Department of Dentistry, Hsinchu MacKay Memorial Hospital, Hsinchu City 30071, Taiwan.
Graduate Institute of Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.
Cells. 2022 Sep 29;11(19):3050. doi: 10.3390/cells11193050.
Oral cancer is a fatal disease, and its incidence in Taiwan is increasing. Thyroid hormone as L-thyroxine (T) 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.
口腔癌是一种致命的疾病，其在台湾的发病率正在上升。甲状腺激素如左甲状腺素（T）通过整合素αvβ3 受体刺激癌细胞增殖。它还诱导程序性死亡配体 1（PD-L1）的表达和癌细胞的增殖。甲状腺激素还激活了癌细胞中 β-catenin 依赖性的细胞增殖。然而，PD-L1 与癌症增殖之间的关系尚未完全阐明。在本研究中，我们研究了诱导性甲状腺激素诱导的 PD-L1 调节基因表达和增殖在口腔癌细胞中的作用。甲状腺素与整合素 αvβ3 结合，通过激活 ERK1/2 和信号转导子和转录激活子 3（STAT3）诱导 PD-L1 的表达。失活的 STAT3 抑制 PD-L1 的表达和核 PD-L1 的积累。PD-L1 表达的抑制减少了 β-catenin 的积累。此外，核 PD-L1 与核蛋白如 p300 形成复合物。通过 shRNA 抑制 PD-L1 表达不仅阻断了 PD-L1 和 β-catenin 的表达，还阻断了信号转导、增殖基因表达和癌细胞生长。总之，甲状腺素通过整合素 αvβ3 激活 ERK1/2 和 STAT3，刺激口腔癌细胞中 PD-L1 依赖性和 β-catenin 相关的生长。
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