Monocyte recruitment and activated inflammation are associated with thyroid carcinogenesis in a mouse model.
Monocyte recruitment and activated inflammation are associated with thyroid carcinogenesis in a mouse model.
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发表时间：
2019-07
影响因子：
5.3
通讯作者：
Sunmi Park;Jack Zhu;G. Altan-Bonnet;S. Cheng
中科院分区：
文献类型：
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作者：
Sunmi Park;Jack Zhu;G. Altan-Bonnet;S. Cheng
甲状腺癌是最常见的内分泌恶性肿瘤。虽然炎症和甲状腺癌之间的关联早已被认识到，但分子水平上的因果关系尚未阐明。我们探讨了炎症如何导致ThrbPV/PVPten+/-小鼠的甲状腺癌发生。ThrbPV/PVPten+/-小鼠表达显性阴性甲状腺激素受体β（表示为PV）和Pten基因的一个单一等位基因缺失。这种突变小鼠表现出与患者相似的侵袭性滤泡性甲状腺癌。我们发现ThrbPV/PVPten+/-小鼠甲状腺肿瘤中炎性单核细胞浸润显著增加，而荷瘤小鼠骨髓和血液中单核细胞稳态无明显变化。使用全局基因表达谱分析，我们发现炎症介质的表达改变，其中Ptgs 1，Sphk 1，OPN，Chil 1，Tnfrsf 18，IL 6和Ccl 12基因的表达显著增加，Kit，Ly 96，Ephx 2，CD 163，IL 15和Ccr 2的表达显著降低。随后通过mRNA分析对基因表达的验证促使我们进一步阐明骨桥蛋白（OPN）在甲状腺癌发生中的炎症作用，因为它在单核细胞/巨噬细胞功能和促炎反应中起着关键作用。我们发现，OPN及其受体整合素β1的蛋白丰度高度增加，同时，下游效应物AKT和NF-κB显著升高，从而驱动ThrbPV/PVPten+/-小鼠的甲状腺肿瘤进展。这些结果表明，由免疫相关基因和细胞因子的表达升高驱动的炎症增加促进了甲状腺癌的进展。重要的是，我们发现OPN是甲状腺癌发生过程中炎症反应的一种新型调节因子。这些临床前研究结果表明，OPN可以通过调节炎症信号传导成为甲状腺癌治疗的潜在靶点。
Thyroid cancer is the most common endocrine malignancy. Although an association between inflammation and thyroid cancer has long been recognized, a cause-effect relationship at the molecular level has yet to be elucidated. We explored how inflammation could contribute to thyroid carcinogenesis in ThrbPV/PVPten+/- mice. The ThrbPV/PVPten+/- mouse expresses a dominantly negative thyroid hormone receptor β (denoted as PV) and a deletion of one single allele of the Pten gene. This mutant mouse exhibits aggressive follicular thyroid cancer similarly as in patients. We found significantly increased infiltration of inflammatory monocytes in thyroid tumors of ThrbPV/PVPten+/- mice, while no apparent changes in monocyte homeostasis in the bone marrow and blood of tumor-bearing mice. Using global gene expression profiling, we found altered expression of inflammation mediators in that the expression of Ptgs1, Sphk1, OPN, Chil1, Tnfrsf18, IL6, and Ccl12 genes was significantly increased and expression of Kit, Ly96, Ephx2, CD163, IL15, and Ccr2 was significantly decreased. Subsequent validation of the gene expression by mRNA analysis prompted us to further delineate the inflammatory role of osteopontin (OPN) in thyroid carcinogenesis because of its critical role in monocyte/macrophage functions and proinflammatory responses. We found that the protein abundance of OPN and its receptor, integrin β1, was highly increased and, concurrently, the downstream effectors AKT and NF-κB were significantly elevated to drive thyroid tumor progression of ThrbPV/PVPten+/- mice. These results demonstrated that increased inflammation driven by elevated expression of immune-related genes and cytokines promoted thyroid cancer progression. Importantly, we uncovered OPN as a novel regulator in inflammatory response during thyroid carcinogenesis. These preclinical findings suggested that OPN can be a potential target for thyroid cancer therapy via modulation of inflammatory signaling.