Decreased Wnt4 expression inhibits thymoma development through downregulation of FoxN1

Chen, Yuan; Liu, Xin; Liu, Yimei; Wang, Yuanguo; Wang, Hai; Lü, Chen; Zhang, Peng

doi:10.21037/jtd.2017.05.28

Cited by 9 publications

(8 citation statements)

References 20 publications

(21 reference statements)

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“…WNT4 plays a pro-carcinogenic role in numerous cancer types. Research has shown that WNT4 is highly expressed in the human breast cancer tissue [90], thymoma tissue [91], and colorectal cancer (CRC) tissue [7]. The WNT4 level was elevated in the serum of CRC patients, and WNT4 expression was increased in the CRC tissue through releasing WNT4-rich exosomes [7].…”

Section: Role Of Wnt4 In Cancersmentioning

confidence: 99%

Roles and action mechanisms of WNT4 in cell differentiation and human diseases: a review

Zhang

Pan

et al. 2021

Cell Death Discov.

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WNT family member 4 (WNT4), which belongs to the conserved WNT protein family, plays an important role in the development and differentiation of many cell types during the embryonic development and adult homeostasis. Increasing evidence has shown that WNT4 is a special ligand that not only activates the β-catenin independent pathway but also acts on β-catenin signaling based on different cellular processes. This article is a summary of the current knowledge about the expression, regulation, and function of WNT4 ligands and their signal pathways in cell differentiation and human disease processes. WNT4 is a promoter in osteogenic differentiation in bone marrow stromal cells (BMSCs) by participating in bone homeostasis regulation in osteoporotic diseases. Non-canonical WNT4 signaling is necessary for metabolic maturation of pancreatic β-cell. WNT4 is also necessary for decidual cell differentiation and decidualization, which plays an important role in preeclampsia. WNT4 promotes neuronal differentiation of neural stem cell and dendritic cell (DC) into conventional type 1 DC (cDC1). Besides, WNT4 mediates myofibroblast differentiation in the skin, kidney, lung, and liver during scarring or fibrosis. On the negative side, WNT4 is highly expressed in cancer tissues, playing a pro-carcinogenic role in many cancer types. This review provides an overview of the progress in elucidating the role of WNT4 signaling pathway components in cell differentiation in adults, which may provide useful clues for the diagnosis, prevention, and therapy of human diseases.

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Section: Role Of Wnt4 In Cancersmentioning

confidence: 99%

Roles and action mechanisms of WNT4 in cell differentiation and human diseases: a review

Zhang

Pan

et al. 2021

Cell Death Discov.

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“…FOXN1 (WHN) regulates the growth of the keratinized epithelial cells and the differentiation of thymic epithelial cells required for T cell development (21, 22). In addition, FOXN1 is regulated by Wnt glycoproteins, important for regulating keratinocyte growth and differentiation of thymic epithelium (23).…”

Section: Foxn Familymentioning

confidence: 99%

Recent Advances in Understanding FOXN3 in Breast Cancer, and Other Malignancies

et al. 2019

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FOXN3 (forkhead box N3; CHES1: check point suppressor 1) belongs to the forkhead box (FOX) protein family. FOXN3 displays transcriptional inhibitory activity, and is involved in cell cycle regulation and tumorigenesis. FOXN3 is a tumor suppresser and alterations in FOXN3 are found in of a variety of cancers including melanoma, osteosarcoma, and hepatocellular carcinoma. While the roles of FOXN3 role in some cancers have been explored, its role in breast cancer remains unclear. Here we describe current state of knowledge of FOXN3 functions, and focus on its roles (known and potential) in breast cancer.

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“…Furthermore, overexpressed WNT4 and FOXN1 (42) and preliminary data from an AB thymoma cell line suggest that increased WNT4 expression plays a role in thymoma development through noncanonical WNT signaling (41). These findings inspired our working hypothesis that interference with thymic senescence could contribute to oncogenesis across the spectrum of thymomas and TCs through the abnormal expression of WNT4 (23,44,45). Furthermore, increased WNT4 levels in TETs did not show any correlation with the age of patients, suggesting physiological senescence signals regulating WNT4 expression in the normal thymus are muted in TETs (Figure 2).…”

Section: Relevance Of Epithelial Wnt4/fzd6 Overexpression and Secreti...mentioning

confidence: 70%

WNT4 overexpression and secretion in thymic epithelial tumors drive an autocrine loop in tumor cells in vitro

et al. 2022

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BackgroundWNT4-driven non-canonical signaling is crucial for homeostasis and age-related involution of the thymus. Abnormal WNT signaling is important in many cancers, but the role of WNT signaling in thymic tumors is largely unknown.Materials & MethodsExpression and function of WNT4 and FZD6 were analyzed using qRT–PCR, Western blot, ELISA, in biopsies of non-neoplastic thymi (NT), thymoma and thymic carcinomas. ShRNA techniques and functional assays were used in primary thymic epithelial cells (pTECs) and TC cell line 1889c. Cells were conventionally (2D) grown and in three-dimensional (3D) spheroids.ResultsIn biopsy, WHO classified B3 thymomas and TCs showed increased WNT4 expression compared with NTs. During short-term 2D culture, WNT4 expression and secretion declined in neoplastic pTECs but not in 3D spheroids or medium supplemented with recombinant WNT4 cultures. Under the latter condition, the growth of pTECs was accompanied by increased expression of non-canonical targets RAC1 and JNK. Down-regulation of WNT4 by shRNA induced cell death in pTECs derived from B3 thymomas and led to decreased RAC1, but not JNK protein phosphorylation. Pharmacological inhibition of NF-κB decreased both RAC1 and JNK phosphorylation in neoplastic pTECs.ConclusionsLack of the age-related decline of non-canonical WNT4 expression in TETs and restoration of declining WNT4 expression through exogeneous WNT4 or 3D culture of pTECs hints at an oncogenic role of WNT4 in TETs and is compatible with the WNT4 autocrine loop model. Crosstalk between WNT4 and NF-κB signaling may present a promising target for combined interventions in TETs.

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Decreased Wnt4 expression inhibits thymoma development through downregulation of FoxN1

Cited by 9 publications

References 20 publications

Roles and action mechanisms of WNT4 in cell differentiation and human diseases: a review

Roles and action mechanisms of WNT4 in cell differentiation and human diseases: a review

Recent Advances in Understanding FOXN3 in Breast Cancer, and Other Malignancies

WNT4 overexpression and secretion in thymic epithelial tumors drive an autocrine loop in tumor cells in vitro

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