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USP13 促进新型小鼠模型中高级别浆液性卵巢癌的发展和转移。

USP13 promotes development and metastasis of high-grade serous ovarian carcinoma in a novel mouse model.

机构信息

Department of Oncology, Georgetown University School of Medicine, Washington, DC, 20007, USA.

Biochemistry and Molecular Biology, Georgetown University School of Medicine, Washington, DC, 20007, USA.

出版信息

Oncogene. 2022 Mar;41(13):1974-1985. doi: 10.1038/s41388-022-02224-x. Epub 2022 Feb 16.

DOI:10.1038/s41388-022-02224-x
PMID:35173307
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8956511/
Abstract

Epithelial ovarian cancer is the most lethal gynecologic malignancy and one of the most common causes of cancer mortality among women worldwide. Ubiquitin-Specific Peptidase 13 (USP13) gene copy is strongly amplified in human epithelial ovarian cancer, and high USP13 expression is correlated with poor survival outcomes. Yet, its pathological contribution to ovarian tumorigenesis remains unknown. We crossed a conditional Usp13 overexpressing knock-in mouse with a conditional knockout of Trp53 and Pten mouse and generated a novel ovarian cancer genetically engineered mouse model (GEMM), which closely recapitulates the genetic changes driving ovarian cancer in humans. Overexpression of USP13 with deletion of Trp53 and Pten in murine ovarian surface epithelium accelerated ovarian tumorigenesis and led to decreased survival in mice. Notably, USP13 greatly enhanced peritoneal metastasis of ovarian tumors with frequent development of hemorrhagic ascites. The primary and metastatic tumors exhibited morphology and clinical behavior similar to human high-grade serous ovarian cancer. Co-inhibition of USP13 and AKT significantly decreased the viability of the primary murine ovarian cancer cells isolated from the GEMM. USP13 also increased the tumorigenic and metastatic abilities of primary murine ovarian cancer cells in a syngeneic mouse study. These findings suggest a critical role of USP13 in ovarian cancer development and reveal USP13 as a potential therapeutic target for ovarian cancer.

摘要

上皮性卵巢癌是最致命的妇科恶性肿瘤之一，也是全球女性癌症死亡的最常见原因之一。人类上皮性卵巢癌中泛素特异性肽酶 13（USP13）基因拷贝强烈扩增，高 USP13 表达与不良生存结局相关。然而，其对卵巢肿瘤发生的病理贡献尚不清楚。我们将条件性过表达 Usp13 的敲入小鼠与条件性敲除 Trp53 和 Pten 的小鼠杂交，生成了一种新型卵巢癌基因工程小鼠模型（GEMM），该模型很好地模拟了驱动人类卵巢癌的遗传变化。在小鼠卵巢表面上皮中过表达 USP13 并缺失 Trp53 和 Pten 可加速卵巢肿瘤发生，并导致小鼠生存率降低。值得注意的是，USP13 极大地增强了卵巢肿瘤的腹膜转移，并经常发生出血性腹水。原发性和转移性肿瘤表现出与人类高级别浆液性卵巢癌相似的形态和临床行为。USP13 和 AKT 的联合抑制显著降低了从 GEMM 分离的原发性小鼠卵巢癌细胞的活力。USP13 还增加了原发性小鼠卵巢癌细胞在同种异体小鼠研究中的致瘤和转移能力。这些发现表明 USP13 在卵巢癌发展中具有关键作用，并揭示 USP13 可能成为卵巢癌的潜在治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d26a/8956511/ce3ab92a0f1d/41388_2022_2224_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d26a/8956511/c23b23b1d23f/41388_2022_2224_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d26a/8956511/9665832de81d/41388_2022_2224_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d26a/8956511/88799f0a7a88/41388_2022_2224_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d26a/8956511/7518d7875780/41388_2022_2224_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d26a/8956511/2afe8dcb7dbc/41388_2022_2224_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d26a/8956511/ce3ab92a0f1d/41388_2022_2224_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d26a/8956511/c23b23b1d23f/41388_2022_2224_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d26a/8956511/9665832de81d/41388_2022_2224_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d26a/8956511/88799f0a7a88/41388_2022_2224_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d26a/8956511/7518d7875780/41388_2022_2224_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d26a/8956511/2afe8dcb7dbc/41388_2022_2224_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d26a/8956511/ce3ab92a0f1d/41388_2022_2224_Fig6_HTML.jpg

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Cognitive Skills and DNA Methylation Are Correlating in Healthy and Novice College Students Practicing Preksha Dhyāna Meditation.在健康的新手大学生中，认知技能与DNA甲基化在练习内观禅修时存在关联。
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