Elevated PTTG and PBF predicts poor patient outcome and modulates DNA damage response genes in thyroid cancer.
Elevated PTTG and PBF predicts poor patient outcome and modulates DNA damage response genes in thyroid cancer.
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DOI：
10.1038/onc.2017.154
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发表时间：
2017-09-14
期刊：
影响因子：
8
通讯作者：
McCabe CJ
中科院分区：
文献类型：
--
作者：
Read ML;Fong JC;Modasia B;Fletcher A;Imruetaicharoenchoke W;Thompson RJ;Nieto H;Reynolds JJ;Bacon A;Mallick U;Hackshaw A;Watkinson JC;Boelaert K;Turnell AS;Smith VE;McCabe CJ
原癌基因PTTG及其结合伴侣PBF已在多种癌症类型中得到广泛研究，特别是甲状腺和结直肠癌，但它们在肿瘤发生中的联合作用尚未确定。在这里，我们第一次表明，PTTG和PBF一起显着调节DNA损伤反应（DDR）基因，包括p53靶基因，需要保持甲状腺细胞基因组的完整性。重要的是，DDR基因在甲状腺特异性PBF和PTTG过表达的双转基因小鼠模型（Bi-Tg）的原代甲状腺细胞中被广泛抑制。与PBF-（P=1.5x10-3）或PTTG-表达甲状腺细胞（P=NS）相比，照射暴露以放大p53水平进一步诱导了Bi-Tg甲状腺细胞（P=2.4x10-4）中DDR基因的显著抑制。与此一致，Bi-Tg甲状腺细胞的遗传不稳定性最大（平均GI指数为35.8±2.6%），以及PBF和PTTG过表达后甲状腺TPC-1细胞中显著诱导的总染色体畸变。我们使用TCGA数据集（n=322）将我们的发现扩展到人类甲状腺癌，并在表征良好的DDR基因组RNA测序数据中发现PBF和PTTG表达与显着相关性。此外，遗传关联和瞬时转染将PBF鉴定为RTK-BRAF信号通路的下游靶点，强调了PBF作为一种新组分在驱动肿瘤生长的通路中的作用。我们还发现，肿瘤PBF/PTTG表达升高和突变激活BRAF的TCGA患者的总生存期（P=1.91x10 - 5）和无病生存期（P=4.9x10-5）较差。总之，我们的研究结果表明，PBF和PTTG在促进甲状腺癌中起着关键作用，可预测患者预后较差。
The proto-oncogene PTTG and its binding partner PBF have been widely studied in multiple cancer types, particularly thyroid and colorectal, but their combined role in tumourigenesis is uncharacterised. Here, we show for the first time that together PTTG and PBF significantly modulate DNA damage response (DDR) genes, including p53 target genes, required to maintain genomic integrity in thyroid cells. Critically, DDR genes were extensively repressed in primary thyrocytes from a bitransgenic murine model (Bi-Tg) of thyroid-specific PBF and PTTG overexpression. Irradiation exposure to amplify p53 levels further induced significant repression of DDR genes in Bi-Tg thyrocytes (P=2.4x10-4) compared to either PBF- (P=1.5x10-3) or PTTG-expressing thyrocytes (P=NS). Consistent with this, genetic instability was greatest in Bi-Tg thyrocytes (mean GI index of 35.8±2.6%), as well as significant induction of gross chromosomal aberrations in thyroidal TPC-1 cells following overexpression of PBF and PTTG. We extended our findings to human thyroid cancer using TCGA datasets (n=322) and found striking correlations with PBF and PTTG expression in well-characterised DDR gene panel RNA-seq data. In addition, genetic associations and transient transfection identified PBF as a downstream target of the RTK-BRAF signalling pathway, emphasising a role for PBF as a novel component in a pathway well-described to drive neoplastic growth. We also showed that overall survival (P=1.91x10-5) and disease-free survival (P=4.9x10-5) was poorer for TCGA patients with elevated tumoural PBF/PTTG expression and mutationally activated BRAF. Together our findings indicate that PBF and PTTG have a critical role in promoting thyroid cancer that is predictive of poorer patient outcome.
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影响因子：
64.5
作者：
Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
影响因子：
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作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
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Kim, D. S.;Franklyn, J. A.;McCabe, C. J.
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