Endogenous YAP1 activation drives immediate onset of cervical carcinoma in situ in mice.
Adaptor Proteins, Signal Transducing
/ metabolism
Animals
Carcinoma
/ metabolism
Carcinoma, Squamous Cell
/ metabolism
Cell Cycle Proteins
/ metabolism
Cell Line
Cell Line, Tumor
Epithelial Cells
/ metabolism
Estrogens
/ metabolism
Humans
Mice
Mice, Knockout
Oncogene Proteins, Viral
/ metabolism
Papillomaviridae
/ metabolism
Papillomavirus E7 Proteins
/ metabolism
Phosphatidylinositol 3-Kinase
/ metabolism
Protein Tyrosine Phosphatases, Non-Receptor
/ metabolism
Repressor Proteins
/ metabolism
Root Caries
/ metabolism
Signal Transduction
/ physiology
Tumor Suppressor Protein p53
/ metabolism
YAP-Signaling Proteins
HPV
Hippo-YAP1 pathway
cervical cancer
oncogenic threshold
p53
Journal
Cancer science
ISSN: 1349-7006
Titre abrégé: Cancer Sci
Pays: England
ID NLM: 101168776
Informations de publication
Date de publication:
Oct 2020
Oct 2020
Historique:
received:
04
05
2020
revised:
15
07
2020
accepted:
17
07
2020
pubmed:
28
7
2020
medline:
16
12
2020
entrez:
28
7
2020
Statut:
ppublish
Résumé
Cervical cancer (CC) is usually initiated by infection with high-risk types of human papillomavirus (HPV). The HPV E6 and E7 proteins target p53 and RB, respectively, but other cellular targets likely exist. We generated uterus-specific MOB1A/B double KO (uMob1DKO) mice, which immediately developed cervical squamous cell carcinoma in situ. Mutant cervical epithelial cells showed YAP1-dependent hyperproliferation, altered self-renewal, impaired contact inhibition, and chromosomal instability. p53 activation was increased in uMob1DKO cells, and additional p53 loss in uMob1DKO mice accelerated tumor invasion. In human CC, strong YAP1 activation was observed from the precancerous stage. Human cells overexpressing HPV16 E6/E7 showed inactivation of not only p53 and RB but also PTPN14, boosting YAP1 activation. Estrogen, cigarette smoke condensate, and PI3K hyperactivation all increased YAP1 activity in human cervical epithelial cells, and PTPN14 depletion along with PI3K activation or estrogen treatment further enhanced YAP1. Thus, immediate CC onset may initiate when YAP1 activity exceeds an oncogenic threshold, making Hippo-YAP1 signaling a major CC driver.
Identifiants
pubmed: 32716083
doi: 10.1111/cas.14581
pmc: PMC7541006
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
Cell Cycle Proteins
0
E6 protein, Human papillomavirus type 16
0
Estrogens
0
Oncogene Proteins, Viral
0
Papillomavirus E7 Proteins
0
Repressor Proteins
0
Tumor Suppressor Protein p53
0
YAP-Signaling Proteins
0
Yap1 protein, mouse
0
oncogene protein E7, Human papillomavirus type 16
0
Phosphatidylinositol 3-Kinase
EC 2.7.1.137
Protein Tyrosine Phosphatases, Non-Receptor
EC 3.1.3.48
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
3576-3587Subventions
Organisme : Japan Agency for Medical Research and Development
ID : JP20cm0106114
Organisme : Cooperative Research Project Program of the MIB, Kyushu University
Organisme : Japan Society for the Promotion of Science
ID : 17H01400
Organisme : Japan Society for the Promotion of Science
ID : 26114005
Organisme : Japan Society for the Promotion of Science
ID : 26640081
Organisme : Nanken-Kyoten, Tokyo Medical and Dental University
Organisme : Kanzawa Medical Research Foundation
Informations de copyright
© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.
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