Endogenous YAP1 activation drives immediate onset of cervical carcinoma in situ in mice.
Endogenous YAP1 activation drives immediate onset of cervical carcinoma in situ in mice.
复制标题
内源性YAP 1激活驱动小鼠原位宫颈癌的立即发生。
DOI：
10.1111/cas.14581
复制
发表时间：
2020-10
期刊：
影响因子：
5.7
通讯作者：
Suzuki A
中科院分区：
文献类型：
--
作者：
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
宫颈癌（CC）通常由感染高危型人乳头瘤病毒（HPV）引起。HPV E6和E7蛋白分别靶向p53和RB，但可能存在其他细胞靶点。我们培育了子宫特异性MOB1A/B双KO （uMob1DKO）小鼠，这些小鼠立即发展为宫颈鳞状细胞原位癌。突变的宫颈上皮细胞表现出YAP1依赖性过度增殖、自我更新改变、接触抑制受损和染色体不稳定。p53激活在uMob1DKO细胞中增加，在uMob1DKO小鼠中p53的额外缺失加速了肿瘤的侵袭。在人类CC中，从癌前阶段就观察到强烈的YAP1激活。过表达HPV16 E6/E7的人细胞不仅p53和RB失活，PTPN14也失活，YAP1的激活增强。雌激素、香烟烟雾凝聚物和PI3K过度激活均可增加人宫颈上皮细胞中YAP1的活性，而PTPN14的缺失以及PI3K激活或雌激素处理进一步增强了YAP1。因此，当YAP1活性超过致癌阈值时，可能会立即发生CC，使Hippo‐YAP1信号成为CC的主要驱动因素。我们培育了子宫特异性MOB1A/B双KO （uMob1DKO）小鼠，这些小鼠立即发展为宫颈鳞状细胞原位癌。当YAP1活性超过致癌阈值时，宫颈癌（CC）的发病可能开始，使Hippo‐YAP1信号成为CC的主要驱动因素。p53激活在uMob1DKO细胞中增加，在uMob1DKO小鼠中p53的额外缺失加速了肿瘤的侵袭。
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. We generated uterus‐specific MOB1A/B double KO (uMob1DKO) mice, which immediately developed cervical squamous cell carcinoma in situ. Cervical cancer (CC) onset may initiate when YAP1 activity exceeds an oncogenic threshold, making Hippo‐YAP1 signaling a major CC driver. p53 activation was increased in uMob1DKO cells, and additional p53 loss in uMob1DKO mice accelerated tumor invasion.
登录
查看更多内容
影响因子：
50.3
作者：
Mello SS;Valente LJ;Raj N;Seoane JA;Flowers BM;McClendon J;Bieging-Rolett KT;Lee J;Ivanochko D;Kozak MM;Chang DT;Longacre TA;Koong AC;Arrowsmith CH;Kim SK;Vogel H;Wood LD;Hruban RH;Curtis C;Attardi LD
通讯作者：
Attardi LD
影响因子：
5.4
作者：
ARBEIT, JM;MUNGER, K;HANAHAN, D
通讯作者：
HANAHAN, D
影响因子：
5.2
作者：
Munoz, Juan P.;Carrillo-Beltran, Diego;Aguayo, Francisco
通讯作者：
Aguayo, Francisco
影响因子：
16
作者：
Basu, S;Totty, NF;Downward, J
通讯作者：
Downward, J
DOI：
10.1097/igc.0b013e31828c8619
发表时间：
2013-05-01
影响因子：
4.8
作者：
Liu, Tianbo;Liu, Yunduo;Lou, Ge
通讯作者：
Lou, Ge