Rewiring of the apoptotic TGF-β-SMAD/NFκB pathway through an oncogenic function of p27 in human papillary thyroid cancer.
作者： A R Garcia-Rendueles , J S Rodrigues , M E R Garcia-Rendueles , M Suarez-Fariña , S Perez-Romero
DOI: 10.1038/ONC.2016.233
关键词:
摘要: Papillary thyroid carcinoma (PTC), the most frequent cancer, is characterized by low proliferation but no apoptosis, presenting lymph-node metastasis. overexpress transforming growth factor-beta (TGF-β). In human cells, TGF-β has two opposing actions: antitumoral through pro-apoptotic and cytostatic activities, pro-tumoral promoting The switch converting from a tumor-suppressor to tumor-promoter not been identified. current study, we have quantified parallel upregulation of nuclear p27, CDK2 inhibitor, in samples PTC. We established primary cultures follicular epithelium homeostatic conditions (h7H medium). TGF-β-dependent cytostasis occurred normal cancer cells p15/CDKN2B induction. However, induced apoptosis benign cultures. TGF-β/SMAD repressed p27/CDKN1B gene, activating CDK2-dependent SMAD3 phosphorylation induce p50 NFκB-dependent BAX apoptosis. oncogene activation prevented TGF-β/SMAD-dependent p27 repression, CDK2/SMAD3 phosphorylation, leading p65 NFκB which BAX, cyclin D1 promoted growth. PTC patients, TGF-β, mRNA were significantly correlated, while expression isoform BAX-β, exclusively transcribed apoptotic was negatively correlated. Additionally, combined ERK inhibitors reduced potentiated affecting survival cells. Our results therefore suggest that oncoprotein reorganizes effects explaining slow lack metastatic behavior
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