Dipeptidyl Peptidase-4 Stabilizes Integrin α4β1 Complex to Promote Thyroid Cancer Cell Metastasis by Activating Transforming Growth Factor-Beta Signaling Pathway
Dipeptidyl Peptidase-4 Stabilizes Integrin α4β1 Complex to Promote Thyroid Cancer Cell Metastasis by Activating Transforming Growth Factor-Beta Signaling Pathway
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DOI：
10.1089/thy.2022.0317
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发表时间：
2022-11-01
期刊：
影响因子：
6.6
通讯作者：
Ji, Meiju
中科院分区：
文献类型：
--
作者：
He, Qingyuan;Cao, Hongxin;Ji, Meiju
背景：转移性疾病是甲状腺癌相关死亡的主要原因。然而，甲状腺癌转移的机制尚不清楚。二肽基肽酶-4 （DPP4）是一种多功能的细胞表面糖蛋白，已被报道为甲状腺癌的一个负面预后因素。我们探讨了DPP4在甲状腺癌细胞转移中的分子机制。方法：采用transwell法观察DPP4对甲状腺癌细胞体外迁移/侵袭的影响。建立肺转移小鼠模型，在体内研究DPP4对肿瘤转移的影响。采用DPP4抑制剂西格列汀检测其对甲状腺癌细胞转移的影响。通过一系列分子和生化实验探讨了DPP4促进甲状腺癌细胞转移的机制。结果：我们观察到DPP4在甲状腺乳头状癌中较对照组显著上调，其表达与淋巴结转移和BRAF（V600E）突变呈正相关。功能研究表明，DPP4敲低显著抑制甲状腺癌细胞的转移潜能，反之亦然。而DPP4抑制剂西格列汀不影响甲状腺癌细胞的转移能力，说明DPP4对肿瘤转移的促进作用不依赖于其酶活性。机制上，DPP4与α 4和β 1整合素亚基相互作用，稳定整合素α 4 β 1复合物的形成。dpp4介导的整合素信号激活通过FAK/AKT通路促进c-Jun的核定位，从而诱导转化生长因子- β 1 （TGFB1编码蛋白tgf - β 1）的转录。tgf - β 1通过诱导上皮-间质转化促进肿瘤转移。结论：DPP4通过整合素/FAK/AKT/c-Jun/ tgf - β 1信号轴促进甲状腺癌细胞转移。这些发现可能会对甲状腺癌的替代治疗策略产生影响。
Background: Metastatic disease is a major cause of thyroid cancer-related death. However, the mechanisms responsible for thyroid cancer metastasis are unclear. Dipeptidyl peptidase-4 (DPP4) is a multifunctional cell surface glycoprotein that has been reported to be a negative prognostic factor in thyroid cancer. We explored the molecular mechanism of the role of DPP4 in thyroid cancer cell metastasis.Methods: The effects of DPP4 on thyroid cancer cell migration/invasion in vitro were assessed by transwell assays. A lung metastatic mouse model was also established to determine the effect of DPP4 on tumor metastasis in vivo. DPP4 inhibitor sitagliptin was used to test its effect on thyroid cancer cell metastasis. The mechanism of which DPP4 promotes thyroid cancer cell metastasis was explored by a series of molecular and biochemical experiments.Results: We observed that DPP4 was significantly upregulated in papillary thyroid cancers compared with control subjects, and its expression was positively associated with lymph node metastasis and BRAF(V600E) mutation. Functional studies showed that DPP4 knockdown significantly inhibited metastatic potential of thyroid cancer cells, and vice versa. However, DPP4 inhibitor sitagliptin did not affect the metastatic ability of thyroid cancer cells, indicating that the promoting effect of DPP4 on tumor metastasis was independent of its enzymatic activity. Mechanistically, DPP4 interacted with the alpha 4 and beta 1 integrin subunits, and stabilized the formation of integrin alpha 4 beta 1 complex. DPP4-mediated integrin signal activation promoted the nuclear localization of c-Jun through the FAK/AKT pathway, thereby inducing the transcription of transforming growth factor-beta 1 (TGFB1 coding for protein TGF-beta 1). TGF-beta 1 then facilitated tumor metastasis by inducing the epithelial-mesenchymal transition.Conclusions: DPP4 promotes thyroid cancer cell metastasis through the integrins/FAK/AKT/c-Jun/TGF-beta 1 signaling axis. These findings may have implications for an alternative therapeutic strategy for thyroid cancer.