Introduction

Head and neck squamous cell carcinoma (HNSCC), which notably includes oral squamous cell carcinoma (OSCC), stands as the sixth most commonly encountered cancer on a global scale, with approximately 600,000 new cases identified annually. Notably, OSCC accounts for 94% of oral cavity and oropharyngeal cancer cases worldwide. Despite advancing technologies in cancer detection and treatment, the prognosis for OSCC remains suboptimal due to the frequent diagnosis at advanced stages of the disease. The majority of OSCC cases are preceded by oral potentially malignant disorders (OPMDs), which exhibit clinically conspicuous but variable changes in the oral mucosa. Identifying and treating high-risk OPMDs at an early stage is crucial for preventing their progression to OSCC. Traditional histologic methods for assessing oral epithelial dysplasia involve subjectivity and may yield inaccurate results. Consequently, novel biomarkers that accurately identify OPMDs at a higher risk for malignant transformation are needed for effective preemptive intervention.

Fig. 1 Clinical features of oral potentially malignant disorders (Warnakulasuriya S. 2018).

Protein Biomarkers

ATP-Binding Cassette, G2 Subfamily (ABCG2)

ABCG2, part of the ATP-binding cassette transporter family, is essential for maintaining the side population phenotype in stem cells and has been isolated from various primary tumors, including OSCC. Studies indicate that ABCG2 is overexpressed in a subset of cancer stem-like cells, playing a significant role in oral carcinogenesis. ABCG2 expression has been observed in oral leukoplakia (43%), oral lichen planus (21%), and OSCC (67%), highlighting its potential as a predictive biomarker for malignant transformation.

Aldehyde Dehydrogenase-1 (ALDH1)

ALDH1, a cytosolic detoxifying isoenzyme, oxidizes aldehydes and converts retinol into retinoic acid during stem cell differentiation. Overexpression of ALDH1 has been identified in oral dysplastic and HNSCC samples, distinguishing malignant from pre-malignant cells. ALDH1's role in maintaining self-renewal properties and tumorigenicity of cancer stem cells underscores its potential as a biomarker for evaluating malignant transformation risk.

B lymphoma Mo-MLV insertion region 1 homolog (BMI-1)

BMI-1, a polycomb group transcription repressor, is involved in gene silencing and self-renovation of cancer stem cells. Overexpression of BMI-1 has been linked with increased tumorigenicity in HNSCC. Studies have reported BMI-1 overexpression in oral leukoplakia and dysplastic lesions, correlating with a 3.81-fold increased risk of malignant transformation. Thus, BMI-1 is a promising biomarker for high-risk OPMDs.

E-cadherin

E-cadherin, a cell membrane-associated protein, is crucial for intercellular adhesion. Its downregulation correlates with loss of cell adhesion, increased cell motility, and invasive phenotypes, marking the epithelial-to-mesenchymal transition (EMT) in OSCC. Studies have shown an inverse relationship between E-cadherin expression and epithelial dysplasia grades, suggesting its potential as a biomarker for OSCC risk assessment.

FGF2 and its receptor FGFR2

FGF2, part of the fibroblast growth factor family, and its receptor FGFR2 are involved in angiogenesis and cancer cell invasion. Overexpression of FGF2 and FGFR2 has been reported in the neoplastic progression of epithelial dysplasia to OSCC. Increased FGF2 staining is associated with dysplastic cells and OSCC, making FGF2 and FGFR2 important biomarkers for evaluating OPMD progression.

HERG1

HERG1, part of the ether-a-go-go potassium channel family, is implicated in tumor growth and cellular proliferation. Overexpression of HERG1 has been noted in various cancer cell lines, including OSCC. Although the correlation between HERG1 expression and OSCC development is not statistically significant, its elevated expression in dysplastic lesions suggests potential utility as a biomarker.

Minichromosome maintenance proteins (MCMs)

MCM family proteins, crucial to DNA replication, are overexpressed in dysplastic lesions and correlate with severe dysplasia. MCM proteins serve as superior proliferation markers compared to Ki-67 and PCNA, indicating their potential as reliable biomarkers for high-risk OPMDs.

Phospholipase C-γ1 (PLCγ1)

PLCγ1 is involved in growth factor-dependent signaling and has been reported in cancers including OSCC. Cytoplasmic and nuclear expression of PLCγ1 in OPMDs correlates with a higher risk of OSCC transformation, demonstrating its significance as an early biomarker in oral cancer progression.

Survivin

Survivin, part of the Inhibitor of Apoptosis (IAP) family, is involved in cell division and apoptosis inhibition. Overexpression of Survivin in OPMDs and OSCC suggests its role as a biomarker for early detection and progression of oral cancer.

Glycoprotein Biomarkers

CD133

CD133, a pentaspan transmembrane protein, is a key biomarker for cancer stem cells. Studies have shown that CD133 expression correlates positively with poor prognosis in oral leukoplakia and higher tumorigenicity in OSCC. Therefore, CD133 can predict the risk of malignant transformation in OPMDs.

Podoplanin (PDPN)

A transmembrane glycoprotein, PDPN is involved in cancer cell invasion and metastasis. Its expression is noted in early oral tumorigenesis and overexpressed in various dysplastic and hyperplastic regions near primary OSCC lesions. Research suggests PDPN overexpression strongly correlates with malignancy risk, indicating its potential as a biomarker for high-risk OPMDs.

Small Integrin-binding Ligand N-linked Glycoproteins (SIBLINGs)

The SIBLING family includes glycoproteins like osteopontin (OPN) and dentin sialophosphoprotein (DSPP), upregulated in several cancers. Studies have shown differential SIBLING expression in oral dysplastic lesions. Expression of DSPP in dysplastic lesions suggests a high likelihood of OSCC transformation, indicating their utility as biomarkers for high-risk OPMDs.

Squamous Cell Carcinoma Antigen (SCCA)

SCCA, specifically SCCA-1 and SCCA-2, is overexpressed in squamous cell carcinomas, including OSCC. Elevated SCCA levels have been observed in dysplastic and OSCC tissue samples. Studies suggest SCCA's potential as a biomarker for detecting malignant potential in OPMDs and monitoring disease progression.

Non-Protein Biomarker

MicroRNAs (miRNAs) are small non-coding RNA molecules regulating gene expression. Differential miRNA expression has been identified in OPMDs, predicting their progression to OSCC. Specifically, miR-21 and miR-31 have shown the potential to indicate malignant transformation. Panels of miRNAs, rather than single markers, provide reliable risk stratification biomarkers for OPMDs.

Conclusion

Understanding the potential biomarkers for OPMDs can assist in assessing their malignant potential. Although no specific well-established biomarker exists for OPMD cancer risk assessment, co-expression analyses of multiple biomarkers suggest promising predictive capabilities. The early identification and management of high-risk OPMDs through biomarker analysis hold promise in reducing the morbidity and mortality associated with OSCC. The continuous discovery and validation of new biomarkers will pave the way for personalized treatment approaches and improved patient outcomes in oral cancer care.