泛素连接酶E2S（UBE2S）是一种E2酶，与多种肿瘤的发生发展及其致癌活性相关。UBE2S在肿瘤中，包括肝细胞癌（HCC）中过度表达。然而，UBE2S在HCC中的关键分子机制仍需要进一步研究。本研究旨在探索UBE2S在HCC中的作用。通过Western blot分析、定量实时聚合酶链反应分析（qRT-PCR）和免疫组织化学（IHC）检测了HCC组织和细胞中UBE2S的表达水平。利用3-(4,5-二甲基噻唑-2-基)-2,5-二苯基-2H-四唑溴化物（MTT）测定法、划痕愈合实验、集落形成实验、透明膜实验和动物模型检测了HCC细胞的增殖和迁移能力。通过Western blot分析、qRT-PCR、免疫荧光、小干扰RNA（siRNA）和质粒转染及共免疫沉淀（Co-IP）实验检测了UBE2S、von Hippel-Lindau（VHL）、低氧诱导因子1α（HIF-1α）、丝裂原激酶2（JAK2）和信号传导子及转录激活子3（STAT3）之间的相互作用。本研究发现，高UBE2S表达与HCC患者的预后不良相关。此外，UBE2S表达在HCC组织和细胞系中上调。UBE2S的沉默抑制了HCC细胞的增殖和迁移能力，通过直接与VHL相互作用，下调HIF-1α和JAK2/STAT3信号通路。相反，UBE2S的过表达通过VHL上调HIF-1α和JAK2/STAT3信号通路，显著增强了HCC细胞的增殖和迁移能力。此外，我们发现通过下调UBE2S表达可以提高HCC细胞对索拉非尼的敏感性，无论在体内还是体外。UBE2S通过VHL/HIF-1α和VHL/JAK2/STAT3信号通路增强了HCC的恶性特性，并降低了对索拉非尼的敏感性。本研究的发现可能为HCC的诊断提供新途径，并为HCC的治疗提供潜在的选择。© 2023年作者。Cancer Medicine由约翰·威利和儿子有限公司出版。

Ubiquitin-conjugating enzyme E2S (UBE2S), an E2 enzyme, is associated with the development of various tumors and exerts oncogenic activities. UBE2S is overexpressed in tumors, including hepatocellular carcinoma (HCC). However, the key molecular mechanisms of UBE2S in HCC still need additional research. The aim of this study was to explore the role of UBE2S in HCC.The expression levels of UBE2S in HCC tissues and cells were detected by western blot analysis, quantitative real-time polymerase chain reaction analysis (qRT-PCR), and immunohistochemistry (IHC). A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, wound healing assay, colony formation assay transwell assay, and animal models were used to detect the proliferation and migration ability of HCC cells. Western blot analysis, qRT-PCR, immunofluorescence, small-interfering RNA (siRNA), and plasmid transfection and coimmunoprecipitation (Co-IP) assays were performed to detect the interaction among UBE2S, von Hippel-Lindau (VHL), hypoxia-inducible factor 1-alpha (HIF-1α), Janus kinase-2 (JAK2), and signal transducer and activator of transcription 3 (STAT3).In this study, we found that high UBE2S expression was associated with poor prognosis in HCC patients. In addition, UBE2S expression was upregulated in HCC tissues and cell lines. Knockdown of UBE2S inhibited the proliferation and migration of HCC cells in vitro and in vivo by directly interacting with VHL to downregulate the HIF-1α and JAK2/STAT3 signaling pathways. Accordingly, overexpression of UBE2S significantly enhanced the proliferation and migration of HCC cells in vitro via VHL to upregulate HIF-1α and JAK2/STAT3 signaling pathways. Furthermore, we found that downregulation of UBE2S expression enhanced the sensitivity of HCC cells to sorafenib in vivo and in vitro.UBE2S enhances malignant properties via the VHL/HIF-1α and VHL/JAK2/STAT3 signaling pathways and reduces sensitivity to sorafenib in HCC. The findings of this study may open a new approach for HCC diagnosis and provide a potential option for the treatment of HCC.© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.