Thyroid Hormone Induces Oral Cancer Growth via the PD-L1-Dependent Signaling Pathway
Kuan-Wei Su,
Hung-Yun Lin,
Hsien-Chung Chiu,
Shin-Yu Shen,
Chun A. ChangOu,
Dana R. Crawford,
Yu-Chen S. H. Yang,
Ya-Jung Shih,
Zi-Lin Li,
Haw-Ming Huang,
Jaqueline Whang-Peng,
Yih Ho,
Kuan Wang
Affiliations
Kuan-Wei Su
Department of Dentistry, Hsinchu MacKay Memorial Hospital, Hsinchu City 30071, Taiwan
Hung-Yun Lin
Graduate Institute of Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
Hsien-Chung Chiu
Department of Periodontology, School of Dentistry, National Defense Medical Center and Tri-Service General Hospital, Taipei 11490, Taiwan
Shin-Yu Shen
Graduate Institute of Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
Chun A. ChangOu
Core Facility, Taipei Medical University, Taipei 11031, Taiwan
Dana R. Crawford
Department of Immunology and Microbial Disease, Albany Medical College, Albany, NY 12208, USA
Yu-Chen S. H. Yang
Joint Biobank, Office of Human Research, Taipei Medical University, Taipei 11031, Taiwan
Ya-Jung Shih
Graduate Institute of Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
Zi-Lin Li
Graduate Institute of Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
Haw-Ming Huang
School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei 11031, Taiwan
Jaqueline Whang-Peng
Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei 11031, Taiwan
Yih Ho
School of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan
Kuan Wang
Graduate Institute of Nanomedicine and Medical Engineering, College of Medical Engineering, Taipei Medical University, Taipei 11031, Taiwan
Oral cancer is a fatal disease, and its incidence in Taiwan is increasing. Thyroid hormone as L-thyroxine (T4) stimulates cancer cell proliferation via a receptor on integrin αvβ3 of plasma membranes. It also induces the expression of programmed death-ligand 1 (PD-L1) and cell proliferation in cancer cells. Thyroid hormone also activates β-catenin-dependent cell proliferation in cancer cells. However, the relationship between PD-L1 and cancer proliferation is not fully understood. In the current study, we investigated the role of inducible thyroid hormone-induced PD-L1-regulated gene expression and proliferation in oral cancer cells. Thyroxine bound to integrin αvβ3 to induce PD-L1 expressions via activation of ERK1/2 and signal transducer and activator of transcription 3 (STAT3). Inactivated STAT3 inhibited PD-L1 expression and nuclear PD-L1 accumulation. Inhibition of PD-L1 expression reduced β-catenin accumulation. Furthermore, nuclear PD-L1 formed a complex with nuclear proteins such as p300. Suppression PD-L1 expression by shRNA blocked not only expression of PD-L1 and β-catenin but also signal transduction, proliferative gene expressions, and cancer cell growth. In summary, thyroxine via integrin αvβ3 activated ERK1/2 and STAT3 to stimulate the PD-L1-dependent and β-catenin-related growth in oral cancer cells.
