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Fibulin-4 is associated with prognosis of endometrial cancer patients and inhibits cancer cell invasion and metastasis via Wnt/β-catenin signaling pathway

Tiantian Wang, Mei Wang, Shuang Fang, Qiang Wang, Rui Fang and Jie Chen _

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Oncotarget. 2017; 8:18991-19012. https://doi.org/10.18632/oncotarget.15086

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Tiantian Wang1, Mei Wang2, Shuang Fang3, Qiang Wang4, Rui Fang5, Jie Chen1

1Department of Maternal and Child Health, School of Public Health, Shandong University, Jinan 250012, China

2Pharmacy Department, Shandong Provincial Hospital affiliated to Shandong University, Jinan 250012, China

3Biochemistry and Molecular Biology, Georgetown University, Georgetown, Washington D.C 20057, USA

4Department of Obstetrics and Gynecology, The Second Hospital affiliated to Jilin University, Jilin 130000, China

5Clinical Medicine, School of Medicine, Shandong University, Jinan 250012, China

Correspondence to:

Jie Chen, email: [email protected]

Keywords: fibulin-4, endometrial cancer, invasion, metastasis, epithelial-mesenchymal transition (EMT)

Received: October 11, 2016     Accepted: January 24, 2017     Published: February 04, 2017


Fibulin-4, an extracellular glycoprotein, which plays significant roles in elastic fiber assembly, is correlated to the progression of some cancers. However, the role of fibulin-4 in endometrial cancer cell invasion and metastasis remains unexplored. In our study, fibulin-4 expression was assessed by immunohistochemistry (IHC) and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) in normal endometrial tissues and endometrial carcinoma tissues. Using single cell cloning, strongly, and weakly, invasive subclones were derived from KLE and Ishikawa endometrial carcinoma cell lines. RT-qPCR, western blotting, and immunocytochemistry (ICC) were used to assess mRNA and protein expressions of fibulin-4 in primary cultured endometrial cells, 4 types of endometrial cancer cell lines, and the different invasive subclones. Using lentivirus transfection, fibulin-4 shRNA and pLVX-fibulin-4 were constructed and used to infect the strongly and weakly invasive subclones. The effects of fibulin-4 on the biological characteristics of endometrial carcinoma cells were detected by cell functional assays in vitro and in vivo. Using Wnt signaling pathway inhibitor XAV-939 and activator LiCl, we detected the role of fibulin-4 in the Wnt/β-catenin pathway and the relationship with epithelial to mesenchymal transition (EMT). Fibulin-4 was decreased in endometrial carcinoma tissues, and loss of fibulin-4 expression was significantly related with poor differentiation, lymph node metastasis, and poor prognosis of endometrial carcinoma. Fibulin-4 significantly inhibited endometrial carcinoma cell proliferation, invasion, metastasis, and EMT through the Wnt/β-catenin pathway. Fibulin-4 has the ability to suppress endometrial cancer progression. These results can contribute to the development of a new potential therapeutic target for patients with endometrial carcinoma.

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