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内源性 YAP1 激活导致小鼠宫颈原位癌的即刻发生。

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

机构信息

Division of Molecular and Cellular Biology, Kobe University Graduate School of Medicine, Kobe, Japan.

Division of Cancer Genetics, MIB, Kyushu University, Fukuoka, Japan.

出版信息

Cancer Sci. 2020 Oct;111(10):3576-3587. doi: 10.1111/cas.14581. Epub 2020 Aug 21.

DOI:10.1111/cas.14581
PMID:32716083
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7541006/
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.

摘要

宫颈癌（CC）通常由高危型人乳头瘤病毒（HPV）感染引发。HPV 的 E6 和 E7 蛋白分别靶向 p53 和 RB，但可能还存在其他细胞靶标。我们生成了子宫特异性 MOB1A/B 双敲除（uMob1DKO）小鼠，它们立即出现宫颈原位鳞状细胞癌。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性。uMob1DKO 细胞中 p53 的激活增加，并且在 uMob1DKO 小鼠中进一步丧失 p53 会加速肿瘤侵袭。在人 CC 中，从癌前阶段开始就观察到强烈的 YAP1 激活。过表达 HPV16 E6/E7 的人细胞不仅失活了 p53 和 RB，还失活了 PTPN14，从而增强了 YAP1 的激活。雌激素、香烟烟雾冷凝物和 PI3K 过度激活均增加了人宫颈上皮细胞中的 YAP1 活性，而 PTPN14 耗竭以及 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，可能会立即引发 CC，从而使 Hippo-YAP1 信号成为主要的 CC 驱动因素。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a08/7541006/50ac72c53058/CAS-111-3576-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a08/7541006/b0e112989c83/CAS-111-3576-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a08/7541006/90cbc2bd9c7e/CAS-111-3576-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a08/7541006/013e2a714b3b/CAS-111-3576-g003.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a08/7541006/50ac72c53058/CAS-111-3576-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a08/7541006/b0e112989c83/CAS-111-3576-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a08/7541006/90cbc2bd9c7e/CAS-111-3576-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a08/7541006/013e2a714b3b/CAS-111-3576-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a08/7541006/a6bfbe4b18b1/CAS-111-3576-g004.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a08/7541006/50ac72c53058/CAS-111-3576-g006.jpg

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