PTTG and PBF Functionally Interact with p53 and Predict Overall Survival in Head and Neck Cancer.
PTTG and PBF Functionally Interact with p53 and Predict Overall Survival in Head and Neck Cancer.
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DOI：
10.1158/0008-5472.can-18-0855
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发表时间：
2018-10-15
期刊：
影响因子：
11.2
通讯作者：
McCabe CJ
中科院分区：
文献类型：
--
作者：
Read ML;Modasia B;Fletcher A;Thompson RJ;Brookes K;Rae PC;Nieto HR;Poole VL;Roberts S;Campbell MJ;Boelaert K;Turnell AS;Smith VE;Mehanna H;McCabe CJ
头颈部鳞状细胞癌（HNSCC）是全球第六大常见癌症，由于其发病率不断上升，造成了重大的健康负担。虽然原癌基因垂体肿瘤转化基因1（PTTG）预测患者预后差，但其作用机制尚不完全清楚。我们在这里表明，蛋白PBF调节PTTG功能，在HNSCC肿瘤中过表达，并与生存率显着降低相关。慢病毒shRNA减弱野生型或突变型p53的HNSCC细胞中PTTG或PBF的表达，以及有和没有HPV感染，导致参与DNA修复和凋亡的p53靶基因的表达失调。从机制上讲，PTTG和PBF影响彼此与p53的相互作用，并合作降低HNSCC细胞中p53蛋白的稳定性，而不依赖于HPV。PTTG或PBF的耗竭显著抑制了HNSCC细胞的细胞迁移和侵袭，并损害了集落形成，这两种原癌基因都参与了肿瘤发生的基本机制。具有高肿瘤PBF和PTTG的HNSCC患者的总体生存率最差，这反映了p53依赖性信号传导的显著受损。
Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer worldwide and poses a significant health burden due to its rising incidence. Although the proto-oncogene pituitary tumor transforming gene 1 (PTTG) predicts poor patient outcome, its mechanisms of action are incompletely understood. We show here that the protein PBF modulates PTTG function, is overexpressed in HNSCC tumors, and correlates with significantly reduced survival. Lentiviral shRNA attenuation of PTTG or PBF expression in HNSCC cells with either wild type or mutant p53, and with and without HPV infection, led to dysregulated expression of p53 target genes involved in DNA repair and apoptosis. Mechanistically, PTTG and PBF affected each other's interaction with p53 and cooperated to reduce p53 protein stability in HNSCC cells independently of HPV. Depletion of either PTTG or PBF significantly repressed cellular migration and invasion and impaired colony formation in HNSCC cells, implicating both proto-oncogenes in basic mechanisms of tumorigenesis. HNSCC patients with high tumoral PBF and PTTG had the poorest overall survival, which reflects a marked impairment of p53-dependent signalling.