Deregulation of Wnt/β-catenin signaling through genetic or epigenetic alterations in human neuroendocrine tumors

Kim, Ji Tae; Li, Jing; Jang, Eun Ryoung; Gulhati, Pat; Rychahou, Piotr G.; Napier, Dana; Wang, Chi; Weiss, Heidi L.; Lee, Eun Y.; Anthony, Lowell; Townsend, Courtney M.; Liu, Chunming; Evers, B. Mark

doi:10.1093/carcin/bgt018

Cited by 80 publications

(88 citation statements)

References 45 publications

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“…Therefore, it is urgent to better understand the molecular mechanisms of metastasis in NPC to develop novel target treatment methods for patients with NPC. The Wnt/b-catenin signaling pathway is one of the most important pathways affecting cell biologic processes, which factor 1, and SFRPs may contribute to it (29)(30)(31)(32)). An SFRP family member, SFRP1, can block Wnt/b-catenin signaling by hindering Wnt-receptor interactions via an N-terminal cysteine-rich domain homologous to Frizzled proteins (33).…”

Section: Discussionmentioning

confidence: 99%

Low SFRP1 Expression Correlates with Poor Prognosis and Promotes Cell Invasion by Activating the Wnt/β-Catenin Signaling Pathway in NPC

Ren

Zhou

Jiang

et al. 2015

Cancer Prevention Research

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Distant metastasis remains the predominant mode of treatment failure in nasopharyngeal carcinoma (NPC). Unfortunately, the molecular events underlying NPC metastasis remain poorly understood. Secreted frizzled-related protein 1 (SFRP1) plays an important role in tumorigenesis and progression. However, little is known about the function and mechanism of SFRP1 in NPC. Immunohistochemistry was used to determine SFRP1 expression levels in patients with NPC. SFRP1 function was evaluated using MTT, colony formation, wound-healing, Transwell assays, and in vivo models. The methylation level of SFRP1 in NPC cells was examined using bisulfate pyrosequencing; the Wnt/b-catenin signaling pathway genes were studied using Western blotting. Compared with patients with high SFRP1 expression, patients with low SFRP1 expression had worse overall survival [HR, 2.32; 95% confidence interval (CI), 1.36-3.94; P ¼ 0.002], diseasefree survival (HR, 1.98; 95% CI, 1.23-3.18; P ¼ 0.005), and distant metastasis-free survival (HR, 2.07; 95% CI, 1.19-3.59; P ¼ 0.009). Multivariate Cox regression analysis indicated that SFRP1 was an independent prognostic factor. Furthermore, SFRP1 was significantly downregulated in NPC cell lines. SFRP1 overexpression suppressed NPC cell proliferation, migration, and invasion in vitro and lung colonization in vivo. SFRP1 expression was restored after treatment with a demethylation agent, and the SFRP1 promoter region was hypermethylated in NPC cells. b-Catenin, c-Myc, and cyclin D1 were downregulated after SFRP1 restoration, which suggested that SFRP1 suppressed growth and metastasis by inhibiting the Wnt/b-catenin signaling pathway in NPC. SFRP1 provides further insight into NPC progression and may provide novel therapeutic targets for NPC treatment.

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Section: Discussionmentioning

confidence: 99%

Low SFRP1 Expression Correlates with Poor Prognosis and Promotes Cell Invasion by Activating the Wnt/β-Catenin Signaling Pathway in NPC

Ren

Zhou

Jiang

et al. 2015

Cancer Prevention Research

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“…1A; refs. 20,63,64). Moreover, it is now clear that G9a/H3K9me patterning is associated with 5-methyl cytosine deposition catalyzed by de novo DNA methyltransferases (DNMT3A/B) that were found to play a pivotal role in the development of preleukemic progenitors (24,65).…”

Section: G9a/glp Histone Lysine Methyltransferase Complexes Affect Wnmentioning

confidence: 99%

Molecular Pathways: Epigenetic Modulation of Wnt–Glycogen Synthase Kinase-3 Signaling to Target Human Cancer Stem Cells

