Protein tyrosine phosphatase PTP4A1 promotes proliferation and epithelial-mesenchymal transition in intrahepatic cholangiocarcinoma via the PI3K/AKT pathway.
Protein tyrosine phosphatase PTP4A1 promotes proliferation and epithelial-mesenchymal transition in intrahepatic cholangiocarcinoma via the PI3K/AKT pathway.
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蛋白酪氨酸磷酸酶 PTP4A1 通过 PI3K/AKT 通路促进肝内胆管癌增殖和上皮间质转化
DOI：
10.18632/oncotarget.12116
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发表时间：
2016-11-15
期刊：
影响因子：
--
通讯作者：
Wang XY
中科院分区：
文献类型：
--
作者：
Liu LZ;He YZ;Dong PP;Ma LJ;Wang ZC;Liu XY;Duan M;Yang LX;Shi JY;Zhou J;Fan J;Gao Q;Wang XY
蛋白酪氨酸磷酸酶PTP 4A 1是激活酪氨酸磷酸化的关键分子，酪氨酸磷酸化对癌症进展和转移很重要。然而，PTP 4A 1在肝内胆管细胞癌（ICC）中的临床意义和生物学功能尚不清楚。在这里，我们发现PTP 4A 1在ICC中经常过表达，而不是在邻近的非肿瘤组织中。这种过度表达与侵袭性肿瘤特征如淋巴结转移和晚期肿瘤阶段的存在显著相关。生存分析进一步表明，PTP 4A 1高表达与ICC患者的生存率下降和复发率增加显著独立相关。此外，通过PTPT 4A 1的强制过表达和敲低，我们证明PTP 4A 1在体外可以显着促进ICC细胞增殖、集落形成、迁移和侵袭，并显着促进体内肿瘤进展。PTP 4A 1参与PI 3 K/AKT信号通路及其下游分子如GSK 3 β磷酸化水平和CyclinD 1的上调，促进ICC细胞增殖。重要的是，PTP 4A 1通过上调Zeb 1和Snail激活PI 3 K/AKT信号通路控制的上皮-间质转化（EMT）过程诱导ICC细胞侵袭。因此，PTP 4A 1可能作为一个潜在的癌基因，是一个有价值的预后生物标志物和治疗ICC的目标。
The protein tyrosine phosphatase PTP4A1 is a key molecule that activates tyrosine phosphorylation, which is important for cancer progression and metastasis. However, the clinical implications and biological function of PTP4A1 in intrahepatic cholangiocarcinoma (ICC) remains unknown. Here, we showed that PTP4A1 was frequently overexpressed in ICC versus adjacent non-tumor tissues. This overexpression significantly correlated with aggressive tumor characteristics like the presence of lymph node metastasis and advanced tumor stages. Survival analysis further indicated that high PTP4A1 expression was significantly and independently associated with worse survival and increased recurrence in ICC patients. Moreover, through forced overexpression and knock-down of PTPT4A1, we demonstrated that PTP4A1 could significantly promote ICC cells proliferation, colony formation, migration, and invasion in vitro, and markedly enhance tumor progression in vivo. Mechanistically, PTP4A1 was involved in PI3K/AKT signaling and its downstream molecules, such as phosphorylation level of GSK3β and up-regulation of CyclinD1, in ICC cells to promote proliferation. Importantly, PTP4A1 induced ICC cells invasion was through activating PI3K/AKT signaling controlled epithelial-mesenchymal transition (EMT) process by up-regulating Zeb1 and Snail. Thus, PTP4A1 may serve as a potential oncogene that was a valuable prognostic biomarker and therapeutic target for ICC.