Alternative splicing of RNA transcripts plays an important role in cancer development and progression. Recent advances in RNA-seq technology have made it possible to identify alternately spliced events in various types of cancer; however, research on hepatocellular carcinoma (HCC) is still limited. Here, by performing RNA-seq profiling of HCC transcripts at isoform level, we identified tumor-specific and molecular subtype-dependent expression of the USO1 isoforms, which we designated as a normal form USO1-N (XM_001290049) and a tumor form USO1-T (NM_003715). The expression of USO1-T, but not USO1-N, was associated with worse prognostic outcomes of HCC patients. We confirmed that the expression of USO1-T promoted an aggressive phenotype of HCC, both in vitro and in vivo. In addition, structural modeling analyses revealed that USO1-T lacks an ARM10 loop encoded by exon 15, which may weaken the dimerization of USO1 and its tethering to GM130. We demonstrated that USO1-T ensured unstacking of the Golgi and accelerated the vesicles trafficking from endoplasmic reticulum (ER) to Golgi and plasma membrane in multiple liver cancer cells. ERK and GRASP65 were found to be involved in the USO1-T-mediated Golgi dysfunction. Conclusively, we provide new mechanophysical insights into the USO1 isoforms that differentially regulate the ER-Golgi network, promoting the heterogeneous HCC progression.

中文翻译：

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USO1 异构体通过失调 ER-高尔基体网络差异性地促进肝癌进展。

RNA 转录本的选择性剪接在癌症的发展和进展中起着重要作用。RNA-seq 技术的最新进展使得识别各种类型癌症中的交替剪接事件成为可能；然而，对肝细胞癌（HCC）的研究仍然有限。在这里，通过在同种型水平对 HCC 转录物进行 RNA-seq 分析，我们确定了 USO1 同种型的肿瘤特异性和分子亚型依赖性表达，我们将其指定为正常形式 USO1-N (XM_001290049) 和肿瘤形式 USO1- T (NM_003715)。USO1-T 的表达，而不是 USO1-N，与 HCC 患者较差的预后结果相关。我们证实 USO1-T 的表达在体外和体内促进了 HCC 的侵袭性表型。此外，结构建模分析表明，USO1-T 缺少由外显子 15 编码的 ARM10 环，这可能会削弱 USO1 的二聚化及其与 GM130 的连接。我们证明了 USO1-T 确保了高尔基体的分离，并加速了多个肝癌细胞中从内质网 (ER) 到高尔基体和质膜的囊泡运输。发现 ERK 和 GRASP65 与 USO1-T 介导的高尔基体功能障碍有关。最后，我们为 USO1 异构体提供了新的机械物理见解，这些异构体差异调节 ER-高尔基体网络，促进异质性 HCC 进展。我们证明了 USO1-T 确保了高尔基体的分离，并加速了多个肝癌细胞中从内质网 (ER) 到高尔基体和质膜的囊泡运输。发现 ERK 和 GRASP65 与 USO1-T 介导的高尔基体功能障碍有关。最后，我们为 USO1 异构体提供了新的机械物理见解，这些异构体差异调节 ER-高尔基体网络，促进异质性 HCC 进展。我们证明了 USO1-T 确保了高尔基体的分离，并加速了多个肝癌细胞中从内质网 (ER) 到高尔基体和质膜的囊泡运输。发现 ERK 和 GRASP65 与 USO1-T 介导的高尔基体功能障碍有关。最后，我们为 USO1 异构体提供了新的机械物理见解，这些异构体差异调节 ER-高尔基体网络，促进异质性 HCC 进展。