Abstract
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.
Highlights
Endometrial carcinoma is the second most common malignant tumor occurring in the female genital tract [1]
We initially detected that low expression of fibulin-4 was associated with poor clinical pathological characteristics of endometrial cancer, and fibulin-4 could inhibit endometrial cancer cell proliferation, invasion and metastasis by preventing epithelial to mesenchymal transition (EMT) via the Wnt/β-catenin pathway
By RT-qPCR, western blot, and IHC or ICC, we found that the expression of fibulin-4 in normal endometrial tissues and cells was much higher than that in endometrial cancer tissues and cells
Summary
Endometrial carcinoma is the second most common malignant tumor occurring in the female genital tract [1]. Many biomarkers that are related with the development of endometrial carcinoma have been evaluated; no information has been www.impactjournals.com/oncotarget found regarding the function of fibulin-4 in endometrial cancer cell invasion and metastasis. Fibulin family members have been observed to participate in modulating cell morphology, growth, adhesion, and motility, which is intimately related to the occurrence and development of various kinds of cancers [8]. The role of fibulin-4 in endometrial cancer cell growth and metastasis remains unexplored. This is the first study to clarify the effects of fibulin-4 on the progression of endometrial cancer and the function of fibulin-4 in endometrial cancer cell proliferation, invasion, and metastasis
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