E-cadherin: Its dysregulation in carcinogenesis and clinical implications

Wong, Sonia How Ming; Fang, Chee‐Mun; Chuah, Lay Hong; Leong, Chee Onn; Ngai, Siew Ching

doi:10.1016/j.critrevonc.2017.11.010

Cited by 329 publications

(259 citation statements)

References 164 publications

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“…54,55 Conversely, strong anti-metastatic roles of E-cadherin were reported in multiple types of cancer, while patients carrying CDH1 mutations or loss of E-cadherin expression displayed poor survival than non-mutated patients. 56,57 Membrane β-catenin links E-cadherin to the cytoskeleton as an integral structural of adherence junctions, while activation of Wnt signaling breaks the anchorage and promotes the accumulation of β-catenin in nucleus, thus activating a series of signaling cascades and eliciting EMT. 43,58 PI3K-Akt signaling also induces E-cadherin downregulation via mTOR or MAPK cascade.…”

Section: Discussionmentioning

confidence: 99%

Reduced m6A modification predicts malignant phenotypes and augmented Wnt/PI3K‐Akt signaling in gastric cancer

et al. 2019

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Background As the most abundant epigenetic modification on mRNAs and long non‐coding RNAs, N6‐methyladenosine (m6A) modification extensively exists in mammalian cells. Controlled by writers (methyltransferases), readers (signal transducers), and erasers (demethylases), m6A influences mRNA structure, maturation, and stability, thus negatively regulating protein expression in a post‐translational manner. Nevertheless, current understanding of m6A's roles in tumorigenesis, especially in gastric cancer (GC) remains to be unveiled. In this study, we assessed m6A's clinicopathological relevance to GC and explored the underlying mechanisms. Methods By referring to a proteomics‐based GC cohort we previously generated and the TCGA‐GC cohort, we merged expressions of canonical m6A writers (METTL3/METTL14), readers (YTHDF1/YTHDF2/YTHDF3), and erasers (ALKBH5/FTO), respectively, as W, R, and E signatures to represent m6A modification. We stratified patients according to these signatures to decipher m6A's associations with crucial mutations, prognosis, and clinical indexes. m6A's biological functions in GC were predicted by gene set enrichment analysis (GSEA) and validated by in vitro experiments. Results We discovered that W and R were potential tumor suppressive signatures, while E was a potential oncogenic signature in GC. According to W/R/E stratifications, patients with low m6A‐indications were accompanied with higher mutations of specific genes ( CDH1 , AR , GLI3 , SETBP1 , RHOA , MUC6 , and TP53 ) and also demonstrated adverse clinical outcomes. GSEA suggested that reduced m6A was correlated with oncogenic signaling and phenotypes. Through in vitro experiments, we proved that m6A suppression (represented by METTL14 knockdown) promoted GC cell proliferation and invasiveness through activating Wnt and PI3K‐Akt signaling, while m6A elevation (represented by FTO knockdown) reversed these phenotypical and molecular changes. m6A may also be involved in interferon signaling and immune responses of GC. Conclusions Our work demonstrated that low‐m6A signatures predicted adverse clinicopathological features of GC, while the reduction of RNA m6A methylation activated oncogenic Wnt/PI3K‐Akt signaling and promoted malignant phenotypes of GC cells.

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Section: Discussionmentioning

confidence: 99%

Reduced m6A modification predicts malignant phenotypes and augmented Wnt/PI3K‐Akt signaling in gastric cancer

et al. 2019

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“…33, 34 It is important to note, however, that it remains uncertain if loss of CDH1 drives EMT or if dysregulation of CDH1 is a result of EMT. 43 …”

Section: Discussionmentioning

confidence: 99%

Functional characterization of recurrent FOXA2 mutations seen in endometrial cancers

