Altered expression of E-cadherin and β-catenin in malignant transformation of sinonasal inverted papillomas

BACKGROUND: E-cadherin and β-catenin are molecules that mediate cell-cell adhesion in normal epithelium. Aberrant expression of these adhesion molecules results in the loss of intercellular adhesion, with possible cell transformation and tumour progression. We determined the role of E-cadherin and β-catenin in the pathogenesis of sinonasal inverted papilloma (IP) and its malignant transformation. METHODS: We determined the expression of E-cadherin and β-catenin by immunohistochemistry in paraffin-embedded tissue of 21 subjects with nasal polyps, 56 with IPs, 7 IPs with dysplasia and 18 IPs with squamous cell carcinoma (SCC). The clinicopathological variables of the IPs with SCC correlated with the degree of expression of E-cadherin and β-catenin. RESULTS: The degree of expression of E-cadherin and β-catenin in the cell membrane was significantly lower in IPs with SCC than in nasal polyps and IPs. The degree of expression of β-catenin was significantly lower in IPs with SCC with a malignant proportion > 50% compared to a malignant proportion ≤ 50%. However, there was no significant association between the degree of expression of E-cadherin and β-catenin and clinicopathological variables, such as age, gender, T stage, tumour differentiation, or SCC type (metachronous vs. synchronous). In addition, there was no significant relationship between recurrence or survival rate in IPs with SCC and the degree of expression of E-cadherin or β-catenin in the cell membrane or nuclear β-catenin. CONCLUSION: Decreased expression of E-cadherin and β-catenin in the cell membrane may be associated with carcinogenesis of IPs and help predict malignant transformation in sinonasal IPs.

Download Full-text

Expression of Three Cell Adhesion Molecules in Bladder Carcinomas: Correlation with Pathological Features

Analytical Cellular Pathology ◽

10.1155/1997/246136 ◽

1997 ◽

Vol 13 (3) ◽

pp. 125-136 ◽

Cited By ~ 9

Author(s):

Agnès Mialhe ◽

Josette Louis ◽

Dominique Pasquier ◽

Jean‐Jacques Rambeaud ◽

Daniel Seigneurin

Keyword(s):

Cell Adhesion ◽

Adhesion Molecules ◽

Cell Adhesion Molecules ◽

Tumour Progression ◽

Histological Grade ◽

Immunohistochemical Analysis ◽

Aberrant Expression ◽

Bladder Carcinomas ◽

Bladder Tumours ◽

E Cadherin

Recently, independent studies have shown that the expression of two integrin chains,β4 andα2, plus the epithelial cadherin are related to tumour progression in human bladder carcinomas. For the first time, we compare the expression of these three cell adhesion molecules using immunohistochemical analysis of consecutive cryosections from a series of 50 bladder tumours. E‐cadherin,β4, andα2 were strongly expressed in normal urothelium. A majority of non‐invasive bladder cancers stained positively for E‐cadherin (62%), whereas only 29% expressed normal positivity forα2, and only 35% forβ4. However, most invasive tumours presented an aberrant expression ofα2 (81%),β4 (100%), and E‐cadherin (75%). We studied the correlation of immunoreactivity with histological grade and stage. Theα2 pattern was not correlated with stage and grade. In contrast, loss of normalβ4 expression was significantly related to increasing tumour grade and deep invasion with a higher correlation for grade. Finally, E‐cadherin expression was highly correlated with stage, but not with grade. Thus our results indicate that, although many invasive bladder tumours presented a disorder in expression of the two integrinsα2 andβ4, E‐cadherin appeared to be a better marker of invasiveness in bladder carcinomas.

Download Full-text

Proto-Oncogenes β- and γ-Catenin in Leukemogenesis in Severe Congenital Neutropenia (CN).

Blood ◽

10.1182/blood.v106.11.94.94 ◽

2005 ◽

Vol 106 (11) ◽

pp. 94-94

Author(s):

Julia Skokowa ◽

Gunnar Cario ◽

Lan Dan ◽

Cornelia Zeidler ◽

Vesna Bucan ◽

...

