The comprehensive role of E-cadherin in maintaining prostatic epithelial integrity during oncogenic transformation and tumor progression.
Animals
Antigens, CD
/ genetics
Cadherins
/ genetics
Cell Line, Tumor
Cell Proliferation
Cell Transformation, Neoplastic
/ pathology
Disease Models, Animal
Disease Progression
Epithelial Cells
Epithelium
HEK293 Cells
Humans
Male
Mice
Mice, Transgenic
PTEN Phosphohydrolase
/ genetics
Primary Cell Culture
Prostate
/ cytology
Prostatic Intraepithelial Neoplasia
/ genetics
Prostatic Neoplasms
/ genetics
RNA, Small Interfering
beta Catenin
/ genetics
Journal
PLoS genetics
ISSN: 1553-7404
Titre abrégé: PLoS Genet
Pays: United States
ID NLM: 101239074
Informations de publication
Date de publication:
10 2019
10 2019
Historique:
received:
10
06
2019
accepted:
01
10
2019
entrez:
29
10
2019
pubmed:
29
10
2019
medline:
15
2
2020
Statut:
epublish
Résumé
E-cadherin complexes with the actin cytoskeleton via cytoplasmic catenins and maintains the functional characteristics and integrity of the epithelia in normal epithelial tissues. Lost expression of E-cadherin disrupts this complex resulting in loss of cell polarity, epithelial denudation and increased epithelial permeability in a variety of tissues. Decreased expression of E-cadherin has also been observed in invasive and metastatic human tumors. In this study, we investigated the effect of E-cadherin loss in prostatic epithelium using newly developed genetically engineered mouse models. Deletion of E-cadherin in prostatic luminal epithelial cells with modified probasin promoter driven Cre (PB-Cre4) induced the development of mouse prostatic intraepithelial neoplasia (PIN). An increase in levels of cytoplasmic and nuclear β-catenin appeared in E-cadherin deleted atypical cells within PIN lesions. Using various experimental approaches, we further demonstrated that the knockdown of E-cadherin expression elevated free cytoplasmic and nuclear β-catenin and enhanced androgen-induced transcription and cell growth. Intriguingly, pathological changes representing prostatic epithelial cell denudation and increased apoptosis accompanied the above PIN lesions. The essential role of E-cadherin in maintaining prostatic epithelial integrity and organization was further demonstrated using organoid culture approaches. To directly assess the role of loss of E-cadherin in prostate tumor progression, we generated a new mouse model with bigenic Cdh1 and Pten deletion in prostate epithelium. Early onset, aggressive tumor phenotypes presented in the compound mice. Strikingly, goblet cell metaplasia was observed, intermixed within prostatic tumor lesions of the compound mice. This study provides multiple lines of novel evidence demonstrating a comprehensive role of E-cadherin in maintaining epithelial integrity during the course of prostate oncogenic transformation, tumor initiation and progression.
Identifiants
pubmed: 31658259
doi: 10.1371/journal.pgen.1008451
pii: PGENETICS-D-19-00932
pmc: PMC6816545
doi:
Substances chimiques
Antigens, CD
0
CDH1 protein, human
0
CTNNB1 protein, mouse
0
Cadherins
0
Cdh1 protein, mouse
0
RNA, Small Interfering
0
beta Catenin
0
PTEN Phosphohydrolase
EC 3.1.3.67
Pten protein, mouse
EC 3.1.3.67
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1008451Subventions
Organisme : NCI NIH HHS
ID : R01 CA070297
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA166894
Pays : United States
Organisme : NCI NIH HHS
ID : R21 CA190021
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK104941
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA151623
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA033572
Pays : United States
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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