Fbxw8 is involved in the proliferation of human choriocarcinoma JEG-3 cells

Abstract

Fbxw8 is the F-box component of a SCF-like E3 ubiquitin ligase complex. Mice lacking Fbxw8 exhibit pathological defects in placenta and embryo similar to fetal growth retardation, suggesting a role of Fbxw8 in placentation. Proliferative capacity of trophoblast cells is very important in placental development. In this context, we revealed that Fbxw8 was expressed in four different human trophoblast cell lines. Silencing of Fbxw8 expression by siRNA inhibited the growth of choriocarcinoma JEG-3 cells. By Western blotting, cell cycle analysis, we showed that down-regulation of Fbxw8 by RNAi induced cell-growth arrest at G2/M phase through decreasing the levels of CDK1, CDK2, cyclin A and cyclin B1 and up-regulation of p27 at protein level. Conversely, over-expression of Fbxw8 led to the opposite effect. These results suggest that Fbxw8 plays an essential role in the proliferation of human trophoblast cells, especially JEG-3 cells, via G2/M phase transition in association with regulation of CDK1, CDK2, cyclin A, cyclin B1 and p27 expression.

Prostate cancer cell proliferation is suppressed by microRNA‑3160‑5p via targeting of F‑box and WD repeat domain containing 8

“…An increasing volume of data has revealed the role of Fbxw8 E3 ligase in cancer (20,21,28,29). Impaired proliferation kinetics was identified in the Fbxw8 -/-mouse embryonic fibroblasts (30).…”

“…It was also revealed that miR-3160-5P inhibited DU145 cell proliferation by targeting Fbxw8. Target-inhibition of Fbxw8 arrested cell cycle progression at the G 2 /M phase in choriocarcinoma JEG3 cells by decreasing the expression level of G 2 /M-associated cell cycle regulators and increasing the expression level of p27 (20,21). The in-depth molecular mechanisms underlying cell cycle arrest induced by miR-3160-5P were investigated further.…”

“…IRS-1 is a critical mediator in insulin and insulin-like growth factor-1 signaling (19). Downregulation of Fbxw8 arrests cell cycle progression at the G 2 /M phase in JEG3 choriocarcinoma cells (20). miRNA-218, which targets Fbxw8, inhibits the proliferation of the human choriocarcinoma JEG-3 cell line (21).…”

Roles of F-box proteins in cancer

“…However, mTOR complex 2 (mTORC2) was recently found to phosphorylate and subsequently stabilize FBXW8, leading to accelerated turnover of insulin receptor substrate 1 (IRS1) 49 . Moreover, it has been reported that FBXW8 negatively regulated cancer cell proliferation through proteolysis of cyclin D1 (REFS 50,51) (see Supplementary information S2 (table)). Nonetheless, tissue-specific knockout mouse models and identification of additional FBXW8 substrates are necessary to determine whether FBXW8 has a crucial role in suppressing tumorigenesis.…”

Deregulation of F-box proteins and its consequence on cancer development, progression and metastasis

“…This is the only example where failure to degrade cyclin D1 was shown to increase its abundance, and was associated with growth inhibition instead of growth stimulation. Suppressed growth following FBXW8 depletion was also seen in the human choriocarcinoma JEG-3 cells, and this was associated with cell cycle arrest in G2/M phase with concurrent upregulation of the p27 protein [268]. Whether cyclin D1 plays a role in this growth suppression remains to be investigated.…”