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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.

SUBMITTER: Nishio M

PROVIDER: S-EPMC7541006 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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

Nishio Miki M To Yoko Y Maehama Tomohiko T Aono Yukari Y Otani Junji J Hikasa Hiroki H Kitagawa Akihiro A Mimori Koshi K Sasaki Takehiko T Nishina Hiroshi H Toyokuni Shinya S Lydon John P JP Nakao Kazuwa K Wah Mak Tak T Kiyono Tohru T Katabuchi Hidetaka H Tashiro Hironori H Suzuki Akira A

Cancer science 20200821 10

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 ...[more]

PMID: 32716083

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Project description:To characterize population-level surgical treatment patterns for cervical carcinoma in situ (CIS) reported to the Michigan Cancer Surveillance Program (MCSP), and to inform data collection strategies.All cases of cervical carcinoma in situ (CIS) (including cervical intraepithelial neoplasia grade 3 and adenocarcinoma in situ [AIS]) reported to the MCSP during 1998-2003 were identified. First course of treatment (ablative procedure, cone biopsy, loop electrosurgical excisional procedure [LEEP], hysterectomy, unspecified surgical treatment, no surgical treatment, unknown if surgically treated) was described by histology, race, and age at diagnosis.Of 17,022 cases of cervical CIS, 82.8 percent were squamous CIS, 3 percent AIS/adenosquamous CIS, and 14.2 percent unspecified/other CIS. Over half (54.7 percent) of cases were diagnosed in women under age 30. Excisional treatments (LEEP, 32.3 percent and cone biopsy, 17.3 percent) were most common, though substantial proportions had no reported treatment (17.8 percent) or unknown treatment (21.1 percent). Less common were hysterectomy (7.2 percent) and ablative procedures (2.6 percent). LEEP was the most common treatment for squamous cases, while hysterectomy was the most treatment for AIS/adenosquamous CIS cases. Across histologic types, a sizeable proportion of women diagnosed ?30 years of age underwent excision, either LEEP (20 percent-38.7 percent) or cone biopsy (13.7 percent-44 percent).Despite evidence suggesting it may be safer and equally effective as excision, ablation was rarely used for treating cervical squamous CIS. These population-based data indicate some notable differences in treatment by histology and age at diagnosis, with observed patterns appearing consistent with consensus guidelines in place at the time of study, but favoring more aggressive procedures. Future data collection strategies may need to validate treatment information, including the large proportion of no or unknown treatment.

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

Publications

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

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