Potential Non-Invasive Biomarkers for Early Diagnosis of Oral Squamous Cell Carcinoma

This study aimed to investigate the role of a panel of salivary cytokines as biomarkers for early detection oral squamous cell carcinoma (OSCC), comparing their levels among healthy individuals, patients with oral leukoplakia (OL), and malignant lesions. Cytokine profiling analysis performed in a minimally invasive sample was correlated with clinicopathological variables in our patient cohorts. Unstimulated saliva was obtained from subjects with OSCC at early (n = 33) and advanced (n = 33) disease, OL with homogeneous (n = 33) and proliferative verrucous (n = 33) clinical presentations, and healthy controls (n = 25). Salivary IL-1α, IL-6, IL-8, IP-10, MCP-1, TNF-α, HCC-1, and PF-4 levels were analyzed by a sensitive bead-based multiplex immunoassay. Mean levels of IL-6, IL-8, TNF-α, HCC-1, MCP-1, and PF-4 differed significantly between OSCC, OL, and control saliva (p < 0.05). We found notably higher IL-6 and TNF-α in advanced compared to early OSCC stages. The area under the curve (AUC) for OSCC vs. control was greater than 0.8 for IL-6, IL-8, TNF-α, and HCC-1, and greater than 0.7 for PF-4. The presence of neck metastases (NM) was associated with increased IL-6 and TNF-α levels. Our findings suggest that salivary IL-6, IL-8, TNF-α, HCC-1, and PF-4 may discriminate between OSCC, OL, and healthy controls. IL-6 and TNF-α may indicate OSCC progression, being distinctive in the presence of NM.

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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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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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99mTc(V)-dimercaptosuccinic acid scintigraphy in detecting neck metastases in oral squamous cell carcinoma with clinically negative necks

Oral Oncology ◽

10.1016/j.oraloncology.2008.06.008 ◽

2009 ◽

Vol 45 (6) ◽

pp. 492-495 ◽

Cited By ~ 3

Author(s):

Ye Zhang ◽

Chuanbin Guo ◽

Guangyan Yu ◽

Chunli Zhang

Keyword(s):

Squamous Cell Carcinoma ◽

Oral Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Dimercaptosuccinic Acid ◽

Neck Metastases ◽

Dimercaptosuccinic Acid Scintigraphy

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Lack of Association of CYP2C9 genetic polymorphism with oral squamous cell carcinoma

10.21203/rs.3.rs-27686/v1 ◽

2020 ◽

Author(s):

Sagheer Ahmed ◽

Saeed Khan ◽

Syeda Uzma Naqvi ◽

Kholood Janjua ◽

Zaira Zulfiqar ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Oral Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Genetic Polymorphisms ◽

Squamous Cell ◽

Heterocyclic Aromatic Amines ◽

P Value ◽

Polycyclic Aromatic ◽

Allele Specific ◽

And Control

Abstract Background: There is increasing evidence for the role of polycyclic aromatic hydrocarbons (PAHs) and heterocyclic aromatic amines (HCAs) in carcinogenesis, including oral squamous cell carcinoma (OSCC). Several of these mutagenic substances are cytochrome (CYP)2C9 enzyme substrates.Methods: In this study, we examined the association of CYP2C9*2 and *3 genetic polymorphisms in 58 OSCC patients and 174 healthy, age, and sex-matched controls. Genotyping was done with allele-specific polymerase chain reaction followed by agarose gel electrophoreses, while selected samples were sequenced for confirmation of genotyping.Results: The wild type genotype (CYP2C9*1*1) was observed at 83%, *1*3 at 8%, *1*2 at 5%, *2*2 at 2% and *2*3 at 2% in combined case and control groups. On further analysis, however, our results did not reveal an association of these variants with OSCC samples (Odds ratio: 0.608, 95% Confidence Interval: 0.289 - 1.281, p-value: 0.190). While larger studies are needed to confirm or refute these results, they show a lack of association of CYP2C9*2 and *3 polymorphisms with OSCC in this population.Conclusions: This study demonstrates that the genetic polymorphisms in CYP2C9 genes (CYP2C9*2 and *3) are not causing the risk and are not associated with OSCC. Also, CYP2C9 has no role in the pathogenesis of OSCC in this population of patients.Trial registration: Not applicable.

