The comprehensive role of E-cadherin in maintaining prostatic epithelial integrity during oncogenic transformation and tumor progression

English version

Autoři: Adam Olson ^aff001; Vien Le ^aff001; Joseph Aldahl ^aff001; Eun-Jeong Yu ^aff001; Erika Hooker ^aff001; Yongfeng He ^aff001; Dong-Hong Lee ^aff001; Won Kyung Kim ^aff001; Robert D. Cardiff ^aff002; Joseph Geradts ^aff003; Zijie Sun ^aff001
Působiště autorů: Department of Cancer Biology, Beckman Research Institute, City of Hope, Duarte, California, United States of America ^aff001; Center for Comparative Medicine, University of California at Davis, Davis, California, United States of America ^aff002; Department of Population Sciences, Beckman Research Institute, City of Hope, Duarte, California, United States of America ^aff003
Vyšlo v časopise: The comprehensive role of E-cadherin in maintaining prostatic epithelial integrity during oncogenic transformation and tumor progression. PLoS Genet 15(10): e32767. doi:10.1371/journal.pgen.1008451
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1008451

Souhrn

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.

Klíčová slova:

Apoptosis – Carcinogenesis – Cell staining – Epithelial cells – Mouse models – Organoids – Prostate cancer – Prostate gland

Zdroje

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