Keyword(s):

Malignant Transformation ◽

Target Genes ◽

Nuclear Translocation ◽

Nuclear Accumulation ◽

Healthy Controls ◽

Severe Congenital Neutropenia ◽

Congenital Neutropenia ◽

Altered Expression ◽

E Cadherin ◽

Myeloid Progenitors

Abstract Severe congenital neutropenia (CN) is characterized by a “maturation arrest” of myeloid progenitors at the promyelocytic stage with few or no mature neutrophils in the bone marrow and blood. Administration of granulocyte colony-stimulating factor (G-CSF) increases neutrophil numbers in most CN patients. Approximately 10–15 % of CN patients develop AML or MDS by mechanisms that are as yet unknown. Since AML/MDS are not observed in cyclic (CyN) or idiopathic neutropenia patients treated with G-CSF, an underlying defect of hematopoiesis rather than G-CSF therapy per se predisposes to malignant transformation in CN patients. Recently, activation of Wnt/β-catenin-/γ-catenin-signaling cascade has been considered as important mechanism in the pathogenesis of AML and CML by enhancement of self-renewal activity and by increase of leukemic potential of myeloid progenitors. Moreover, stabilization of β-catenin led to an increased formation of nuclear β-catenin-T-cell factor complexes and altered expression of Wnt-inducible target genes in a variety of human malignancies. In the present study we investigated the role of β-catenin/γ-catenin in leukemogenesis in CN patients. CD33+ progenitors from CN patients expressed 2.5 times higher levels of b-catenin and 4 times higher levels of γ-catenin mRNA and protein, as assessed by quantitative real-time PCR and Western Blot analysis. Most important, in CN patients this increase was paralleled by dramatically elevated levels of activated nuclear β-catenin and intracellular γ-catenin proteins in CD33+ cells, as compared to G-CSF-treated healthy controls and CyN patients. Moreover, mRNA and protein levels of β- and γ-catenins were further increased in CD33+ cells and leukemic blasts from 4 CN patients, who developed AML. In line with high β-/γ-catenins levels, expression of target genes c-jun, fra-1 and PPARD was also up-regulated. There was no correlation between activated Wnt/β-/γ-catenin signaling system and mutations in G-CSF receptor, or ELA2 gene. To investigate the mechanisms of stabilization and increased nuclear translocation of b-catenin, we analyzed the components of b-catenin-degradation multiprotein complex, which contains of Axin, GSK3β, and APC. No differences in expression of Axin, GSK3β and APC as well as in phosphorylation status of GSK3β in CD33+ cells from CN patients and controls were observed. Sequence analysis revealed no mutations in β-catenin gene. Furthermore we analysed the expression of E-cadherin, which forms the transmembrane core of adherent junctions by bridging to β-catenin and therefore modulates its subcellular localization and nuclear translocation. E-cadherin mRNA and protein expression was dramatically downregulated in CD33+ myeloid progenitors from CN patients, in comparison to G-CSF treated healthy controls. Moreover, confocal microscopy revealed very low levels of co-localized E-cadherin and β-catenin in CD33+ cells from CN patients. Therefore, we hypothesize that loss of E-cadherin expression results in nuclear accumulation of β-catenin and activation of its downstream signaling in CN. Taken together, high expression of the proto-oncogenes β- and γ-catenins and nuclear accumulation of β-catenin could contribute to the malignant transformation of myelopoiesis in CN.

Download Full-text

E-cadherin-catenin complex in the rat ovary: cell-specific expression during folliculogenesis and luteal formation

Reproduction ◽

10.1530/reprod/118.2.375 ◽

2000 ◽

pp. 375-385 ◽

Cited By ~ 10

Author(s):

K Sundfeldt ◽

Y Piontkewitz ◽

H Billig ◽

L Hedin

Keyword(s):

Granulosa Cells ◽

Interstitial Cells ◽

Ovary Cell ◽

Beta Catenin ◽

Oestrogen Treatment ◽

Altered Expression ◽

Preantral Follicles ◽

Rat Ovary ◽

E Cadherin ◽

Cell Cell

The cadherins and their cytoplasmic counterparts, the catenins, form the adherens junctions, which are of importance for tissue integrity and barrier functions. The development and maturation of the ovarian follicle is characterized by structural changes, which require altered expression or function of the components involved in cell-cell contacts. The present study examined the cell-specific localization and temporal expression of epithelial cadherin (E-cadherin) and alpha- and beta-catenin during follicular development, ovulation and corpus luteum formation in the immature gonadotrophin- and oestrogen-stimulated rat ovary. Immunohistochemistry and immunoblotting demonstrated the expression of E-cadherin in theca and interstitial cells of immature ovaries before and after injection of equine chorionic gonadotrophin (eCG). E-cadherin was not detected in granulosa cells, except in the preantral follicles located to the inner region of the ovary. The content of E-cadherin in theca and interstitial cells decreased after an ovulatory dose of hCG. Granulosa cells of apoptotic follicles did not express E-cadherin. Oestrogen treatment (diethylstilboestrol) of immature rats for up to 3 days did not result in a measurable expression of E-cadherin in granulosa cells. alpha- and beta-catenin were expressed in all ovarian compartments. The concentration of beta-catenin was constant during the follicular phase, whereas the content of alpha-catenin decreased in granulosa cells after treatment with diethylstilboestrol or hCG. The expression of alpha-catenin was also reduced in theca and interstitial cells after hCG. alpha- and beta-catenin were present in most ovarian cells at all stages of folliculogenesis. Therefore, the catenins have the potential to associate with different members of the cadherin family and to participate in the regulation of cytoskeletal structures and intracellular signalling. The restricted expression of E-cadherin in granulosa cells of preantral follicles indicates a role in the recruitment of these follicles to subsequent cycles. The specific decrease of alpha-catenin in granulosa cells and the reduction of both alpha-catenin and E-cadherin in theca cells of ovulatory follicles might reflect some of the molecular changes in cell-cell adhesion associated with ovulation and luteinization.

