Dipeptidyl Peptidase-4 Stabilizes Integrin α4β1 Complex to Promote Thyroid Cancer Cell Metastasis by Activating Transforming Growth Factor-Beta Signaling Pathway

作者：Qingyuan He, Hongxin Cao, Yuelei Zhao, Pu Chen, Na Wang, Wenyuan Li, Rongrong Cui, Peng Hou, Xiaozhi Zhang, Meiju Ji · 发表于：Thyroid · 年份：2022 · DOI：10.1089/thy.2022.0317 · 被引用次数：30 · 研究领域：Peptidase Inhibition and Analysis、Ubiquitin and proteasome pathways、Cancer-related gene regulation

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 α4 and β1 integrin subunits, and stabiliz...