Usp22 Overexpression Leads to Aberrant Signal Transduction of Cancer-Related Pathways but Is Not Sufficient to Drive Tumor Formation in Mice.
Usp22 Overexpression Leads to Aberrant Signal Transduction of Cancer-Related Pathways but Is Not Sufficient to Drive Tumor Formation in Mice.
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DOI：
10.3390/cancers13174276
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发表时间：
2021-08-25
期刊：
影响因子：
5.2
通讯作者：
Koutelou E
中科院分区：
文献类型：
--
作者：
Kuang X;McAndrew MJ;Mustachio LM;Chen YC;Atanassov BS;Lin K;Lu Y;Shen J;Salinger A;Macatee T;Dent SYR;Koutelou E
在几种类型的人类癌症中，尤其是高度侵袭性、治疗耐药的肿瘤中，观察到 Usp22 去泛素酶水平升高。然而，Usp22 过度表达在癌症病因学中的作用尚不清楚。为了解决 Usp22 过度表达是否足以在体内诱导肿瘤，我们创造了一种在从胚胎发生到成年的所有组织中高水平表达 Usp22 的小鼠。对这些小鼠的分析清楚地表明，虽然 Usp22 过度表达改变了几种与肿瘤相关的信号通路并诱导相关的形态变化，例如乳腺的超分支，但单独的 Usp22 过度表达不足以诱导肿瘤发生。这些发现表明，Usp22 可能通过与加剧异常信号转导的癌蛋白合作来增强肿瘤的形成和进展。在多种人类癌症中观察到 Usp22 过度表达，并且与患者不良预后相关。这种相关性的分子基础尚不清楚。 Usp22 是 SAGA 组蛋白修饰复合物中去泛素化模块的催化亚基，负责调节基因转录。我们之前的工作表明，小鼠中 Usp22 的缺失会导致受体酪氨酸激酶和 TGFβ 信号通路的几种成分的表达降低。为了确定当 Usp22 过度表达时这些途径是否上调，我们创建了一个在所有组织中高水平表达 Usp22 的小鼠模型。这些小鼠的表型特征揭示了雌性小鼠乳腺的过度分支。转录组分析表明，来自 Usp22 过表达小鼠的乳腺上皮细胞中涉及乳腺分支的关键通路上调，包括雌激素受体、ERK/MAPK 和 TGFβ 信号传导。然而，Usp22 过度表达并不会导致任何组织中肿瘤发生的增加。我们的研究结果表明，Usp22 水平升高不足以诱发肿瘤，但它可能会增强与肿瘤发生相关的信号异常。
Increased levels of the Usp22 deubiquitinase have been observed in several types of human cancer, particularly highly aggressive, therapy-resistant tumors. However, the role of Usp22 overexpression in cancer etiology is not known. To address whether Usp22 overexpression is sufficient to induce tumors in vivo, we created a mouse that expresses high levels of Usp22 in all tissues beginning in embryogenesis through to adulthood. Analyses of these mice clearly show that while Usp22 overexpression alters several tumor-related signaling pathways and induces associated morphological changes such as hyperbranching of the mammary gland, Usp22 overexpression alone is not sufficient to induce tumorigenesis. These findings indicate that Usp22 likely enhances tumor formation and progression through cooperation with oncoproteins that exacerbate abnormal signal transduction. Usp22 overexpression is observed in several human cancers and is correlated with poor patient outcomes. The molecular basis underlying this correlation is not clear. Usp22 is the catalytic subunit of the deubiquitylation module in the SAGA histone-modifying complex, which regulates gene transcription. Our previous work demonstrated that the loss of Usp22 in mice leads to decreased expression of several components of receptor tyrosine kinase and TGFβ signaling pathways. To determine whether these pathways are upregulated when Usp22 is overexpressed, we created a mouse model that expresses high levels of Usp22 in all tissues. Phenotypic characterization of these mice revealed over-branching of the mammary glands in females. Transcriptomic analyses indicate the upregulation of key pathways involved in mammary gland branching in mammary epithelial cells derived from the Usp22-overexpressing mice, including estrogen receptor, ERK/MAPK, and TGFβ signaling. However, Usp22 overexpression did not lead to increased tumorigenesis in any tissue. Our findings indicate that elevated levels of Usp22 are not sufficient to induce tumors, but it may enhance signaling abnormalities associated with oncogenesis.
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DOI：
10.1186/bcr3487
发表时间：
2013
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Bray K;Gillette M;Young J;Loughran E;Hwang M;Sears JC;Vargo-Gogola T
通讯作者：
Vargo-Gogola T
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
14.9
作者：
Frankish A;Diekhans M;Ferreira AM;Johnson R;Jungreis I;Loveland J;Mudge JM;Sisu C;Wright J;Armstrong J;Barnes I;Berry A;Bignell A;Carbonell Sala S;Chrast J;Cunningham F;Di Domenico T;Donaldson S;Fiddes IT;García Girón C;Gonzalez JM;Grego T;Hardy M;Hourlier T;Hunt T;Izuogu OG;Lagarde J;Martin FJ;Martínez L;Mohanan S;Muir P;Navarro FCP;Parker A;Pei B;Pozo F;Ruffier M;Schmitt BM;Stapleton E;Suner MM;Sycheva I;Uszczynska-Ratajczak B;Xu J;Yates A;Zerbino D;Zhang Y;Aken B;Choudhary JS;Gerstein M;Guigó R;Hubbard TJP;Kellis M;Paten B;Reymond A;Tress ML;Flicek P
通讯作者：
Flicek P
影响因子：
4.8
作者：
Bocchinfuso, WP;Lindzey, JK;Korach, KS
通讯作者：
Korach, KS
影响因子：
5.6
作者：
Kim, Dongyeon;Hong, Ahyoung;Chung, Kwang Chul
通讯作者：
Chung, Kwang Chul