Download Full-text

The m6A RNA methylation regulates oncogenic signaling pathways driving cell malignant transformation and carcinogenesis

Molecular Cancer ◽

10.1186/s12943-021-01356-0 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Mohammad Burhan Uddin ◽

Zhishan Wang ◽

Chengfeng Yang

Keyword(s):

Signaling Pathways ◽

Malignant Transformation ◽

Noncoding Rna ◽

Rna Modification ◽

Oncogenic Signaling ◽

Aberrant Expression ◽

Rna Methylation ◽

Rna Molecules ◽

M6a Rna Methylation ◽

Oncogenic Signaling Pathways

AbstractThe m6A RNA methylation is the most prevalent internal modification in mammalian mRNAs which plays critical biological roles by regulating vital cellular processes. Dysregulations of the m6A modification due to aberrant expression of its regulatory proteins are frequently observed in many pathological conditions, particularly in cancer. Normal cells undergo malignant transformation via activation or modulation of different oncogenic signaling pathways through complex mechanisms. Accumulating evidence showing regulation of oncogenic signaling pathways at the epitranscriptomic level has added an extra layer of the complexity. In particular, recent studies demonstrated that, in many types of cancers various oncogenic signaling pathways are modulated by the m6A modification in the target mRNAs as well as noncoding RNA transcripts. m6A modifications in these RNA molecules control their fate and metabolism by regulating their stability, translation or subcellular localizations. In this review we discussed recent exciting studies on oncogenic signaling pathways that are modulated by the m6A RNA modification and/or their regulators in cancer and provided perspectives for further studies. The regulation of oncogenic signaling pathways by the m6A modification and its regulators also render them as potential druggable targets for the treatment of cancer.

Download Full-text

miR-29a sensitizes the response of glioma cells to temozolomide by modulating the P53/MDM2 feedback loop

Cellular & Molecular Biology Letters ◽

10.1186/s11658-021-00266-9 ◽

2021 ◽

Vol 26 (1) ◽

Author(s):

Qiudan Chen ◽

Weifeng Wang ◽

Shuying Chen ◽

Xiaotong Chen ◽

Yong Lin

Keyword(s):

Molecular Mechanism ◽

Feedback Loop ◽

Glioma Cells ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Transcriptional Level ◽

Aberrant Expression ◽

Altered Expression ◽

P53 Signaling

AbstractRecently, pivotal functions of miRNAs in regulating common tumorigenic processes and manipulating signaling pathways in brain tumors have been recognized; notably, miR‐29a is closely associated with p53 signaling, contributing to the development of glioma. However, the molecular mechanism of the interaction between miR-29a and p53 signaling is still to be revealed. Herein, a total of 30 glioma tissues and 10 non-cancerous tissues were used to investigate the expression of miR‐29a. CCK-8 assay and Transwell assay were applied to identify the effects of miR-29a altered expression on the malignant biological behaviors of glioma cells in vitro, including proliferation, apoptosis, migration and invasion. A dual-luciferase reporter assay was used to further validate the regulatory effect of p53 or miR-29a on miR-29a or MDM2, respectively, at the transcriptional level. The results showed that miR-29a expression negatively correlated with tumor grade of human gliomas; at the same time it inhibited cell proliferation, migration, and invasion and promoted apoptosis of glioma cells in vitro. Mechanistically, miR-29a expression was induced by p53, leading to aberrant expression of MDM2 targeted by miR-29a, and finally imbalanced the activity of the p53-miR-29a-MDM2 feedback loop. Moreover, miR-29a regulating p53/MDM2 signaling sensitized the response of glioma cells to temozolomide treatment. Altogether, the study demonstrated a potential molecular mechanism in the tumorigenesis of glioma, while offering a possible target for treating human glioma in the future.