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Evaluation of protein level’s changes in saliva and sera of Oral Squamous Cell Carcinoma patients

Baghdad Science Journal ◽

10.21123/bsj.11.2.447-454 ◽

2014 ◽

Vol 11 (2) ◽

pp. 447-454

Author(s):

Baghdad Science Journal

Keyword(s):

Squamous Cell Carcinoma ◽

Oral Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Total Protein ◽

Healthy Controls ◽

And Gender ◽

Albumin To Globulin Ratio ◽

Sera Samples

This study aimed to identify the changes in total protein in saliva and sera samples of patients with oral squamous cell carcinoma in comparison to those of healthy controls. These changes were followed using electrophoresis (PAGE). Meanwhile, determinations of albumin, globulin and albumin to globulin ratio were carried out on sera samples only.Two groups were the participants in the present study, 18 patients with Oral Squamous Cell Carcinoma (OSCC), and 20 ages and gender matched healthy controls.

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Association of TNF-α (-238 and -308) promoter polymorphisms with susceptibility of oral squamous cell carcinoma in North Indian population

Cancer Biomarkers ◽

10.3233/cbm-140444 ◽

2015 ◽

Vol 15 (2) ◽

pp. 125-131 ◽

Cited By ~ 9

Author(s):

Prithvi Kumar Singh ◽

Jaishri Bogra ◽

Girish Chandra ◽

Mohammad Kaleem Ahmad ◽

Rajni Gupta ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Oral Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Indian Population ◽

North Indian Population ◽

Promoter Polymorphisms ◽

Tnf Α

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Oct4 downregulation–induced inflammation increases the migration and invasion rate of oral squamous cell carcinoma

Acta Biochimica et Biophysica Sinica ◽

10.1093/abbs/gmab127 ◽

2021 ◽

Author(s):

Shuntao Sun ◽

Hongyu Yang ◽

Feng Wang ◽

Shanshan Zhao

Keyword(s):

Squamous Cell Carcinoma ◽

Oral Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Migration And Invasion ◽

Invasion And Migration ◽

Tnf Α ◽

And Migration ◽

Inflammatory Changes

Abstract Inflammatory changes are involved in tumor cell proliferation, migration, and invasion. Tumor necrosis factor-α (TNF-α) and lipopolysaccharide (LPS) play important roles in inflammatory regulation during tumor development. Oct4 acts as a transcription factor that modulates inflammatory changes in mesenchymal stem cells. In this study, we explored the role of Oct4 in the invasion and migration of oral squamous cell carcinoma (OSCC) cells. LPS and TNF-α were used to treat the OSCC cell lines HN4 and CAL27 to induce inflammation. The generation of inflammatory cytokines, including TNF-α, interleukin (IL)-1β, and IL-6, was evaluated by enzyme-linked immunosorbent assay and real-time quantitative PCR. Western blot analysis was employed to detect the expression and phosphorylation of JNK1, p65, and STAT3, which are key modulators of inflammation. Wound scratch healing and transwell invasion assays were further used to determine the role of inflammation in the invasion and migration of OSCC cells. Robust inflammation was observed in HN4 and CAL27 cells treated with LPS and TNF-α. A marked increase in JNK1, p65, and STAT3 phosphorylation levels in OSCC cells was also detected after LPS and TNF-α treatment. The migration and invasion of HN4 and CAL27 cells were significantly boosted by stimulation with LPS and TNF-α. Furthermore, Oct4 mRNA and protein levels were significantly upregulated by stimulation with LPS and TNF-α. Silencing of Oct4 led to reduced inflammation and decreased levels of phosphorylated JNK1, p65, and STAT3 and impaired invasion and migration in LPS- and TNF-α-stimulated OSCC cells. Overall, LPS- and TNF-α-induced inflammation suppressed the migration and invasion of OSCC cells by upregulating Oct4 expression.

