WAPL induces cervical intraepithelial neoplasia modulated with estrogen signaling without HPV E6/E7

• Published in: Oncogene Vol. 40; no. 21; pp. 3695 - 3706
• Main Authors: Kumagai, Katsuyoshi, Takanashi, Masakatsu, Ohno, Shin-ichiro, Harada, Yuichirou, Fujita, Koji, Oikawa, Keiki, Sudo, Katsuko, Ikeda, Shun-ichi, Nishi, Hirotaka, Oikawa, Kosuke, Kuroda, Masahiko
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27.05.2021; Nature Publishing Group
• Subjects: 13/1; 13/51; 13/89; 14/1; 38/77; 631/67/1517/1371; 631/80/86/2363; 64/60; Animals; Animals, Genetically Modified; Apoptosis; Cancer; Carrier Proteins - genetics; Cell Biology; Cervical cancer; Cervix dysplasia; Chromosomal Instability; Cyclin D1; Development and progression; Disease Models, Animal; Estrogen; Estrogen receptors; Estrogens; Estrogens - metabolism; Female; Gene expression; Gene Knock-In Techniques; Genetic aspects; Genomic instability; Growth factors; Human Genetics; Human papillomavirus; Internal Medicine; Lesions; Medicine; Medicine & Public Health; Mice; Mice, Transgenic; Myc protein; Nuclear Proteins - genetics; Oncogene Proteins, Viral - physiology; Oncology; Oncology, Experimental; Papillomavirus E7 Proteins - physiology; Papillomavirus infections; Papillomavirus Infections - genetics; Papillomavirus Infections - metabolism; Papillomavirus Infections - virology; Precancerous Conditions; Proto-Oncogene Proteins - genetics; Receptors; Repressor Proteins - physiology; Signal Transduction; Tumorigenesis; Uterine Cervical Dysplasia - genetics; Uterine Cervical Dysplasia - metabolism; Uterine Cervical Dysplasia - pathology; Uterine Cervical Neoplasms - genetics; Uterine Cervical Neoplasms - metabolism; Uterine Cervical Neoplasms - pathology; Uterus; Japan
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-021-01787-5

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.