Pituitary adenoma-induced IGF-I triggers increased proliferation and tumorigenic potential of thyroid cells by suppressing KLLN via MET/TP53 axis.

Pituitary adenoma (PA) is a chronic endocrine disease leading to various physiological abnormities. Our previous study has revealed that PA would result in thyroid diseases including goiter and thyroid cancer, which are caused by increased proliferation and tumorigenic potential of thyroid cells. However, the mechanism of PA inducing thyroid diseases remains unclear. Our recent study has indicated that insulin-like growth factor I (IGF-I) might be positively correlated with thyroid diseases in PA patients. Therefore, the primary aim of this study was to investigate the mechanism of PA-induced IGF-I triggering increased proliferation and tumorigenic potential of thyroid cells. In this study, cell proliferation was detected using CCK-8 assay, clone formation ability was identified by clone formation assay, and nude mice xenograft tumor model was established to determine the tumorigenicity of IGF-I-treated thyroid cells in vivo. The current study confirms that IGF-I is positively associated with thyroid diseases in PA patients. Besides, IGF-I is found to promote thyroid cell proliferation and increase tumorigenic potential of thyroid cells by decreasing Killin (KLLN). Moreover, IGF-I declines KLLN by activating MET proto-oncogene, receptor tyrosine kinase (MET) in thyroid cells. Additionally, IGF-I-activated MET reduces KLLN by suppressing KLLN transcription via repressing tumor protein 53 (TP53) in thyroid cells. These findings uncover that the PA-dependent IGF-I/MET/TP53/KLLN signaling axis contributes to increased proliferation and tumorigenic potential of thyroid cells, which should provide potential therapeutic targets for thyroid diseases in PA.