Protein tyrosine phosphatase PTP4A1 promotes proliferation and epithelial-mesenchymal transition in intrahepatic cholangiocarcinoma via the PI3K/AKT pathway
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Long-Zi Liu1,*, Yi-Zhou He2,*, Ping-Ping Dong3,*, Li-Jie Ma1, Zhi-Chao Wang1, Xin-Yang Liu4, Meng Duan1, Liu-Xiao Yang1, Jie-Yi Shi1, Jian Zhou1, Jia Fan1, Qiang Gao1, Xiao-Ying Wang1
1Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, P. R. China
2Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R, China
3Department of Gastroenterology and Hepatology, Zhongshan Hospital, Shanghai Institute of Liver Disease, Fudan University, Shanghai 200032, P. R. China
4Department of Medical Oncology, Fudan University Shanghai Cancer Center, and Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P. R. China
*These authors have contributed equally to this work
Qiang Gao, email: firstname.lastname@example.org
Xiao-Ying Wang, email: email@example.com
Keywords: PTP4A1, intrahepatic cholangiocarcinoma, prognosis, oncogene, epithelial-mesenchymal transition
Received: February 19, 2016 Accepted: September 02, 2016 Published: September 19, 2016
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.
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