Oridonin represses epithelial-mesenchymal transition and angiogenesis of thyroid cancer via downregulating JAK2/STAT3 signaling

Wei Liu; Xindi Wang; Le Wang; Yu Mei; Yanning Yun; Xiaobao Yao; Qian Chen; Jinsong Zhou; Bo Kou

doi:10.7150/ijms.70733

Oridonin represses epithelial-mesenchymal transition and angiogenesis of thyroid cancer via downregulating JAK2/STAT3 signaling

Int J Med Sci. 2022 May 27;19(6):965-974. doi: 10.7150/ijms.70733. eCollection 2022.

Authors

Wei Liu¹, Xindi Wang², Le Wang¹, Yu Mei¹, Yanning Yun^{3

4}, Xiaobao Yao³, Qian Chen³, Jinsong Zhou^{5

6}, Bo Kou³

Affiliations

¹ Department of Vascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
² Department of Clinical Medicine, Medical School of Xian Jiaotong University, Xi'an, Shaanxi 710061, China.
³ Department of Otorhinolaryngology-Head&Neck Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
⁴ Department of Otorhinolaryngology-Head&Neck Surgery, The First Affiliated Hospital of Xi'an Medical University, Xi'an, Shaanxi 710061, China.
⁵ Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China.
⁶ Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education of China, Xi'an, Shaanxi 710061, China.

Abstract

Oridonin, a bioactive diterpenoid isolated from Rabdosia rubescens, has been reported to exert anticancer activity in various cancers. However, the molecular mechanism of oridonin in thyroid cancer has not yet been elucidated. In the present study, oridonin was found to significantly inhibit migration and invasion of thyroid cancer TPC-1 and BCPAP cells, as evidenced by wound healing assay, transwell migration assay and Matrigel invasion assay. In addition, oridonin could partially impede epithelial-mesenchymal transition by upregulating E-Cadherin expression and downregulating N-Cadherin and vimentin expressions in a concentration-dependent manner. Accumulating evidence indicated that JAK2 (Janus kinase-2)/STAT3 (Signal Transducer and Activator of Transcription 3) signaling pathway was associated with epithelial-mesenchymal transition. As expected, the protein levels of phosphorylated-JAK2 and phosphorylated-STAT3 were dramatically reduced upon oridonin treatment in thyroid cancer TPC-1 and BCPAP cells. Subsequently, the findings revealed that JAK2 overexpression could weaken the anti-metastatic effect and partially attenuate MET (mesenchymal-to-epithelial transition) by oridonin, while AG490, a JAK2 antagonist, enhanced the above process in thyroid cancer cells. The subsequent results showed that oridonin inhibited angiogenesis and VEGFA expression in thyroid cancer cells by tube formation assay, western blot and ELISA assay. Meanwhile, AG490 could further attenuate oridonin-treated VEGFA protein level. In addition, the in vivo results further confirmed that oridonin inhibited tumorigenicity in thyroid cancer xenograft. In conclusion, the results demonstrated that oridonin repressed metastatic phenotype, angiogenesis and modulated EMT (epithelial-mesenchymal transition) of thyroid cancer cells via the inactivation of JAK2/STAT3 signaling pathway, suggesting that JAK2 may be a novel therapeutic target of oridonin against thyroid cancer.

Keywords: EMT; JAK2; STAT3; angiogenesis; oridonin; thyroid cancer.

MeSH terms

Cell Line, Tumor
Cell Movement
Cell Proliferation
Diterpenes, Kaurane
Epithelial-Mesenchymal Transition*
Gene Expression Regulation, Neoplastic
Humans
Janus Kinase 2 / genetics
Neovascularization, Pathologic / drug therapy
Neovascularization, Pathologic / genetics
STAT3 Transcription Factor / metabolism
Signal Transduction
Thyroid Neoplasms* / pathology

Substances

Diterpenes, Kaurane
STAT3 Transcription Factor
STAT3 protein, human
oridonin
JAK2 protein, human
Janus Kinase 2