Department of Breast and Thyroid Surgery, Changhai Hospital, Naval Medical University, China.
Department of General Surgery, Tengchong People's Hospital, China.
Exp Cell Res. 2024 Oct 1;442(2):114229. doi: 10.1016/j.yexcr.2024.114229. Epub 2024 Aug 27.
The incidence of thyroid cancer keeps rising and obesity emerges as an important risk factor for thyroid cancer, but the underlying mechanism is far from clear. Here, we hypothesize that leptin and insulin, two hormones closely related to obesity, may contribute to the pathogenesis of thyroid cancer. By using a combination of assays like CRISPR KO, cancer cell-T cell co-culture, ApoLive-Glo™ multiplex assay and syngeneic mouse model, we show that PD-L1 protein levels are increased dose-dependently by leptin or insulin in multiple thyroid cancer cell lines. Leptin and insulin converge to activate the PI3K-AKT pathway to enhance PD-L1 expression and activity. In addition, we use CRISPR KO to generate human thyroid cancer cells expressing WT PIK3CA or PIK3CA-E545K mutant. PIK3CA- E545K mutation makes the thyroid cancer cells to produce more PD-L1 protein upon leptin or insulin treatment. Thus, leptin and insulin synergize with PIK3CA mutation to enhance PD-L1 expression. Dual blockade of leptin and insulin signaling pathways reduces tumor size in a syngeneic mouse model. Our study suggests that understanding the interaction between genetic mutation and obesity is crucial for comprehensively assessing thyroid cancer risk and developing effective treatment strategies.
甲状腺癌的发病率不断上升，肥胖已成为甲状腺癌的一个重要危险因素，但其中的潜在机制尚不清楚。在这里，我们假设与肥胖密切相关的两种激素——瘦素和胰岛素，可能会促进甲状腺癌的发病机制。通过使用 CRISPR KO、癌细胞-T 细胞共培养、ApoLive-Glo™多重检测试剂盒和同基因小鼠模型的组合实验，我们发现瘦素或胰岛素可使多种甲状腺癌细胞系中 PD-L1 蛋白水平呈剂量依赖性增加。瘦素和胰岛素共同作用激活 PI3K-AKT 通路，增强 PD-L1 的表达和活性。此外，我们还使用 CRISPR KO 生成表达 WT PIK3CA 或 PIK3CA-E545K 突变的人甲状腺癌细胞系。PIK3CA-E545K 突变使甲状腺癌细胞在瘦素或胰岛素处理后产生更多的 PD-L1 蛋白。因此，瘦素和胰岛素与 PIK3CA 突变协同作用增强 PD-L1 的表达。瘦素和胰岛素信号通路的双重阻断可减少同基因小鼠模型中的肿瘤大小。我们的研究表明，了解基因突变与肥胖之间的相互作用对于全面评估甲状腺癌风险和制定有效的治疗策略至关重要。