Download Full-text

Evaluation of E-Cadherin and β-Catenin Immunoreactivity for Determining Undifferentiated Cells in Anaplastic Thyroid Carcinoma

Pathobiology ◽

10.1159/000516263 ◽

2021 ◽

pp. 1-8

Author(s):

Risa Kanematsu ◽

Mitsuyoshi Hirokawa ◽

Aki Tanaka ◽

Ayana Suzuki ◽

Miyoko Higuchi ◽

...

Keyword(s):

Cell Membrane ◽

Thyroid Carcinoma ◽

Undifferentiated Carcinoma ◽

Anaplastic Thyroid Carcinoma ◽

Carcinoma Cells ◽

Membrane Expression ◽

Thyroid Carcinomas ◽

Nuclear Expression ◽

Thyroid Transcription Factor 1 ◽

E Cadherin

Introduction: An immunohistochemical study has occasionally been performed to diagnose anaplastic thyroid carcinoma (ATC). However, antibodies to confirm the undifferentiated nature of ATC have not yet been evaluated. The aim of this study was to evaluate E-cadherin and β-catenin expressions in immunoreactivity to determine undifferentiated carcinoma cells in the diagnosis of ATC. Methods: We immunohistochemically examined 29 ATCs, 30 poorly differentiated thyroid carcinomas (PDTCs), 22 well-differentiated thyroid carcinomas (WDTCs), and 3 squamous cell carcinomas. Antibodies for thyroid transcription factor-1 (TTF-1), paired-box gene 8 (PAX8), β-catenin, and E-cadherin were used. Results: All WDTCs tested positive for TTF-1, PAX8, and E-cadherin. The positive rates of TTF-1, PAX8, and E-cadherin were 93.3, 93.3, and 100%, respectively, in PDTCs and 17.2, 51.7, and 10.3%, respectively, in ATCs. WDTC expressed the lateral cell membrane staining for β-catenin and E-cadherin, whereas PDTC showed circumferential cell membranous expression (fishnet pattern). β-catenin cell membrane expression in ATCs is lost or discontinuous. Carcinoma cells with β-catenin nuclear expression without cell membranous expression were scattered in 72.4% of ATCs but were not observed in the other carcinomas. Conclusion: We propose 3 immunohistochemical findings to determine undifferentiated carcinoma cells in the diagnosis of ATC: (1) β-catenin nuclear expression with no or reduced cell membranous expression, (2) the loss or discontinuous pattern of E-cadherin expression, and (3) the loss of PAX8 nuclear expression.

Download Full-text

Alcohol use disorder causes global changes in splicing in the human brain

Translational Psychiatry ◽

10.1038/s41398-020-01163-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Derek Van Booven ◽

Mengying Li ◽

J. Sunil Rao ◽

Ilya O. Blokhin ◽

R. Dayne Mayfield ◽

...

Keyword(s):

Alcohol Use ◽

Human Brain ◽

Alcohol Use Disorder ◽

Brain Regions ◽

Gene Set Enrichment Analysis ◽

Splicing Factor ◽

Central Nucleus ◽

Global Changes ◽

Aberrant Expression ◽

Altered Expression

AbstractAlcohol use disorder (AUD) is a widespread disease leading to the deterioration of cognitive and other functions. Mechanisms by which alcohol affects the brain are not fully elucidated. Splicing constitutes a nuclear process of RNA maturation, which results in the formation of the transcriptome. We tested the hypothesis as to whether AUD impairs splicing in the superior frontal cortex (SFC), nucleus accumbens (NA), basolateral amygdala (BLA), and central nucleus of the amygdala (CNA). To evaluate splicing, bam files from STAR alignments were indexed with samtools for use by rMATS software. Computational analysis of affected pathways was performed using Gene Ontology Consortium, Gene Set Enrichment Analysis, and LncRNA Ontology databases. Surprisingly, AUD was associated with limited changes in the transcriptome: expression of 23 genes was altered in SFC, 14 in NA, 102 in BLA, and 57 in CNA. However, strikingly, mis-splicing in AUD was profound: 1421 mis-splicing events were detected in SFC, 394 in NA, 1317 in BLA, and 469 in CNA. To determine the mechanism of mis-splicing, we analyzed the elements of the spliceosome: small nuclear RNAs (snRNAs) and splicing factors. While snRNAs were not affected by alcohol, expression of splicing factor heat shock protein family A (Hsp70) member 6 (HSPA6) was drastically increased in SFC, BLA, and CNA. Also, AUD was accompanied by aberrant expression of long noncoding RNAs (lncRNAs) related to splicing. In summary, alcohol is associated with genome-wide changes in splicing in multiple human brain regions, likely due to dysregulation of splicing factor(s) and/or altered expression of splicing-related lncRNAs.

Download Full-text