The Wnt/JNK signaling target gene <i>alcam</i> is required for embryonic kidney development

Cizelsky, Wiebke; Tata, Aleksandra; Kühl, Michael; Kühl, Susanne J.

doi:10.1242/dev.107938

Cited by 30 publications

(27 citation statements)

References 67 publications

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“…In addition to cytoreductive surgery, cisplatin-based chemotherapy is one of the most important therapeutic strategies for ovarian cancer (2). Previous studies have shown that Wnt signaling pathway deregulation correlates with ovarian cancer cell proliferation, survival, invasion and metastasis (25,26,28,30,31). Furthermore, cisplatin chemoresistance has been an obstacle in the successful treatment of ovarian cancer (8,32,33).…”

Section: Discussionmentioning

confidence: 99%

“…In the non-canonical Wnt/JNK signaling pathway, Wnt-Fzd binding activates a number of small guanosine-5′-triphosphate (GTP) -binding proteins, including c-Jun N-terminal kinase (JNK), which affect a wide range of cellular processes, including cytoskeleton rearrangement, cell polarity, cell migration and gene expression (28). Previous studies have identified that aberrant Wnt/JNK signaling may initiate and stimulate the development of malignant phenotypes through effects on cell proliferation, survival, polarity, invasion and metastasis (Fig.…”

Section: Introductionmentioning

confidence: 99%

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Role of Wnt/β-catenin, Wnt/c-Jun N-terminal kinase and Wnt/Ca2+ pathways in cisplatin-induced chemoresistance in ovarian cancer

Jin

Feng

Zou

et al. 2016

Experimental and Therapeutic Medicine

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The aim of the present study was to explore the expression of Wnt signaling proteins β-catenin, c-Jun N-terminal kinase (JNK) and Ca2+/calmodulin-dependent protein kinase II (CaMKII) in ovarian cancer cells, and assess the correlation between this expression and cisplatin-induced chemoresistance. SKOV3 ovarian carcinoma cells and SKOV3/DDP (cisplatin resistant) cells were treated with cisplatin in the absence or presence of a Wnt signaling activator (CHIR-99021, glycogen synthase kinase 3β inhibitor) or inhibitor (XAV-939, tankyrase inhibitor). Following incubation for 48 h, cell viability, proliferation and cytotoxicity were measured using a sensitive colorimetric cell counting kit. Expression levels of β-catenin, JNK and CaMKII were detected by western blot and immunofluorescence staining. The results of the current study identified that β-catenin and JNK expression levels were significantly higher (P<0.01 and P<0.05 respectively), while CaMKII expression was lower (P>0.05), in SKOV3/DDP cells compared with SKOV3 cells. Moreover, following treatment with 20 µM cisplatin, reduced expression of β-catenin and JNK (P<0.05 and P<0.01 respectively), and increased expression of CaMKII (P<0.01), was observed in SKOV3 and SKOV3/DPP cell lines. Furthermore, inhibition of β-catenin signaling by XAV-939 effectively reversed cisplatin chemoresistance in SKOV3/DDP cells. Similarly, XAV-939 downregulated JNK expression (P<0.001), but upregulated CaMKII expression (P<0.001), in SKOV3/DDP cells. In conclusion, abnormal activation of Wnt/β-catenin and Wnt/JNK signaling pathways in ovarian cancer cells promotes cisplatin resistance, while the Wnt/Ca2+ signaling pathway reduces cisplatin resistance. This indicates that β-catenin, JNK and CaMKII are potential therapeutic targets in chemoresistant ovarian cancers.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Role of Wnt/β-catenin, Wnt/c-Jun N-terminal kinase and Wnt/Ca2+ pathways in cisplatin-induced chemoresistance in ovarian cancer

Jin

Feng

Zou

et al. 2016

Experimental and Therapeutic Medicine

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“…Besides acting via the non-canonical PCP WNT pathway [29], it can signal through the WNT receptor Fzd3 (reviewed in [30][31][32]). Downstream of WNT receptor Fzd3, the cell adhesion molecule Alcam acts via the non-canonical WNT/JNK pathway to affect proximal tubule development [33]. Strikingly, WNT5A, FZD3 and ALCAM were all upregulated in IRX5 −/− cells (Figure 5B,C).…”