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A comparative study of Candida species diversity among patients with oral squamous cell carcinoma and oral potentially malignant disorders

BMC Research Notes ◽

10.1186/s13104-020-05336-3 ◽

2020 ◽

Vol 13 (1) ◽

Author(s):

Sankar Leena Sankari ◽

Krishnan Mahalakshmi ◽

Venkatesan Naveen Kumar

Keyword(s):

Squamous Cell Carcinoma ◽

Oral Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Risk Ratio ◽

Candida Species ◽

Healthy Controls ◽

Oral Potentially Malignant Disorders ◽

Potentially Malignant Disorders ◽

Potentially Malignant

Abstract Objectives To determine the prevalence of Candida species by PCR–RFLP method in the saliva of patients with oral squamous cell carcinoma (OSCC), oral potentially malignant disorders (OPMD) and healthy cohorts. Unstimulated saliva was collected from patients with OSCC (n = 97), OPMD (n = 200), and healthy controls (n = 200). Candida species were isolated using the standard protocol. The isolates were identified using phenotypic and genotypic methods. The odds/risk ratio was calculated using Pearson’s Chi-square test. The significance of Candidal carriage was calculated by independent T-test. Results Oral Candidal carriage was 72.2%, 58% and 20.5% among patients with OSCC, OPMD, and healthy controls respectively. The oral Candidal carriage in OSCC and OPMD was highly significant (p = 0.0001). Non albicans Candida predominated over Candida albicans. Candida species were diverse among the study groups with a predominance of Candida krusei, Candida tropicalis, and Pichia anomala formerly Candida pelliculosa. P. anomala occurrence outnumbered in health. The odds/risk ratio for OSCC and OPMD were 4.25/11.87 and 3.52/6.99 respectively. A high prevalence of non albicans Candida was observed both in all the three groups (OSCC, OPMD and healthy controls). High odds and risk ratio associates Candida species to OSCC and OPMD. Candida famata may be associated with OSCC and OPMD.

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Increased Phosphatidylserine on Blood Cells in Oral Squamous Cell Carcinoma

Journal of Dental Research ◽

10.1177/0022034519843106 ◽

2019 ◽

Vol 98 (7) ◽

pp. 763-771 ◽

Cited By ~ 2

Author(s):

Y. Liu ◽

B. Li ◽

T.L. Hu ◽

T. Li ◽

Y. Zhang ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Confocal Microscopy ◽

Oral Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Blood Cells ◽

Therapeutic Strategy ◽

Stage Iii ◽

Healthy Controls ◽

Rapid Coagulation

The specific function of phosphatidylserine (PS) in the context of the development of a hypercoagulable state among individuals with oral squamous cell carcinoma (OSCC) is uncertain. The goal of this study was therefore to assess the exposure of PS on microparticles (MPs) as well as on endothelial and blood cells and to assess procoagulant activity (PCA) as a function of the stage of OSCC progression. We recruited patients with OSCC ( n = 63) as well as healthy controls ( n = 26) to participate in this study. PS exposure was then assessed via confocal microscopy and flow cytometry, revealing that patients with stage III/IV OSCC exhibited higher frequencies of PS-exposing blood cells, MPs, and serum-cultured endothelial cells (ECs) than did patients with stage I/II OSCC or healthy controls. When we conducted functional coagulation assays, we discovered that PS+blood cells, MPs, and serum-cultured ECs from patients with stage III/IV OSCC mediated more rapid coagulation and more substantial production of FXa, thrombin, and fibrin as compared with controls. When samples were treated with the PS antagonist lactadherin, this resulted in an 80% disruption of PCA. Strikingly, when pre- and postoperative samples were compared from patients with stage III/IV OSCC undergoing resective surgery, PCA was significantly reduced in the postoperative samples. After stimulating ECs with inflammatory cytokines, we found by confocal microscopy that they expose PS on their cell membranes, thus generating FVa and FXa binding sites and mediating the formation of fibrin. Together our findings provide evidence that PS+blood cells and MPs are important mediators of the development of a hypercoagulable and prothrombotic state among individuals afflicted by advanced-stage OSCC. As such, a PS blockade may be a viable therapeutic strategy for treating such patients.

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