Table 1.

Expression of different molecules and their participation in biological behavior and epithelial-to-mesenchymal transition (EMT). HNSCC: Head and neck squamous cell carcinoma.

Established EMT-Markers	Biological Behavior	Role in EMT/Tumorigenesis	Reference
Vimentin	Type III intermediate filament that is found in mesenchymal cells of various types	Marker of cells undergoing an epithelial-to-mesenchymal transition (EMT) during both normal development and metastatic progression	[16]
E-cadherin	Protein encoded by the CDH1 gene, also been designated as CD324, tumor suppressor gene	Loss of E-cadherin function/expression is implicated in cancer progression/metastasis, downregulation decreases the strength of cellular adhesion, resulting in an increase in cellular motility	[17]
N-cadherin	In embryogenesis, N-cadherin is the key molecule during gastrulation and neural crest development	Promotes tumor cell survival, migration, and invasion, and high levels are often associated with poor prognosis	[18]
Fibronectin	Many different cells are capable of incorporating plasma fibronectin into their extracellular matrix of any tissue	Cancer-associated fibroblasts (CAFs) are essential sources of increased extracellular matrix deposition and altered remodeling to pave the way for cancer cell invasion.	[19]
SNAI1/2	Snail superfamily of zinc-finger transcription factors, involved in cell differentiation and survival. Snail1: essential for gastrulation. Snail2: embryonic development	Snail1: Common sign of poor prognosis in metastatic cancer, and tumors with elevated Snail1 expression show high rates of treatment failure	[20]
		Snail2: Tumor metastasis promotes EMT through activation of SNAIL2 in HNSCC
TWIST1	Helix-loop-helix transcription factor, plays an essential and pivotal role in multiple stages of embryonic development	Promotes the formation of cancer stem cells and EMT, targeting TWIST1-related molecules significantly inhibits tumor growth and thus improves the survival of cancer patients	[21]
ZEB1/2	Zinc finger E-box binding homeobox 1/2, acts as transcriptional repressor	Dual role: (1) repressor for epithelial genes. (2) a transcriptional activator when associated with YAP (Hippo Pathway); also known to induce EMT in various cancers, but has also been linked to promote treatment failure in an EMT-independent manner	[22]
Markers Associated with EMT	Biological Behavior	Role in EMT/Tumorigenesis	Reference
PD-L1 and PD-1	PD-L1: cluster of differentiation 274(CD274) or B7 homolog 1 (B7-H1), 40kDa type 1 transmembrane protein, plays a role in suppressing the immune system during pregnancy, tissue allografts, autoimmune disease, and others, ligand of programmed cell death protein-1 (PD-1). PD-1: Cell surface receptor that plays a role in promoting self-tolerance by suppressing T cell inflammatory activity	Many tumor cells express PD-L; inhibition of the interaction between PD-1 and PD-L1 can enhance T-cell responses in vitro and mediate preclinical antitumor activity. This is known as immune checkpoint blockade	[23]
SOX2	Pluripotency-associated transcription factor SOX2 (sex determining region Y-box 2), essential during mammalian embryogenesis, adult tissue regeneration, and homeostasis	Identified as a lineage-survival oncogene in lung and esophageal SCC and recurrent copy number gain of chromosome 3q26, the gene locus encoding SOX2 represents a frequent alteration in HNSCC	[24]
KLK6	Kallikrein-related peptidase 6 (KLK6), Family of 15 secreted serine proteases with trypsin or chymotrypsin-like activity, encoded by a cluster of genes located on chromosome 19q13.3–13.4	Common feature for many human cancers, promising biomarker for early diagnosis or unfavorable prognosis. KLK6 can degrade components of the extracellular matrix and is implicated in tissue remodeling and induction of tumor-relevant processes such as proliferation, migration, and invasion	[25]
BMI1	BMI1 (B lymphoma Mo-MLV insertion region 1 homolog) has been reported as an oncogene by regulating p16 and p19	BMI1 deregulation is associated with enhanced migration, invasion, and poor prognosis in salivary adenoid cystic carcinoma	[26]
BDNF	Brain-derived neurotrophic factor (BDNF) acts on certain neurons of the central and the peripheral nervous system, helping to support the survival of existing neurons and encourage the growth and differentiation of new neurons and synapses	Elevated expression of the brain-derived neurotrophic factor (BDNF) and its receptor NTRK2 together with reduced E-cadherin expression is a common feature of salivary adenoid cystic carcinoma (ACC) and significantly correlated with invasion, metastasis, and poor prognosis of ACC	[27]
NTRK2	Receptor tyrosine kinase involved in the development and maturation of the central and the peripheral nervous systems through regulation of neuron survival, proliferation, migration, differentiation, and synapse formation and plasticity	NTRK2 levels are positively correlated with expression of the EMT-related protein S100A4 but negatively associated with E-cadherin levels	[27]