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.

中文翻译：

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肝细胞癌中泛素结合酶E2 L3的过表达通过抑制GSK3β/ p65途径来增强细胞凋亡逃避。

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。在这项研究中，我们发现与非肿瘤样本相比，临床HCC样本中的UBE2L3通常被上调，并且HBE患者中高的UBE2L3表达与肿瘤大小，临床等级和预后之间有着密切的联系。UBE2L3耗竭抑制HCC细胞增殖并诱导其凋亡。在分子水平上，我们观察到UBE2L3耗尽增强了GSK3β的蛋白质稳定性，从而促进了GSK3β的表达和激活。随后，激活的GSK3β磷酸化了p65，并促进了其核易位，以增加包括PUMA，Bax，Bim，Bad和Bid在内的靶基因的表达。体内，在原位肝注射裸鼠模型中，敲除HCC细胞中的UBE2L3可抑制肿瘤生长。而且，抑制p65或GSK3β可显着恢复HBE中UBE2L3敲除诱导的效应。总之，这项研究揭示了UBE2L3对HCC细胞增殖的刺激作用，表明UBE2L3可能是肝癌发生中的重要促肿瘤因素，也是HCC的潜在治疗靶标。