USP13 promotes development and metastasis of high-grade serous ovarian carcinoma in a novel mouse model.
USP13 promotes development and metastasis of high-grade serous ovarian carcinoma in a novel mouse model.
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DOI：
10.1038/s41388-022-02224-x
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发表时间：
2022-03
期刊：
影响因子：
8
通讯作者：
Han C
中科院分区：
文献类型：
--
作者：
Kwon J;Choi H;Ware AD;Morillo BC;Wang H;Bouker KB;Lu X;Waldman T;Han C
上皮性卵巢癌是最致命的妇科恶性肿瘤，也是全世界妇女癌症死亡的最常见原因之一。泛素特异性肽酶13 （USP13）基因拷贝在人上皮性卵巢癌中被强烈扩增，USP13的高表达与较差的生存结果相关。然而，其在卵巢肿瘤发生中的病理作用尚不清楚。我们将条件Usp13过表达敲入小鼠与条件敲除Trp53和Pten小鼠杂交，建立了一种新的卵巢癌基因工程小鼠模型（GEMM），该模型紧密地概括了人类卵巢癌的遗传变化。在小鼠卵巢表面上皮中，USP13过表达并缺失Trp53和Pten会加速卵巢肿瘤的发生，导致小鼠存活时间降低。值得注意的是，USP13极大地促进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的共抑制显著降低了从GEMM分离的小鼠原发性卵巢癌细胞的活力。在一项同基因小鼠研究中，USP13还增加了原发性小鼠卵巢癌细胞的致瘤性和转移能力。这些发现提示了USP13在卵巢癌发展中的关键作用，并揭示了USP13是卵巢癌的潜在治疗靶点。
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.
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影响因子：
16.6
作者：
Labidi-Galy SI;Papp E;Hallberg D;Niknafs N;Adleff V;Noe M;Bhattacharya R;Novak M;Jones S;Phallen J;Hruban CA;Hirsch MS;Lin DI;Schwartz L;Maire CL;Tille JC;Bowden M;Ayhan A;Wood LD;Scharpf RB;Kurman R;Wang TL;Shih IM;Karchin R;Drapkin R;Velculescu VE
通讯作者：
Velculescu VE
影响因子：
28.2
作者：
Hanrahan AJ;Schultz N;Westfal ML;Sakr RA;Giri DD;Scarperi S;Janakiraman M;Olvera N;Stevens EV;She QB;Aghajanian C;King TA;Stanchina Ed;Spriggs DR;Heguy A;Taylor BS;Sander C;Rosen N;Levine DA;Solit DB
通讯作者：
Solit DB
DOI：
10.1038/nrc2644
发表时间：
2009-06
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
82.9
作者：
Dinulescu, DM;Ince, TA;Jacks, T
通讯作者：
Jacks, T
DOI：
10.1038/nrc4019
发表时间：
2015-11
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Bowtell DD;Böhm S;Ahmed AA;Aspuria PJ;Bast RC Jr;Beral V;Berek JS;Birrer MJ;Blagden S;Bookman MA;Brenton JD;Chiappinelli KB;Martins FC;Coukos G;Drapkin R;Edmondson R;Fotopoulou C;Gabra H;Galon J;Gourley C;Heong V;Huntsman DG;Iwanicki M;Karlan BY;Kaye A;Lengyel E;Levine DA;Lu KH;McNeish IA;Menon U;Narod SA;Nelson BH;Nephew KP;Pharoah P;Powell DJ Jr;Ramos P;Romero IL;Scott CL;Sood AK;Stronach EA;Balkwill FR
通讯作者：
Balkwill FR