Abstract. The angiopoietin 1 (Ang1)/angiopoietin receptor (Tie2) signaling pathway may have a notable role in the pathogenesis of inflammatory diseases. The abnormal expression of angiopoietin 1 and Tie2 has also been reported in various malignant tumors, including papillary thyroid carcinoma (PTC). However, the role and mechanism of the Ang1/Tie2 pathway in the progression of PTC remains unclear. Therefore, the aims of the present study were to clarify this. Significantly high expression levels of Ang1 and Tie2 were observed in PTC tissues and cell lines. Furthermore, MTT and wound-healing assays revealed that the Ang1-mediated stimulation of human PTC cells resulted in increased proliferation and migration. Conversely, the downregulation of Tie2 levels using short hairpin RNA targeted at Tie2 abrogated the Ang1-mediated effect on cell proliferation and migration. In studying the expression of phosphoinositide-3 kinase (PI3K)/RAC serine/threonine-protein kinase (Akt) pathway, the upregulation of Ang1/Tie2 was found to be associated with the activation of the PI3K/Akt pathway in PTC. In conclusion, the data from the present study indicated that the Ang1/Tie2 induces PTC oncogenesis via the PI3K/Akt pathway, providing novel insights into human PTC therapy.
IntroductionPapillary thyroid carcinoma (PTC) is the most prevalent histological thyroid carcinoma subtype, accounting for ~80% of cases (1,2). Although recent advances in diagnosis and treatment strategies have been made in clinical and experimental oncology, ≤30% of patients present with local/regional recurrence or distant metastasis within 10 years (2,3). Thus, the elucidation of the molecular mechanisms underlying PTC progression is urgently required in order to develop effective diagnostic, prognostic and therapeutic strategies.Receptor tyrosine kinases are cell surface proteins that transduce signals from extracellular growth factors intracellularly, to elicit biological responses (4). Receptor tyrosine kinases act as potent oncoproteins and are abnormally expressed in a number of cancer types, including gliomas (5). Angiopoietin-1 (Ang1) receptor (TEK, also known as Tie2) is a receptor tyrosine kinase that was identified as an endothelial-cell-specific receptor with a critical role in the modulation of vasculogenesis and remodeling (6). Tie2 expression occurs, and is partially maintained, during differentiation in human neural stem cells (7), but not in mature neurons (8). Dysregulated Tie2 expression has also been observed in several tumor tissues, including oral squamous cell carcinoma, breast, gastric, leukemia and thyroid cancer (9-13). These studies revealed that Tie2 expression is associated with the identification and prognosis of these cancer types (12). Ang1 is a secreted ligand for Tie2 that maintains vascular plasticity, perturbations in which can contribute to abnormal vascular growth (4). Daly et al (6) revealed that Ang2 functions as a Tie2 agonist in tumor models, limiting the effects of VEGF inhibition (6). Mitsutake et al (13) revealed ...