Fibulin-4 is associated with prognosis of endometrial cancer patients and inhibits cancer cell invasion and metastasis via Wnt/β-catenin signaling pathway.
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.
Department of Maternal and Child Health, School of Public Health, Shandong University, Jinan 250012, China.
Tiantian
T
Wang
Pharmacy Department, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250012, China.
Mei
M
Wang
Department of Biochemistry and Molecular Biology, Georgetown University, Georgetown, Washington DC 20057, USA.
Shuang
S
Fang
Department of Obstetrics and Gynecology, The Second Hospital Affiliated to Jilin University, Jilin 130000, China.
Qiang
Q
Wang
Clinical Medicine, School of Medicine, Shandong University, Jinan 250012, China.
Rui
R
Fang
Department of Maternal and Child Health, School of Public Health, Shandong University, Jinan 250012, China.
Jie
J
Chen
D000818:Animals; D015153:Blotting, Western; D002277:Carcinoma / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D018572:Disease-Free Survival; D016889:Endometrial Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005260:Female; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000473:pathology; D016133:Polymerase Chain Reaction; D011379:Prognosis; D060449:Wnt Signaling Pathway / Q000502:physiology*
C403672:EFEMP2 protein, human; D016326:Extracellular Matrix Proteins
endometrial cancer; epithelial-mesenchymal transition (EMT); fibulin-4; invasion; metastasis