Department of Infectious Disease, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders (Chongqing), China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China; Department of Clinical Laboratory, Chongqing Traditional Chinese Medicine Hospital, Chongqing, China.
Department of Infectious Disease, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders (Chongqing), China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.
Cancer Lett. 2020 Jul 1;481:1-14. doi: 10.1016/j.canlet.2020.03.028. Epub 2020 Apr 5.
UBE2L3 is a ubiquitin-conjugating protein belonging to the E2 family that consists of 153 amino acid residues. In this study, we found that UBE2L3 was generally upregulated in clinical HCC samples compared to non-tumour samples and that there was a strong association between high UBE2L3 expression and tumour size, clinical grade and prognosis in HCC patients. UBE2L3 depletion inhibited the proliferation and induced the apoptosis of HCC cells. At the molecular level, we observed that UBE2L3 depletion enhanced the protein stability of GSK3β, thus promoting the expression and activation of GSK3β. Subsequently, activated GSK3β phosphorylated p65 and promoted its nuclear translocation to increase the expression of target genes, including PUMA, Bax, Bim, Bad, and Bid. In vivo, knockout of UBE2L3 in HCC cells inhibited tumour growth in orthotopic liver injection nude mouse models. Moreover, inhibition of p65 or GSK3β significantly restored the effects induced by UBE2L3 knockout in HCC. Together, this study reveals the stimulatory effect of UBE2L3 on HCC cell proliferation, suggesting that UBE2L3 may be an important pro-tumorigenic factor in liver carcinogenesis and a potential therapeutic target of HCC.
UBE2L3 是一种泛素结合蛋白，属于 E2 家族，由 153 个氨基酸残基组成。在本研究中，我们发现 UBE2L3 在临床 HCC 样本中普遍上调，与非肿瘤样本相比，UBE2L3 的高表达与 HCC 患者的肿瘤大小、临床分级和预后有很强的相关性。UBE2L3 耗竭抑制 HCC 细胞的增殖并诱导其凋亡。在分子水平上，我们观察到 UBE2L3 耗竭增强了 GSK3β 的蛋白稳定性，从而促进了 GSK3β 的表达和激活。随后，激活的 GSK3β 磷酸化 p65 并促进其核转位，增加包括 PUMA、Bax、Bim、Bad 和 Bid 在内的靶基因的表达。在体内，HCC 细胞中 UBE2L3 的敲除抑制了原位肝注射裸鼠模型中的肿瘤生长。此外，p65 或 GSK3β 的抑制显著恢复了 UBE2L3 敲除在 HCC 中诱导的作用。总之，这项研究揭示了 UBE2L3 对 HCC 细胞增殖的刺激作用，表明 UBE2L3 可能是肝致癌发生中的一个重要促癌因子，也是 HCC 的一个潜在治疗靶点。
