USO1 isoforms differentially promote liver cancer progression by dysregulating the ER–Golgi network

Abstract

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 trafficking from 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.

USO1 expression is dysregulated in non-small cell lung cancer

“…USO1 has been implicated in tumourigenesis in multiple cancers including gastric ( 10 ), colon ( 11 ), breast ( 12 ), liver cancer ( 13 ) as well as multiple myeloma ( 14 ) and leukaemia ( 38 ). Overexpression of USO1 has been shown to play a role in cell proliferation and cell cycle transition in these studies, and as such in general, one would expect high expression of USO1 to be associated with worse OS.…”

“…The exact reason for this remains to be elucidated and warrants further investigation. It may be that a tumour specific transcript of USO1 is a key element as recently described for hepatocellular carcinoma, where a specific mRNA variant USO1-T (RefSeq NM_003715.4, transcript variant 2) is associated with worse prognostic outcomes and an aggressive phenotype in HCC ( 13 ).…”

“…USO1 has been shown to have higher levels of expression in these cancers and its role in tumourigenesis contributes to cell proliferation and evasion of apoptosis. Furthermore, multiple studies have identified USO1 exerts its oncogenic role by interfering with the Erk signalling pathway (13)(14)(15). Currently, to our knowledge there have been no studies regarding the expression of USO1 and its clinical implications in NSCLC.…”

“…It plays a critical role in both mitosis and apoptosis and is essential for mitotic spindle function through interacting with γ-tubulin ( 9 ). USO1 has been shown to be involved in the tumourigenesis of multiple cancers including gastric cancer ( 10 ), colorectal cancer ( 11 ), breast cancer ( 12 ), hepatocellular carcinoma ( 13 ) and multiple myeloma ( 14 ). USO1 has been shown to have higher levels of expression in these cancers and its role in tumourigenesis contributes to cell proliferation and evasion of apoptosis.…”

MCT4 Promotes Hepatocellular Carcinoma Progression by Upregulating TRAPPC5 Gene

“…ERK and GRASP65 were found to be involved in the USO1-T-mediated Golgi dysfunction. 20 In another study, Golgi compaction was found in cells that had completed an Epithelial to Mesenchymal transition (EMT), driven by the scaffolding protein PAQR11. 21 Experimental evidence also indicates that ER and Golgi apparatus can activate both pro-survival (recovery) mechanisms as well as cell suicide programs if the stress-signaling threshold is exceeded.…”