Benoit

Guezguez

Boyd

et al. 2014

Clinical Cancer Research

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Aberrant regulation of the canonical Wnt signaling pathway (Wnt-b-catenin-GSK3 axis) has been a prevalent theme in cancer biology since earlier observations until recent genetic discoveries gleaned from tumor genome sequencing. During the last few decades, a large body of work demonstrated the involvement of the Wnt-b-catenin-GSK3 signaling axis in the formation and maintenance of cancer stem cells (CSC) responsible for tumor growth in several types of human malignancies. Recent studies have elucidated epigenetic mechanisms that control pluripotency and stemness, and allow a first assessment on how embryonic and normal tissue stem cells are dysregulated in cancer to give rise to CSCs, and how canonical Wnt signaling might be involved. Here, we review emerging concepts highlighting the critical role of epigenetics in CSC development through abnormal canonical Wnt signaling. Finally, we refer to the characterization of novel and powerful inhibitors of chromatin organization machinery that, in turn, restore the Wnt-b-catenin-GSK3 signaling axis in malignant cells, and describe attempts/relevance to bring these compounds into preclinical and clinical studies.

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“…The loss of APC function stabilizes β-catenin and promotes its nuclear translocation, resulting in cell cycle progression, and enhances the expression of oncogenes [23][24][25]. There are only two reports investigating APC mutation in PanNET; one study examined a clinical sample with no mutation and the other examined two PanNET cell lines with APC mutations [22,26]. However, there are seven reports that examined β-catenin abnormality, and only six (3.1%) of 191 reported cases have either nuclear accumulation of β-catenin or β-catenin mutations [27][28][29][30][31][32][33].…”

Section: Discussionmentioning

confidence: 99%

Alterations in Cancer-related Genes Associated with Grading of Well Differentiated Pancreatic Neuroendocrine Neoplasms

Yokota¹,

Fukasawa²,

Takano³

et al. 2017

Pancreat Disord Ther

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Objectives: Although recent advances in next-generation sequencing (NGS) have revealed some genetic alterations in various tumors, including pancreatic neuroendocrine tumors (PanNETs), their clinical significance is not fully understood. To investigate the clinical significance of gene alteration in PanNETs, we performed genetic analysis of well differentiated PanNETs using NGS.Methods: Twenty-nine resected primary PanNET tissue samples and three samples of metastatic liver tissues, obtained from 29 PanNET patients, were analyzed. DNA was extracted from laser-captured formalin-fixed paraffinembedded tissues, and 50 cancer-associated genes, including approximately 2,800 hotspots, were amplified by multiplex PCR. Amplified libraries were sequenced using NGS, and the results were analyzed in conjunction with respective clinicopathological features. Results:Among 50 investigated genes, somatic mutations were observed in four of 29 PanNET cases. We identified APC mutations in three cases, PTEN in two, and VHL and STK11 in one. The identified mutations were observed only in NET G2 tumors. All liver metastases contained at least one mutation, such as PTEN or TP53, which was not observed in the primary tumor. Conclusion:The cancer-related gene mutations observed in PanNETs were associated with G2 grade tumors. The mutations were more frequent in PanNET liver metastasis than in the primary tumors. Our analysis of liver metastasis cases suggested that cancer-related gene mutations might raise the tumor grade and promote liver metastasis. Further studies of associations between genetic alterations and clinicopathological features should help in the cancer diagnosis and prediction of therapeutic effects of molecular-target drugs.

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Deregulation of Wnt/β-catenin signaling through genetic or epigenetic alterations in human neuroendocrine tumors

Cited by 80 publications

References 45 publications

Low SFRP1 Expression Correlates with Poor Prognosis and Promotes Cell Invasion by Activating the Wnt/β-Catenin Signaling Pathway in NPC

Low SFRP1 Expression Correlates with Poor Prognosis and Promotes Cell Invasion by Activating the Wnt/β-Catenin Signaling Pathway in NPC

Molecular Pathways: Epigenetic Modulation of Wnt–Glycogen Synthase Kinase-3 Signaling to Target Human Cancer Stem Cells

Alterations in Cancer-related Genes Associated with Grading of Well Differentiated Pancreatic Neuroendocrine Neoplasms

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