PMID- 33947962
OWN - NLM
STAT- MEDLINE
DCOM- 20220121
LR  - 20230201
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 40
IP  - 21
DP  - 2021 May
TI  - WAPL induces cervical intraepithelial neoplasia modulated with estrogen signaling 
      without HPV E6/E7.
PG  - 3695-3706
LID - 10.1038/s41388-021-01787-5 [doi]
AB  - Since cervical cancer still afflicts women around the world, it is necessary to 
      understand the underlying mechanism of cervical cancer development. Infection 
      with HPV is essential for the development of cervical intraepithelial neoplasia 
      (CIN). In addition, estrogen receptor signaling is implicated in the development 
      of cervical cancer. Previously, we have isolated human wings apart-like (WAPL), 
      which is expected to cause chromosomal instability in the process of HPV-infected 
      precancerous lesions to cervical cancer. However, the role of WAPL in the 
      development of CIN is still unknown. In this study, in order to elucidate the 
      role of WAPL in the early lesion, we established WAPL overexpressing mice (WAPL 
      Tg mice) and HPV E6/E7 knock-in (KI) mice. WAPL Tg mice developed CIN lesion 
      without HPV E6/E7. Interestingly, in WAPL Tg mice estrogen receptor 1 (ESR1) 
      showed reduction as compared with the wild type, but cell growth factors MYC and 
      Cyclin D1 controlled by ESR1 expressed at high levels. These results suggested 
      that WAPL facilitates sensitivity of ESR1 mediated by some kind of molecule, and 
      as a result, affects the expression of MYC and Cyclin D1 in cervical cancer 
      cells. To detect such molecules, we performed microarray analysis of the uterine 
      cervix in WAPL Tg mice, and focused MACROD1, a co-activator of ESR1. MACROD1 
      expression was increased in WAPL Tg mice compared with the wild type. In 
      addition, knockdown of WAPL induced the downregulation of MACROD1, MYC, and 
      Cyclin D1 but not ESR1 expression. Furthermore, ESR1 sensitivity assay showed 
      lower activity in WAPL or MACROD1 downregulated cells than control cells. These 
      data suggested that WAPL increases ESR1 sensitivity by activating MACROD1, and 
      induces the expression of MYC and Cyclin D1. Therefore, we concluded that WAPL 
      not only induces chromosomal instability in cervical cancer tumorigenesis, but 
      also plays a key role in activating estrogen receptor signaling in early 
      tumorigenesis.
FAU - Kumagai, Katsuyoshi
AU  - Kumagai K
AD  - Pre-clinical Research Center, Tokyo Medical University, Tokyo, Japan.
FAU - Takanashi, Masakatsu
AU  - Takanashi M
AUID- ORCID: 0000-0002-7127-1153
AD  - Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan.
FAU - Ohno, Shin-Ichiro
AU  - Ohno SI
AUID- ORCID: 0000-0003-1064-4750
AD  - Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan.
FAU - Harada, Yuichirou
AU  - Harada Y
AD  - Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan.
FAU - Fujita, Koji
AU  - Fujita K
AD  - Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan.
FAU - Oikawa, Keiki
AU  - Oikawa K
AD  - Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan.
FAU - Sudo, Katsuko
AU  - Sudo K
AD  - Pre-clinical Research Center, Tokyo Medical University, Tokyo, Japan.
FAU - Ikeda, Shun-Ichi
AU  - Ikeda SI
AD  - Department of Obstetrics and Gynecology, Kohseichuo General Hospital, Tokyo, 
      Japan.
FAU - Nishi, Hirotaka
AU  - Nishi H
AD  - Department of Obstetrics and Gynecology, Tokyo Medical University, Tokyo, Japan.
FAU - Oikawa, Kosuke
AU  - Oikawa K
AD  - Department of Pathology, Wakayama Medical University, Wakayama, Japan.
FAU - Kuroda, Masahiko
AU  - Kuroda M
AUID- ORCID: 0000-0001-7052-4289
AD  - Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan. 
      kuroda@tokyo-med.ac.jp.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210504
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Carrier Proteins)
RN  - 0 (E6 protein, Human papillomavirus type 16)
RN  - 0 (Estrogens)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Oncogene Proteins, Viral)
RN  - 0 (Papillomavirus E7 Proteins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Repressor Proteins)
RN  - 0 (WAPL protein, human)
RN  - 0 (oncogene protein E7, Human papillomavirus type 16)
SB  - IM
MH  - Animals
MH  - Animals, Genetically Modified
MH  - Carrier Proteins/*genetics
MH  - Chromosomal Instability
MH  - Disease Models, Animal
MH  - Estrogens/*metabolism
MH  - Female
MH  - Gene Knock-In Techniques
MH  - Mice
MH  - Mice, Transgenic
MH  - Nuclear Proteins/*genetics
MH  - Oncogene Proteins, Viral/physiology
MH  - Papillomavirus E7 Proteins/physiology
MH  - Papillomavirus Infections/*genetics/metabolism/virology
MH  - Precancerous Conditions
MH  - Proto-Oncogene Proteins/*genetics
MH  - Repressor Proteins/physiology
MH  - Signal Transduction
MH  - Uterine Cervical Neoplasms/genetics/metabolism/*pathology
MH  - Uterine Cervical Dysplasia/genetics/metabolism/*pathology
PMC - PMC8154587
COIS- The authors declare no competing interests.
EDAT- 2021/05/06 06:00
MHDA- 2022/01/22 06:00
PMCR- 2021/05/04
CRDT- 2021/05/05 06:18
PHST- 2020/08/21 00:00 [received]
PHST- 2021/04/12 00:00 [accepted]
PHST- 2021/03/30 00:00 [revised]
PHST- 2021/05/06 06:00 [pubmed]
PHST- 2022/01/22 06:00 [medline]
PHST- 2021/05/05 06:18 [entrez]
PHST- 2021/05/04 00:00 [pmc-release]
AID - 10.1038/s41388-021-01787-5 [pii]
AID - 1787 [pii]
AID - 10.1038/s41388-021-01787-5 [doi]
PST - ppublish
SO  - Oncogene. 2021 May;40(21):3695-3706. doi: 10.1038/s41388-021-01787-5. Epub 2021 
      May 4.