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Targeting the Wnt Signaling in Cancer

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (15 December 2022) | Viewed by 12695

Special Issue Editor

Special Issue Information

Dear Colleagues,

Cancer is a heterogeneous disease that promotes cell growth, disables cell death mechanisms, and evades immune surveillance and therapy. Wnt signalling orchestrates development and tissue homeostasis, and its dysregulation is reported in cancer. Members of the Wnt family of secreted proteins are known to play a significant role in determining the “stemness”, epithelial mesenchymal transition (EMT), acquisition of neuronal characteristics and invasiveness of carcinomas such as brain tumors, melanoma, breast, prostate, liver, pancreatic, and colon cancers.

In this special issue of IJMS, our objective is to explore our understanding of the mechanisms of Wnt signalling and its members both in cancer metastasis and drug resistance. Authors are invited and welcome to submit original research papers, reviews, and short communications.

Dr. Pinar Uysal Onganer
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Keywords

  • Wnt signalling
  • canonical Wnt pathway
  • beta catenin
  • non canonical Wnt pathway
  • invasion
  • cancer
  • metastasis

Published Papers (5 papers)

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Research

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14 pages, 2781 KiB  
Article
Prohibitin Links Cell Cycle, Motility and Invasion in Prostate Cancer Cells
by Sarah Koushyar, Pinar Uysal-Onganer, Wen Guo Jiang and Dafydd Alwyn Dart
Int. J. Mol. Sci. 2023, 24(12), 9919; https://doi.org/10.3390/ijms24129919 - 8 Jun 2023
Cited by 1 | Viewed by 1405
Abstract
Prohibitin (PHB) is a tumour suppressor gene with several different molecular activities. PHB overexpression leads to G1/S-phase cell cycle arrest, and PHB represses the androgen receptor (AR) in prostate cancer cells. PHB interacts with and represses members of the E2F family [...] Read more.
Prohibitin (PHB) is a tumour suppressor gene with several different molecular activities. PHB overexpression leads to G1/S-phase cell cycle arrest, and PHB represses the androgen receptor (AR) in prostate cancer cells. PHB interacts with and represses members of the E2F family in a manner that may also be AR-linked, therefore making the AR:PHB:E2F interaction axis highly complex. PHB siRNA increased the growth and metastatic potential of LNCaP mouse xenografts in vivo. Conversely, PHB ectopic cDNA overexpression affected several hundred genes in LNCaP cells. Furthermore, gene ontology analysis showed that in addition to cell cycle regulation, several members of the WNT family were significantly downregulated (WNT7B, WNT9A and WNT10B), as well as pathways for cell adhesion. Online GEO data studies showed PHB expression to be decreased in clinical cases of metastatic prostate cancer, and to be correlated with higher WNT expression in metastasis. PHB overexpression reduced prostate cancer cell migration and motility in wound-healing assays, reduced cell invasion through a Matrigel layer and reduced cellular attachment. In LNCaP cells, WNT7B, WNT9A and WNT10B expression were also upregulated by androgen treatment and downregulated by androgen antagonism, indicating a role for AR in the control of these WNT genes. However, these WNTs were strongly cell cycle regulated. E2F1 cDNA ectopic expression and PHB siRNA (both cell cycle promoting effects) increased WNT7B, WNT9A and WNT10B expression, and these genes were also upregulated as cells were released from G1 to S phase synchronisation, indicating further cell cycle regulation. Therefore, the repressive effects of PHB may inhibit AR, E2F and WNT expression and its loss may increase metastatic potential in human prostate cancer. Full article
(This article belongs to the Special Issue Targeting the Wnt Signaling in Cancer)
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13 pages, 2260 KiB  
Article
ETC-159, an Upstream Wnt inhibitor, Induces Tumour Necrosis via Modulation of Angiogenesis in Osteosarcoma
by Kenon Chua, Arthur Yi Loong Sim, Eric Yew Meng Yeo, Muhammad Sufyan Bin Masroni, Wah Wah Naw, Sai Mun Leong, Kee Wah Lee, Huey Jin Lim, David M. Virshup and Victor Kwan Min Lee
Int. J. Mol. Sci. 2023, 24(5), 4759; https://doi.org/10.3390/ijms24054759 - 1 Mar 2023
Cited by 2 | Viewed by 2412
Abstract
There is an increasing urgency in the search for new drugs to target high-grade cancers such as osteosarcomas (OS), as these have limited therapeutic options and poor prognostic outlook. Even though key molecular events leading to tumorigenesis are not well understood, it is [...] Read more.
There is an increasing urgency in the search for new drugs to target high-grade cancers such as osteosarcomas (OS), as these have limited therapeutic options and poor prognostic outlook. Even though key molecular events leading to tumorigenesis are not well understood, it is widely agreed that OS tumours are Wnt-driven. ETC-159, a PORCN inhibitor that inhibits the extracellular secretion of Wnt, has recently progressed on to clinical trials. In vitro and in vivo murine and chick chorioallantoic membrane xenograft models were established to examine the effect of ETC-159 on OS. Consistent with our hypothesis, we noted that ETC-159 treatment not only resulted in markedly decreased β-catenin staining in xenografts, but also increased tumour necrosis and a significant reduction in vascularity—a hereby yet undescribed phenotype following ETC-159 treatment. Through further understanding the mechanism of this new window of vulnerability, therapies can be developed to potentiate and maximize the effectiveness of ETC-159, further increasing its clinical utility for the treatment of OS. Full article
(This article belongs to the Special Issue Targeting the Wnt Signaling in Cancer)
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17 pages, 5839 KiB  
Article
RNA-Binding Protein MEX3A Interacting with DVL3 Stabilizes Wnt/β-Catenin Signaling in Endometrial Carcinoma
by Pusheng Yang, Panpan Zhang and Shu Zhang
Int. J. Mol. Sci. 2023, 24(1), 592; https://doi.org/10.3390/ijms24010592 - 29 Dec 2022
Cited by 5 | Viewed by 2225
Abstract
Disease recurrence and metastasis lead to poor prognosis in patients with advanced endometrial carcinoma (EC). RNA-binding proteins (RBPs) are closely associated with tumor initiation and metastasis, but the function and molecular mechanisms of RBPs in EC are unclear. RBPs were screened and identified [...] Read more.
Disease recurrence and metastasis lead to poor prognosis in patients with advanced endometrial carcinoma (EC). RNA-binding proteins (RBPs) are closely associated with tumor initiation and metastasis, but the function and molecular mechanisms of RBPs in EC are unclear. RBPs were screened and identified using the TCGA, GEO, and RBPTD databases. The effect of MEX3A on EC was verified by in vitro and in vivo experiments. Gene set enrichment analysis (GSEA), immunofluorescence (IF), and co-immunoprecipitation (Co-IP) were used to identify potential molecular mechanisms of action. We identified 148 differentially expressed RBPs in EC. MEX3A was upregulated and related to poor prognosis in patients with EC. In vitro and vivo experiments demonstrated that MEX3A promoted the growth, migration, and invasion capacities of EC cells. Mechanistically, DVL3, a positive regulator of the Wnt/β-catenin pathway, also increased the proliferation and metastasis of EC cells. MEX3A enhanced EMT and played a pro-carcinogenic role by interacting with DVL3 to stabilize β-catenin and upregulated the expression of its downstream target genes. MEX3A is upregulated in EC and promotes tumor progression by activating EMT and regulating the Wnt/β-catenin pathway via DVL3. MEX3A may therefore be a novel therapeutic target for EC. Full article
(This article belongs to the Special Issue Targeting the Wnt Signaling in Cancer)
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Review

