Endogenous YAP1 activation drives immediate onset of cervical carcinoma in situ in mice

Miki Nishio; Yoko To; Tomohiko Maehama; Yukari Aono; Junji Otani; Hiroki Hikasa; Akihiro Kitagawa; Koshi Mimori; Takehiko Sasaki; Hiroshi Nishina; Shinya Toyokuni; John P. Lydon; Kazuwa Nakao; Tak Wah Mak; Tohru Kiyono; Hidetaka Katabuchi; Hironori Tashiro; Akira Suzuki

doi:10.1111/cas.14581

Endogenous YAP1 activation drives immediate onset of cervical carcinoma in situ in mice

Miki Nishio, Yoko To, Tomohiko Maehama, Yukari Aono, Junji Otani, Hiroki Hikasa, Akihiro Kitagawa, Koshi Mimori, Takehiko Sasaki, Hiroshi Nishina, Shinya Toyokuni, John P. Lydon, Kazuwa Nakao, Tak Wah Mak, Tohru Kiyono, Hidetaka Katabuchi, Hironori Tashiro, Akira Suzuki

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Abstract

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.

Original language	English
Pages (from-to)	3576-3587
Number of pages	12
Journal	Cancer Science
Volume	111
Issue number	10
DOIs	https://doi.org/10.1111/cas.14581
Publication status	Published - Oct 1 2020

All Science Journal Classification (ASJC) codes

Oncology
Cancer Research

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10.1111/cas.14581

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Nishio, M., To, Y., Maehama, T., Aono, Y., Otani, J., Hikasa, H., Kitagawa, A., Mimori, K., Sasaki, T., Nishina, H., Toyokuni, S., Lydon, J. P., Nakao, K., Wah Mak, T., Kiyono, T., Katabuchi, H., Tashiro, H., & Suzuki, A. (2020). Endogenous YAP1 activation drives immediate onset of cervical carcinoma in situ in mice. Cancer Science, 111(10), 3576-3587. https://doi.org/10.1111/cas.14581

Nishio, M, To, Y, Maehama, T, Aono, Y, Otani, J, Hikasa, H, Kitagawa, A, Mimori, K, Sasaki, T, Nishina, H, Toyokuni, S, Lydon, JP, Nakao, K, Wah Mak, T, Kiyono, T, Katabuchi, H, Tashiro, H & Suzuki, A 2020, 'Endogenous YAP1 activation drives immediate onset of cervical carcinoma in situ in mice', Cancer Science, vol. 111, no. 10, pp. 3576-3587. https://doi.org/10.1111/cas.14581

@article{e620032acf7040d1904c544b312f893e,

title = "Endogenous YAP1 activation drives immediate onset of cervical carcinoma in situ in mice",

abstract = "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.",

author = "Miki Nishio and Yoko To and Tomohiko Maehama and Yukari Aono and Junji Otani and Hiroki Hikasa and Akihiro Kitagawa and Koshi Mimori and Takehiko Sasaki and Hiroshi Nishina and Shinya Toyokuni and Lydon, {John P.} and Kazuwa Nakao and {Wah Mak}, Tak and Tohru Kiyono and Hidetaka Katabuchi and Hironori Tashiro and Akira Suzuki",

note = "Funding Information: Japan Agency for Medical Research and Development (Grant/Award Number: {"}JP20cm0106114{"}); Cooperative Research Project Program of the MIB, Kyushu University; Japan Society for the Promotion of Science (Grant/Award Number: {"}17H01400,{"} {"}26114005,{"} {"}26640081{"}); Nanken-Kyoten, Tokyo Medical and Dental University; Kanzawa Medical Research Foundation. We thank J. Wrana (Lunenfeld-Tanenbaum Research Institute) for Tazflox/flox mice. We are grateful for the funding provided by the Japanese Society for the Promotion of Science (JSPS; grants 17H01400, 26114005, 26640081); the Cooperative Research Project Program of the MIB, Kyushu University; Nanken-Kyoten, Tokyo Medical and Dental University (TMDU); the Japanese Agency for Medical Research and Development [P-CREATE(AMED) grant; JP20cm0106114]; and the Kanzawa Medical Research Foundation. Funding Information: We thank J. Wrana (Lunenfeld‐Tanenbaum Research Institute) for Tazflox/flox mice. We are grateful for the funding provided by the Japanese Society for the Promotion of Science (JSPS; grants 17H01400, 26114005, 26640081); the Cooperative Research Project Program of the MIB, Kyushu University; Nanken‐Kyoten, Tokyo Medical and Dental University (TMDU); the Japanese Agency for Medical Research and Development [P‐CREATE(AMED) grant; JP20cm0106114]; and the Kanzawa Medical Research Foundation. Funding Information: Japan Agency for Medical Research and Development (Grant/Award Number: {"}JP20cm0106114{"}); Cooperative Research Project Program of the MIB, Kyushu University; Japan Society for the Promotion of Science (Grant/Award Number: {"}17H01400,{"} {"}26114005,{"} {"}26640081{"}); Nanken‐Kyoten, Tokyo Medical and Dental University; Kanzawa Medical Research Foundation. Publisher Copyright: {\textcopyright} 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.",

