among the differentially expressed circRNAs, hsa_circ_0001874, hsa_circ_0001971, and hsa_circ_0008068 were upregulated and hsa_circ_0000140, hsa_circ_0002632, and hsa_circ_0008792 were downregulated in the OSCC group versus the healthy group. Clinical data indicated that salivary hsa_circ_0001874 was correlated with TNM stage (P=0.006) and tumor grade (P=0.023) and that hsa_circ_0001971 was correlated with TNM stage (P=0.019). The combination of hsa_circ_0001874 and hsa_circ_0001971 showed an area under the ROC curve of 0.922 (95% confidence interval, 0.883-0.961; P< 0.001). The risk score based on the combination of hsa_circ_0001874 and hsa_circ_0001971 also discriminated patients with OSCC from patients with oral leukoplakia (P< 0.001). Moreover, the expression levels of salivary hsa_circ_0001874 and hsa_circ_0001971 were clearly decreased in the postoperative samples compared with preoperative samples (P< 0.001). Conclusions: This is the first study to demonstrate the potential of salivary hsa_circ_0001874 and hsa_circ_0001971 as biomarkers for the diagnosis of OSCC.

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