Wnt signaling in cancer: therapeutic targeting of Wnt signaling beyond β-catenin and the destruction complex

Jung, Youn-Sang; Park, Jae-Il

doi:10.1038/s12276-020-0380-6

Cited by 354 publications

(278 citation statements)

References 148 publications

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“…Therefore, we suggest that development of therapies which target ß-catenin might be highly beneficial for the patients belonging to neuronal subtype bladder cancer. In fact, there are several therapeutics developed and which are in different phases of clinical trials against ß-catenin itself or the components of the ß-catenin destruction complex for the treatment of colorectal cancer 57 , pancreas cancer, and several other solid tumors 58 .…”

Section: Discussionmentioning

confidence: 99%

Analysis of open chromatin regions in bladder cancer links β-catenin mutations and Wnt signaling with neuronal subtype of bladder cancer

Eray¹,

Güneri

Yılmaz³

et al. 2020

Sci Rep

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Urothelial carcinoma of the bladder is the most frequent bladder cancer affecting more than 400,000 people each year. Histopathologically, it is mainly characterized as muscle invasive bladder cancer (MIBC) and non-muscle invasive bladder cancer (NMIBC). Recently, the studies largely driven by consortiums such as TCGA identified the mutational landscape of both MIBC and NMIBC and determined the molecular subtypes of bladder cancer. Because of the exceptionally high rate of mutations in chromatin proteins, bladder cancer is thought to be a disease of chromatin, pointing out to the importance of studying epigenetic deregulation and the regulatory landscape of this cancer. In this study, we have analyzed ATAC-seq data generated for MIBC and integrated our findings with gene expression and DNA methylation data to identify subgroup specific regulatory patterns for MIBC. Our computational analysis revealed three MIBC regulatory clusters, which we named as neuronal, non-neuronal and luminal outlier. We have identified target genes of neuronal regulatory elements to be involved in WNT signaling, while target genes of non-neuronal and luminal outlier regulatory regions were enriched in epithelial differentiation and drug metabolism, respectively. Neuronal regulatory elements were determined to be ß-catenin targets (p value = 3.59e−08) consisting of genes involved in neurogenesis such as FGF9, and PROX1, and significantly enriched for TCF/LEF binding sites (p value = 1e−584). Our results showed upregulation of ß-catenin targets regulated by neuronal regulatory elements in three different cohorts, implicating ß-catenin signature in neuronal bladder cancer. Further, integration with mutation data revealed significantly higher oncogenic exon 3 ß-catenin mutations in neuronal bladder cancer compared to non-neuronal (odds ratio = 31.33, p value = 1.786e−05). Our results for the first time identify regulatory elements characterizing neuronal bladder cancer and links these neuronal regulatory elements with WNT signaling via mutations in β-catenin and its destruction complex components.

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Section: Discussionmentioning

confidence: 99%

Analysis of open chromatin regions in bladder cancer links β-catenin mutations and Wnt signaling with neuronal subtype of bladder cancer

Eray¹,

Güneri

Yılmaz³

et al. 2020

Sci Rep

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“…The incidence of activating mutations in β-catenin in HCC is as higher than p53 alterations [ 159 ]. Usually, aberrantly activated Wnt/β-catenin signaling can result in the abnormal stabilization of positive modulators of Wnt/β-catenin such as β-catenin or loss-of-function mutations in negative modulators of the signaling such as APC and Axin [ 160 , 161 ]. Consistently, loss-of-function mutations of many positive or negative regulators of the signaling such as TP53, AXIN (axis inhibition protein), and CTNNB1/β-catenin were observed in hepatocellular tumors [ 162 , 163 ].…”

Section: Signaling Pathway-based Therapiesmentioning

confidence: 99%

Targeting Liver Cancer Stem Cells: An Alternative Therapeutic Approach for Liver Cancer

Lee

Hong

2020

Cancers

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The first report of cancer stem cell (CSC) from Bruce et al. has demonstrated the relatively rare population of stem-like cells in acute myeloid leukemia (AML). The discovery of leukemic CSCs prompted further identification of CSCs in multiple types of solid tumor. Recently, extensive research has attempted to identity CSCs in multiple types of solid tumors in the brain, colon, head and neck, liver, and lung. Based on these studies, we hypothesize that the initiation and progression of most malignant tumors rely largely on the CSC population. Recent studies indicated that stem cell-related markers or signaling pathways, such as aldehyde dehydrogenase (ALDH), CD133, epithelial cell adhesion molecule (EpCAM), Wnt/β-catenin signaling, and Notch signaling, contribute to the initiation and progression of various liver cancer types. Importantly, CSCs are markedly resistant to conventional therapeutic approaches and current targeted therapeutics. Therefore, it is believed that selectively targeting specific markers and/or signaling pathways of hepatic CSCs is an effective therapeutic strategy for treating chemotherapy-resistant liver cancer. Here, we provide an overview of the current knowledge on the hepatic CSC hypothesis and discuss the specific surface markers and critical signaling pathways involved in the development and maintenance of hepatic CSC subpopulations.

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“…Oncogenic mutations can affect proteins implicated in several signaling pathways, such as Hedgehog (Hh), Wnt and Hippo, which not only are frequently activated in many physiological responses but also in cancer development and invasiveness [14-17]. Wnt pathway cross talks with Hh and Hippo pathways, which has implications for theragnostic targets in cancers [18][19][20]. Several pieces of evidence indicate that association therapeutic approaches combining Wnt inhibitors and chemotherapy might enhance tumor shrinkage in several solid neoplasias, holding promise aimed at immune microenvironment targeting too [21][22][23].…”

Section: Tumorigenesis and Signaling Pathwaysmentioning

confidence: 99%

An Overview of the Oncogenic Signaling Pathways in Different Types of Cancers

Derakhshani¹,

Rostami²,

Taefehshokr³

et al. 2020

Preprint

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Cancer is a leading cause of death worldwide. It is theorized that underlying genetic and epigenetic changes enable cells to proliferate out of control by escaping regulatory mechanisms. The progression of cancer is associated with increased cell proliferation, metabolic modifications, resistance to apoptosis, genetic instability, induction of angiogenesis and augmented migratory capability. Recent developments in DNA and RNA analysis have made it possible to study these genetic changes systematically. These advances have enabled us to possess a deeper knowledge of the signaling pathways and involved processes. In-depth studies of the pathways involved in carcinogenesis have led to the identification of pathways that may be targeted for therapeutic purposes. In this review, we provide an overview of the relevant mechanisms and pathways involved in the development and progression of cancer.

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Wnt signaling in cancer: therapeutic targeting of Wnt signaling beyond β-catenin and the destruction complex

Cited by 354 publications

References 148 publications

Analysis of open chromatin regions in bladder cancer links β-catenin mutations and Wnt signaling with neuronal subtype of bladder cancer

Analysis of open chromatin regions in bladder cancer links β-catenin mutations and Wnt signaling with neuronal subtype of bladder cancer

Targeting Liver Cancer Stem Cells: An Alternative Therapeutic Approach for Liver Cancer

An Overview of the Oncogenic Signaling Pathways in Different Types of Cancers

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