year = "2020",

month = oct,

day = "1",

doi = "10.1111/cas.14581",

language = "English",

volume = "111",

pages = "3576--3587",

journal = "Cancer Science",

issn = "1347-9032",

publisher = "Wiley-Blackwell",

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TY - JOUR

T1 - Endogenous YAP1 activation drives immediate onset of cervical carcinoma in situ in mice

AU - Nishio, Miki

AU - To, Yoko

AU - Maehama, Tomohiko

AU - Aono, Yukari

AU - Otani, Junji

AU - Hikasa, Hiroki

AU - Kitagawa, Akihiro

AU - Mimori, Koshi

AU - Sasaki, Takehiko

AU - Nishina, Hiroshi

AU - Toyokuni, Shinya

AU - Lydon, John P.

AU - Nakao, Kazuwa

AU - Wah Mak, Tak

AU - Kiyono, Tohru

AU - Katabuchi, Hidetaka

AU - Tashiro, Hironori

AU - Suzuki, Akira

N1 - Funding Information: Japan Agency for Medical Research and Development (Grant/Award Number: "JP20cm0106114"); Cooperative Research Project Program of the MIB, Kyushu University; Japan Society for the Promotion of Science (Grant/Award Number: "17H01400," "26114005," "26640081"); Nanken-Kyoten, Tokyo Medical and Dental University; Kanzawa Medical Research Foundation. We thank J. Wrana (Lunenfeld-Tanenbaum Research Institute) for Tazflox/flox mice. We are grateful for the funding provided by the Japanese Society for the Promotion of Science (JSPS; grants 17H01400, 26114005, 26640081); the Cooperative Research Project Program of the MIB, Kyushu University; Nanken-Kyoten, Tokyo Medical and Dental University (TMDU); the Japanese Agency for Medical Research and Development [P-CREATE(AMED) grant; JP20cm0106114]; and the Kanzawa Medical Research Foundation. Funding Information: We thank J. Wrana (Lunenfeld‐Tanenbaum Research Institute) for Tazflox/flox mice. We are grateful for the funding provided by the Japanese Society for the Promotion of Science (JSPS; grants 17H01400, 26114005, 26640081); the Cooperative Research Project Program of the MIB, Kyushu University; Nanken‐Kyoten, Tokyo Medical and Dental University (TMDU); the Japanese Agency for Medical Research and Development [P‐CREATE(AMED) grant; JP20cm0106114]; and the Kanzawa Medical Research Foundation. Funding Information: Japan Agency for Medical Research and Development (Grant/Award Number: "JP20cm0106114"); Cooperative Research Project Program of the MIB, Kyushu University; Japan Society for the Promotion of Science (Grant/Award Number: "17H01400," "26114005," "26640081"); Nanken‐Kyoten, Tokyo Medical and Dental University; Kanzawa Medical Research Foundation. Publisher Copyright: © 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

PY - 2020/10/1

Y1 - 2020/10/1

N2 - 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.

AB - 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.

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U2 - 10.1111/cas.14581

DO - 10.1111/cas.14581

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C2 - 32716083

AN - SCOPUS:85089563250

SN - 1347-9032

VL - 111

SP - 3576

EP - 3587

JO - Cancer Science

JF - Cancer Science

IS - 10

ER -

Endogenous YAP1 activation drives immediate onset of cervical carcinoma in situ in mice

Abstract

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