Section: Irx3 and Irx5 Knockout Affects Wnt And Hippo Signalling In Dmentioning

confidence: 97%

The Iroquois homeobox proteins IRX3 and IRX5 have distinct roles in Wilms tumour development and human nephrogenesis

Mengelbier

Lindell-Munther

Yasui

et al. 2018

The Journal of Pathology

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Wilms tumour is a paediatric malignancy with features of halted kidney development. Here, we demonstrate that the Iroquois homeobox genes IRX3 and IRX5 are essential for mammalian nephrogenesis and govern the differentiation of Wilms tumour. Knock‐out Irx3 − /Irx5 − mice showed a strongly reduced embryonic nephron formation. In human foetal kidney and Wilms tumour, IRX5 expression was already activated in early proliferative blastema, whereas IRX3 protein levels peaked at tubular differentiation. Accordingly, an orthotopic xenograft mouse model of Wilms tumour showed that IRX3 −/− cells formed bulky renal tumours dominated by immature mesenchyme and active canonical WNT/β‐catenin‐signalling. In contrast, IRX5 −/− cells displayed activation of Hippo and non‐canonical WNT‐signalling and generated small tumours with abundant tubulogenesis. Our findings suggest that promotion of IRX3 signalling or inhibition of IRX5 signalling could be a route towards differentiation therapy for Wilms tumour, in which WNT5A is a candidate molecule for enforced tubular maturation. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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“…Among these, we screened ALCAM (P=3.00E-08), HLA-G (P=3.00E-08), and HLA-E (P=3.00E-08), which are closely related to embryonic development, as candidate genes of RM (Cizelsky & Tata 2014;Gelmini et al 2016;Verloes et al 2017).…”

Section: Pathway Enrichment Analysis Of the Dmrsmentioning

confidence: 99%

Peer Review #1 of "DNA methylation profiling in recurrent miscarriage (v0.1)"

2020

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Recurrent miscarriage (RM) is a complex clinical problem. However, specific diagnostic biomarkers and candidate regulatory targets have not yet been identified. To explore RMrelated biological markers and processes, we performed a genome-wide DNA methylation analysis using the Illumina Infinium HumanMethylation450 array platform. Methylation variable positions and differentially methylated regions (DMRs) were selected using the Limma package in R language. Thereafter, gene ontology (GO) enrichment analysis and pathway enrichment analysis were performed on these DMRs. A total of 1799 DMRs were filtered out between patients with RM and healthy pregnant women. The GO terms were mainly related to system development, plasma membrane part, and sequence-specific DNA binding, while the enriched pathways included cell adhesion molecules, type I diabetes mellitus, and ECM-receptor interactions. In addition, genes, including ABR, ALCAM, HLA-E, HLA-G, and ISG15, were obtained. These genes may be potential candidates for diagnostic biomarkers and possible regulatory targets in RM. We then detected the mRNA expression levels of the candidate genes. The mRNA expression levels of the candidate genes in the RM group were significantly higher than those in the control group. However, additional research is still required to confirm their potential roles in the occurrence of RM.

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The Wnt/JNK signaling target gene alcam is required for embryonic kidney development

Cited by 30 publications

References 67 publications

Role of Wnt/β-catenin, Wnt/c-Jun N-terminal kinase and Wnt/Ca2+ pathways in cisplatin-induced chemoresistance in ovarian cancer

Role of Wnt/β-catenin, Wnt/c-Jun N-terminal kinase and Wnt/Ca2+ pathways in cisplatin-induced chemoresistance in ovarian cancer

The Iroquois homeobox proteins IRX3 and IRX5 have distinct roles in Wilms tumour development and human nephrogenesis

Peer Review #1 of "DNA methylation profiling in recurrent miscarriage (v0.1)"

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