The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou 310053, China.
The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou 310014, China.
Int J Med Sci. 2021 Oct 11;18(16):3749-3758. doi: 10.7150/ijms.63220. eCollection 2021.
The ubiquitin-conjugating enzyme (E2) is a critical component of the ubiquitin-proteasome system and regulates hepatocarcinogenesis by controlling protein degradation. Ubiquitin-conjugating enzyme E2 O (UBE2O), a member of the E2 family, functions as an oncogene in human cancers. Nevertheless, the role of UBE2O in hepatocellular carcinoma (HCC) remains unknown yet. Here, we demonstrated that the UBE2O level was markedly upregulated in HCC compared with adjacent noncancerous tissues. UBE2O overexpression was also confirmed in HCC cell lines. UBE2O overexpression was prominently associated with advanced tumor stage, high tumor grade, venous infiltration, and reduced HCC patients' survivals. UBE2O knockdown inhibited the migration, invasion, and proliferation of HCCLM3 cells. UBE2O overexpression enhanced the proliferation and mobility of Huh7 cells. Mechanistically, UBE2O mediated the ubiquitination and degradation of AMP-activated protein kinase α2 (AMPKα2) in HCC cells. UBE2O silencing prominently increased AMPKα2 level and reduced phosphorylated mechanistic target of rapamycin kinase (p-mTOR), MYC, Cyclin D1, HIF1α, and SREBP1 levels in HCCLM3 cells. UBE2O depletion markedly activated the AMPKα2/mTOR pathway in Huh7 cells. Moreover, AMPKα2 silencing reversed UBE2O downregulation-induced mTOR pathway inactivation. Rapamycin, an inhibitor of mTOR, remarkably abolished UBE2O-induced mTOR phosphorylation and HCC cell proliferation and mobility. To conclude, UBE2O was highly expressed in HCC and its overexpression conferred to the poor clinical outcomes of patients. UBE2O contributed to the malignant behaviors of HCC cells, including cell proliferation, migration, and invasion, by reducing AMPKα2 stability and activating the mTOR pathway.
泛素结合酶 (E2) 是泛素-蛋白酶体系统的关键组成部分，通过控制蛋白质降解来调节肝癌的发生。泛素结合酶 E2 O (UBE2O) 是 E2 家族的成员，在人类癌症中作为癌基因发挥作用。然而，UBE2O 在肝细胞癌 (HCC) 中的作用尚不清楚。在这里，我们证明与相邻非癌组织相比，HCC 中 UBE2O 的水平明显上调。还证实 HCC 细胞系中存在 UBE2O 过表达。UBE2O 过表达与晚期肿瘤分期、高肿瘤分级、静脉浸润和降低 HCC 患者生存率显著相关。UBE2O 敲低抑制 HCCLM3 细胞的迁移、侵袭和增殖。UBE2O 过表达增强 Huh7 细胞的增殖和迁移能力。机制上，UBE2O 在 HCC 细胞中介导 AMP 激活蛋白激酶 α2 (AMPKα2) 的泛素化和降解。UBE2O 沉默显著增加 HCCLM3 细胞中 AMPKα2 水平，并降低磷酸化雷帕霉素靶蛋白激酶 (p-mTOR)、MYC、细胞周期蛋白 D1、HIF1α 和 SREBP1 水平。UBE2O 耗竭在 Huh7 细胞中显著激活 AMPKα2/mTOR 通路。此外，AMPKα2 沉默逆转了 UBE2O 下调诱导的 mTOR 通路失活。mTOR 抑制剂雷帕霉素显著消除了 UBE2O 诱导的 mTOR 磷酸化和 HCC 细胞增殖和迁移。总之，UBE2O 在 HCC 中高表达，其过表达赋予患者不良的临床结局。UBE2O 通过降低 AMPKα2 稳定性并激活 mTOR 通路，促进 HCC 细胞的恶性行为，包括细胞增殖、迁移和侵袭。