Neff

Rush

Smith

et al. 2018

Intl Journal of Cancer

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FOXA2, a member of the forkhead family of DNA-binding proteins, is frequently mutated in uterine cancers. Most of the mutations observed in uterine cancers are frameshifts and stops. FOXA2 is considered to be a driver gene in uterine cancers, functioning as a haploinsufficient tumor suppressor. The functional consequences of FOXA2 mutations, however, have not yet been determined. We evaluated the effects that frameshift mutations and a recurrent missense mutation have on FOXA2 transcriptional activity. Recurrent N-terminal frameshifts resulted in truncated proteins that failed to translocate to the nucleus and have no transcriptional activity using an E-cadherin/luciferase reporter assay. Protein abundance was reduced for the recurrent p.S169 W mutation, as was transcriptional activity. A C-terminal frameshift mutation had increased FOXA2 levels evidenced by both Western blot and immunofluorescence. Given that FOXA2 is a recognized activator of E-cadherin (CDH1) expression and E-cadherin's potential role in epithelial-to-mesenchymal transition in a wide range of cancer types, we tested the hypothesis that FOXA2 mutations in primary uterine cancer specimens would be associated with reduced CDH1 transcript levels. qRT-PCR revealed significantly lower levels of CDH1 expression in primary tumors with FOXA2 mutations. Our findings in vitro and in vivo suggest that reduced transcriptional activity associated with FOXA2 mutations in uterine cancers is likely to contribute to protumorigenic changes in gene expression.

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“…Epithelial-mesenchymal transition (EMT) is the process of acquisition of the mesenchymal properties by epithelial cells involved in metastasis, invasion, and progression of various cancers (Figure 1) [51]. As a physiological process, EMT is observed during organogenesis, tissue development, remodeling, and wound healing [52][53][54]; contrarily, any deregulations might induce carcinogenesis [55,56]. EMT-induced carcinogenesis is the prevalent cause of various malignancies including head and neck squamous cell carcinoma, papillary thyroid carcinoma, lung, pancreatic, gastric, ovarian, prostate, and breast cancer [57][58][59][60][61][62][63][64][65][66][67][68].…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of the Epithelial–Mesenchymal Transition and Tumor Microenvironment in Helicobacter pylori-Induced Gastric Cancer

Baj

Korona-Głowniak

Forma

et al. 2020

Cells

124

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Helicobacter pylori (H. pylori) is one of the most common human pathogens, affecting half of the world's population. Approximately 20% of the infected patients develop gastric ulcers or neoplastic changes in the gastric stroma. An infection also leads to the progression of epithelial-mesenchymal transition within gastric tissue, increasing the probability of gastric cancer development. This paper aims to review the role of H. pylori and its virulence factors in epithelial-mesenchymal transition associated with malignant transformation within the gastric stroma. The reviewed factors included: CagA (cytotoxin-associated gene A) along with induction of cancer stem-cell properties and interaction with YAP (Yes-associated protein pathway), tumor necrosis factor α-inducing protein, Lpp20 lipoprotein, Afadin protein, penicillin-binding protein 1A, microRNA-29a-3p, programmed cell death protein 4, lysosomal-associated protein transmembrane 4β, cancer-associated fibroblasts, heparin-binding epidermal growth factor (HB-EGF), matrix metalloproteinase-7 (MMP-7), and cancer stem cells (CSCs). The review summarizes the most recent findings, providing insight into potential molecular targets and new treatment strategies for gastric cancer.

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E-cadherin: Its dysregulation in carcinogenesis and clinical implications

Cited by 329 publications

References 164 publications

Reduced m6A modification predicts malignant phenotypes and augmented Wnt/PI3K‐Akt signaling in gastric cancer

Reduced m6A modification predicts malignant phenotypes and augmented Wnt/PI3K‐Akt signaling in gastric cancer

Functional characterization of recurrent FOXA2 mutations seen in endometrial cancers

Mechanisms of the Epithelial–Mesenchymal Transition and Tumor Microenvironment in Helicobacter pylori-Induced Gastric Cancer

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