Plasma glutamate carboxypeptidase is a negative regulator in liver cancer metastasis.
Plasma glutamate carboxypeptidase is a negative regulator in liver cancer metastasis.
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DOI：
10.18632/oncotarget.12967
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发表时间：
2016-11-29
期刊：
影响因子：
--
通讯作者：
Kim NS
中科院分区：
文献类型：
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作者：
Lee JH;Cho HS;Lee JJ;Jun SY;Ahn JH;Min JS;Yoon JY;Choi MH;Jeon SJ;Lim JH;Jung CR;Kim DS;Kim HT;Factor VM;Lee YH;Thorgeirsson SS;Kim CH;Kim NS
肿瘤转移是癌症死亡的主要原因。在转移过程中，EMT是一种独特的表型变化，在细胞侵袭和细胞形态变化中起重要作用。尽管具有临床意义，但肿瘤转移的机制仍然知之甚少。在这里，我们报告了一种新的机制，分泌的血浆谷氨酸羧肽酶（PGCP）负性参与Wnt/β-catenin信号通过DKK 4调节肝癌转移。RNA测序数据的通路分析表明，肝癌细胞系中PGCP敲低丰富了细胞迁移、运动和间充质细胞分化的功能。PGCP的消耗通过激活Wnt/β-catenin信号通路组分如磷酸化LRP 6和β-catenin促进细胞迁移和侵袭。此外，添加DKK 4以甲状腺素（T4）依赖性方式拮抗Wnt/β-连环蛋白信号级联反应。在体内研究中，在注射shPGCP稳定细胞系后，在小鼠肺中观察到转移性结节。我们的研究结果表明，PGCP与转移过程中的Wnt/β-catenin信号负相关。靶向这种调节可能代表了一种新的和有效的治疗肝癌的选择，通过防止原发性肿瘤细胞的转移活性。
Tumor metastasis is the leading cause of cancer death. In the metastatic process, EMT is a unique phenotypic change that plays an important role in cell invasion and changes in cell morphology. Despite the clinical significance, the mechanism underlying tumor metastasis is still poorly understood. Here we report a novel mechanism by which secreted plasma glutamate carboxypeptidase(PGCP) negatively involves Wnt/β-catenin signaling by DKK4 regulation in liver cancer metastasis. Pathway analysis of the RNA sequencing data showed that PGCP knockdown in liver cancer cell lines enriched the functions of cell migration, motility and mesenchymal cell differentiation. Depletion of PGCP promoted cell migration and invasion via activation of Wnt/β-catenin signaling pathway components such as phospho-LRP6 and β-catenin. Also, addition of DKK4 antagonized the Wnt/β-catenin signaling cascade in a thyroxine (T4)-dependent manner. In an in vivo study, metastatic nodules were observed in the lungs of the mice after injection of shPGCP stable cell lines. Our findings suggest that PGCP negatively associates with Wnt/β-catenin signaling during metastasis. Targeting this regulation may represent a novel and effective therapeutic option for liver cancer by preventing metastatic activity of primary tumor cells.