MRP4 sustains Wnt/β-catenin signaling for pregnancy, endometriosis and endometrial cancer

Abstract

Rationale : Abnormal Wnt/β-catenin signaling in the endometrium can lead to both embryo implantation failure and severe pathogenic changes of the endometrium such as endometrial cancer and endometriosis. However, how Wnt/β-catenin signaling is regulated in the endometrium remains elusive. We explored possible regulation of Wnt/β-catenin signaling by multi-drug resistance protein 4 (MRP4), a potential target in cancer chemotherapy, and investigated the mechanism. Methods : Knockdown of MRP4 was performed in human endometrial cells in vitro or in a mouse embryo-implantation model in vivo . Immunoprecipitation, immunoblotting and immunofluorescence were used to assess protein interaction and stability. Wnt/β-catenin signaling was assessed by TOPflash reporter assay and quantitative PCR array. Normal and endometriotic human endometrial tissues were examined. Data from human microarray or RNAseq databases of more than 100 participants with endometriosis, endometrial cancer or IVF were analyzed. In vitro and in vivo tumorigenesis was performed. Results : MRP4-knockdown, but not its transporter-function-inhibition, accelerates β-catenin degradation in human endometrial cells. MRP4 and β-catenin are co-localized and co-immunoprecipitated in mouse and human endometrium. MRP4-knockdown in mouse uterus reduces β-catenin levels, downregulates a series of Wnt/β-catenin target genes and impairs embryo implantation, which are all reversed by blocking β-catenin degradation. Analysis of human endometrial biopsy samples and available databases reveals significant and positive correlations of MRP4 with β-catenin and Wnt/β-catenin target genes in the receptive endometrium in IVF, ectopic endometriotic lesions and endometrial cancers. Knockdown of MRP4 also inhibits in vitro and in vivo endometrial tumorigenesis. Conclusion : A previously undefined role of MRP4 in stabilizing β-catenin to sustain Wnt/β-catenin signaling in endometrial cells is revealed for both embryo implantation and endometrial disorders, suggesting MRP4 as a theranostic target for endometrial diseases associated with Wnt/β-catenin signaling abnormality.

Long non‑coding RNA CCAT2 promotes prostate cancer cell proliferation and invasion by regulating the Wnt/β‑catenin signaling pathway

“…Activation of the Wnt/β-catenin signaling pathway alters receptor-mediated signaling, primarily by inhibiting the degradation of β-catenin in cells, which causes cytoplasmic β-catenin to accumulate and transfer to the nucleus, thereby affecting the transcriptional activity of the target gene ( 26 , 27 ). Alterations to the activity of the Wnt/β-catenin signaling pathway are often associated with inflammatory responses, cell proliferation and differentiation, transcriptional activity and cell membrane structure, which in turn affect the progression of various types of cancer, neuronal diseases, bone diseases and developmental disorders ( 28 – 30 ). An increasing number of studies have reported that abnormal Wnt/β-catenin signaling is associated with the development and progression of a variety of malignancies ( 31 , 32 ).…”

Cyclooxygenase-2 and β-Catenin as Potential Diagnostic and Prognostic Markers in Endometrial Cancer

“…Wnt signaling, a cellular pathway pivotal for embryonic development and tissue homeostasis, was found to be effective in primary axis formation, organogenesis, stem cell proliferation, and cell fate decisions as well (35)(36)(37)(38)(39)(40). Its aberrant activation has been associated with the majority of human malignancies, including EC (41,42). In particular, β-catenin is the primary mediator of the oncogenic effect in this signaling pathway (17,21).…”

Berberine inhibits the proliferation, invasion and migration of endometrial stromal cells by downregulating miR‑429

“…BBR and metformin have been revealed to prevent endometrial cancer cell migration and invasion by inhibiting the expression of lipolysis-stimulated lipoprotein receptor (20). Moreover, there are numerous links between endometrial cancer and EM (21)(22)(23). However, whether BBR exerts a therapeutic effect in EM was not reported in these previous studies.…”