Tripartite motif (TRIM) family proteins are post-translational protein modifiers with E3-ubiquitin ligase activity, thereby involved in various biological processes. The molecular mechanisms driving prostate cancer (PCa) bone metastasis (BM) are incompletely understood, and targetable genetic alterations are lacking in the majority of cases. Therefore, we aimed to explore the expression and potential functional relevance of 71 TRIM members in bone metastatic PCa. We performed transcriptome analysis of all human TRIM family members and 770 cancer-related genes in 29 localized PCa and 30 PCa BM using Nanostring. KEGG, STRING and Ubibrowser were used for further bioinformatic gene correlation and pathway enrichment analyses. Compared to localized tumors, six TRIMs are under-expressed while nine TRIMs are over-expressed in BM. The differentially expressed TRIM proteins are linked to TNF-, TGFβ-, PI3K/AKT- and HIF-1-signaling, and to features such as proteoglycans, platelet activation, adhesion and ECM-interaction based on correlation to cancer-related genes. The identification of TRIM-specific E3-ligase-substrates revealed insight into functional connections to oncogenes, tumor suppressors and cancer-related pathways including androgen receptor- and TGFβ signaling, cell cycle regulation and splicing. In summary, this is the first study that comprehensively and systematically characterizes the expression of all TRIM members in PCa BM. Our results describe post-translational protein modification as an important regulatory mechanism of oncogenes, tumor suppressors, and pathway molecules in PCa progression. Therefore, this study may provide evidence for novel therapeutic targets, in particular for the treatment or prevention of BM.

中文翻译：

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分析前列腺癌骨转移中三方基序（TRIM）家族基因的表达。

三方基序 (TRIM) 家族蛋白是具有 E3-泛素连接酶活性的翻译后蛋白修饰剂，因此参与了各种生物过程。驱动前列腺癌 (PCa) 骨转移 (BM) 的分子机制尚不完全清楚，并且在大多数情况下缺乏可靶向的基因改变。因此，我们旨在探索 71 个 TRIM 成员在骨转移性 PCa 中的表达和潜在的功能相关性。我们使用 Nanostring 对 29 个局部 PCa 和 30 个 PCa BM 中的所有人类 TRIM 家族成员和 770 个癌症相关基因进行了转录组分析。KEGG、STRING 和 Ubibrowser 用于进一步的生物信息学基因关联和通路富集分析。与局部肿瘤相比，6 个 TRIM 表达不足，而 9 个 TRIM 在 BM 中过度表达。差异表达的 TRIM 蛋白与 TNF-、TGFβ-、PI3K/AKT- 和 HIF-1 信号传导有关，并与基于与癌症相关基因相关的蛋白聚糖、血小板活化、粘附和 ECM 相互作用等特征相关。TRIM 特异性 E3 连接酶底物的鉴定揭示了对与癌基因、肿瘤抑制因子和癌症相关途径（包括雄激素受体和 TGFβ 信号传导、细胞周期调节和剪接）的功能联系的深入了解。总之，这是第一项全面系统地描述 PCa BM 中所有 TRIM 成员表达的研究。我们的结果将翻译后蛋白质修饰描述为 PCa 进展中癌基因、肿瘤抑制因子和通路分子的重要调节机制。所以，