Thyroid Hormone Induces Oral Cancer Growth via the PD-L1-Dependent Signaling Pathway

Area of Science:

• Oncology
• Molecular Biology
• Endocrinology

Background:

• Oral cancer incidence is rising, particularly in Taiwan.
• Thyroid hormone (L-thyroxine, T4) promotes cancer cell proliferation via plasma membrane receptors like integrin αvβ3.
• T4 also upregulates programmed death-ligand 1 (PD-L1) and activates β-catenin signaling in cancer cells, but the PD-L1-proliferation link is unclear.

Purpose of the Study:

• To investigate the role of thyroid hormone-induced PD-L1 in regulating gene expression and proliferation in oral cancer cells.
• To elucidate the molecular mechanisms connecting T4, integrin αvβ3, PD-L1, and β-catenin in oral cancer growth.

Main Methods:

• Utilized oral cancer cell models to study the effects of thyroxine (T4).
• Investigated the roles of integrin αvβ3, ERK1/2, STAT3, PD-L1, and β-catenin signaling pathways.
• Employed short hairpin RNA (shRNA) to suppress PD-L1 expression and assessed downstream effects on proliferation and gene expression.

Main Results:

• T4 binding to integrin αvβ3 activated ERK1/2 and STAT3, inducing PD-L1 expression.
• Inactivated STAT3 inhibited PD-L1 expression and its nuclear accumulation.
• Suppression of PD-L1 reduced β-catenin accumulation and blocked T4-induced proliferation, signal transduction, and cancer cell growth.
• Nuclear PD-L1 formed complexes with nuclear proteins like p300.

Conclusions:

• Thyroxine promotes oral cancer cell proliferation through a pathway involving integrin αvβ3, ERK1/2, STAT3, and PD-L1.
• PD-L1 plays a crucial role in mediating T4-stimulated, β-catenin-dependent oral cancer growth.
• Targeting the T4-integrin αvβ3-PD-L1 axis may offer a therapeutic strategy for oral cancer.