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26 pages, 1717 KiB  
Review
Wnt Signaling Inhibitors and Their Promising Role in Tumor Treatment
by Nives Pećina-Šlaus, Sara Aničić, Anja Bukovac and Anja Kafka
Int. J. Mol. Sci. 2023, 24(7), 6733; https://doi.org/10.3390/ijms24076733 - 4 Apr 2023
Cited by 7 | Viewed by 2303
Abstract
In a continuous search for the improvement of antitumor therapies, the inhibition of the Wnt signaling pathway has been recognized as a promising target. The altered functioning of the Wnt signaling in human tumors points to the strategy of the inhibition of its [...] Read more.
In a continuous search for the improvement of antitumor therapies, the inhibition of the Wnt signaling pathway has been recognized as a promising target. The altered functioning of the Wnt signaling in human tumors points to the strategy of the inhibition of its activity that would impact the clinical outcomes and survival of patients. Because the Wnt pathway is often mutated or epigenetically altered in tumors, which promotes its activation, inhibitors of Wnt signaling are being intensively investigated. It has been shown that knocking down specific components of the Wnt pathway has inhibitory effects on tumor growth in vivo and in vitro. Thus, similar effects are expected from the application of Wnt inhibitors. In the last decades, molecules acting as inhibitors on the pathway’s specific molecular levels have been identified and characterized. This review will discuss the inhibitors of the canonical Wnt pathway, summarize knowledge on their effectiveness as therapeutics, and debate their side effects. The role of the components frequently mutated in various tumors that are principal targets for Wnt inhibitors is also going to be brought to the reader’s attention. Some of the molecules identified as Wnt pathway inhibitors have reached early stages of clinical trials, and some have only just been discovered. All things considered, inhibition of the Wnt signaling pathway shows potential for the development of future therapies. Full article
(This article belongs to the Special Issue Targeting the Wnt Signaling in Cancer)
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14 pages, 1175 KiB  
Review
Wnt Signaling Pathways: From Inflammation to Non-Melanoma Skin Cancers
by Luca Di Bartolomeo, Federico Vaccaro, Natasha Irrera, Francesco Borgia, Federica Li Pomi, Francesco Squadrito and Mario Vaccaro
Int. J. Mol. Sci. 2023, 24(2), 1575; https://doi.org/10.3390/ijms24021575 - 13 Jan 2023
Cited by 12 | Viewed by 3750
Abstract
Canonical and non-canonical Wnt signaling pathways are involved in cell differentiation and homeostasis, but also in tumorigenesis. In fact, an exaggerated activation of Wnt signaling may promote tumor growth and invasion. We summarize the most intriguing evidence about the role of Wnt signaling [...] Read more.
Canonical and non-canonical Wnt signaling pathways are involved in cell differentiation and homeostasis, but also in tumorigenesis. In fact, an exaggerated activation of Wnt signaling may promote tumor growth and invasion. We summarize the most intriguing evidence about the role of Wnt signaling in cutaneous carcinogenesis, in particular in the pathogenesis of non-melanoma skin cancer (NMSC). Wnt signaling is involved in several ways in the development of skin tumors: it may modulate the inflammatory tumor microenvironment, synergize with Sonic Hedgehog pathway in the onset of basal cell carcinoma, and contribute to the progression from precancerous to malignant lesions and promote the epithelial-mesenchymal transition in squamous cell carcinoma. Targeting Wnt pathways may represent an additional efficient approach in the management of patients with NMSC. Full article
(This article belongs to the Special Issue Targeting the Wnt Signaling in Cancer)
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