Pro-invasive Effect of Proto-oncogene PBF Is Modulated by an Interaction with Cortactin.
Pro-invasive Effect of Proto-oncogene PBF Is Modulated by an Interaction with Cortactin.
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原始癌基因PBF的促侵入作用是通过与Cortactin的相互作用调节的。
DOI：
10.1210/jc.2016-1932
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发表时间：
2016-12
期刊：
影响因子：
--
通讯作者：
McCabe CJ
中科院分区：
文献类型：
--
作者：
Watkins RJ;Imruetaicharoenchoke W;Read ML;Sharma N;Poole VL;Gentilin E;Bansal S;Bosseboeuf E;Fletcher R;Nieto HR;Mallick U;Hackshaw A;Mehanna H;Boelaert K;Smith VE;McCabe CJ
转移性疾病是大多数内分泌癌死亡的原因。迫切需要新的治疗靶点来提高患者的生存率。原癌基因PTTG 1结合因子（PBF/PTTG 1 IP）在多种内分泌癌中过表达，并与肿瘤侵袭性密切相关。本研究旨在了解PBF在肿瘤细胞侵袭中的作用，并确定抑制其作用的可能途径。用PBF转染甲状腺、乳腺和结直肠细胞，并培养用于体外分析。在分化型甲状腺癌和癌症基因组图谱RNA-seq数据中测定PBF和coronin（CTTN）表达。通过2D Boyden小室、3D器官型和邻近连接试验评价PBF的促侵袭作用。我们的研究确定PBF和CTTN物理相互作用和共定位，并且这发生在细胞外围，特别是在迁移癌细胞的前沿。关键的是，PBF诱导甲状腺癌和乳腺癌细胞的有效细胞侵袭和迁移，这在CTTN不存在的情况下完全被废除。重要的是，我们发现CTTN在分化型甲状腺癌中过度表达，特别是在区域淋巴结转移的患者中，这与PBF表达升高显著相关。PBF（Y174 A）突变或药物干预调节PBF：CTTN相互作用并减弱癌细胞的侵袭性。我们的研究结果表明PBF在调节CTTN功能以促进内分泌细胞侵袭和迁移方面具有独特的作用，并确定了一种新的靶向相互作用以阻断肿瘤细胞的运动。这项研究确定了原癌基因PBF和coronin之间的一种新的相互作用，为阻断内分泌癌中肿瘤细胞的运动开辟了新的治疗途径。
Metastatic disease is responsible for the majority of endocrine cancer deaths. New therapeutic targets are urgently needed to improve patient survival rates. The proto-oncogene PTTG1-binding factor (PBF/PTTG1IP) is overexpressed in multiple endocrine cancers and circumstantially associated with tumor aggressiveness. This study aimed to understand the role of PBF in tumor cell invasion and identify possible routes to inhibit its action. Thyroid, breast, and colorectal cells were transfected with PBF and cultured for in vitro analysis. PBF and cortactin (CTTN) expression was determined in differentiated thyroid cancer and The Cancer Genome Atlas RNA-seq data. Pro-invasive effects of PBF were evaluated by 2D Boyden chamber, 3D organotypic, and proximity ligation assays. Our study identified that PBF and CTTN physically interact and co-localize, and that this occurs at the cell periphery, particularly at the leading edge of migrating cancer cells. Critically, PBF induces potent cellular invasion and migration in thyroid and breast cancer cells, which is entirely abrogated in the absence of CTTN. Importantly, we found that CTTN is over-expressed in differentiated thyroid cancer, particularly in patients with regional lymph node metastasis, which significantly correlates with elevated PBF expression. Mutation of PBF (Y174A) or pharmacological intervention modulates the PBF: CTTN interaction and attenuates the invasive properties of cancer cells. Our results demonstrate a unique role for PBF in regulating CTTN function to promote endocrine cell invasion and migration, as well as identify a new targetable interaction to block tumor cell movement. This study identifies a novel interaction between proto-oncogene PBF and cortactin which opens up new therapeutic avenues for blocking tumour cell movement in endocrine cancer.
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通讯作者：
McCabe CJ