The Third Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, Jilin, China.
Department of Prosthodontics, Hospital of Stomatology, Jilin University, Changchun, Jilin, China.
Cell Biol Int. 2022 May;46(5):806-818. doi: 10.1002/cbin.11772. Epub 2022 Mar 7.
Oral squamous cell carcinoma (OSCC) and hypopharyngeal squamous cell carcinoma (HSCC) are representative of head and neck squamous cell carcinoma (HNSCC) and the molecular pathogenesis has not been completely clarified. Ubiquitin-conjugating enzyme E2 L3 (UBE2L3) is the key member of the E2 family that encodes 153 amino acid residues. Previous studies demonstrate that UBE2L3 is aberrantly overexpressed in various types of human cancers, suggesting that UBE2L3 may function as an oncogene. However, its functional role and the potential mechanisms in the OSCC and HSCC remain unclear. In the present study, we found that UBE2L3 was significantly upregulated in clinical HNSCC samples and HNSCC cell lines, and patients with lower UBE2L3 expression have a higher survival rate. Two HNSCC cell lines FaDu (HSCC cells) and CAL-27 (OSCC cells) with moderate expression of UBE2L3 were selected for in vitro experiments. We proved that UBE2L3 overexpression was positively associated with cellular malignant phenotypes in vitro, including proliferation, invasion, migration, and tumor growth in vivo. Conversely, UBE2L3 suppression diametrically yielded opposing results. Our further study demonstrated that overexpression of UBE2L3 significantly activated the nuclear factor kappa B (NF-κB) signaling pathway through promoting NF-κB p65 nuclear translocation and the ubiquitination and degradation of IκBα protein. Additionally, UBE2L3 was proved to be targeted and negatively regulated by miR-378a-5p, and UBE2L3 overexpression reversed the effects of miR-378a-5p upregulation. Collectively, the present study indicates that UBE2L3 may promote OSCC and HSCC progression via activating the NF-κB signaling by increasing IκBα degradation, indicating that UBE2L3 may be a potential therapeutic target for the treatment of HNSCC.
口腔鳞状细胞癌 (OSCC) 和下咽鳞状细胞癌 (HSCC) 是头颈部鳞状细胞癌 (HNSCC) 的代表，其分子发病机制尚未完全阐明。泛素结合酶 E2 L3 (UBE2L3) 是 E2 家族的关键成员，编码 153 个氨基酸残基。先前的研究表明，UBE2L3 在各种类型的人类癌症中异常过表达，表明 UBE2L3 可能发挥癌基因的作用。然而，其在 OSCC 和 HSCC 中的功能作用和潜在机制尚不清楚。在本研究中，我们发现 UBE2L3 在临床 HNSCC 样本和 HNSCC 细胞系中显著上调，UBE2L3 表达较低的患者生存率较高。选择具有中等 UBE2L3 表达的两种 HNSCC 细胞系 FaDu (HSCC 细胞) 和 CAL-27 (OSCC 细胞) 进行体外实验。我们证明 UBE2L3 的过表达与体外细胞恶性表型呈正相关，包括增殖、侵袭、迁移和体内肿瘤生长。相反，UBE2L3 抑制则产生相反的结果。我们的进一步研究表明，UBE2L3 的过表达通过促进 NF-κB p65 核易位和 IκBα 蛋白的泛素化和降解，显著激活核因子 κB (NF-κB) 信号通路。此外，UBE2L3 被证明是 miR-378a-5p 的靶向和负调控因子，UBE2L3 的过表达逆转了 miR-378a-5p 上调的作用。综上所述，本研究表明 UBE2L3 通过增加 IκBα 降解来激活 NF-κB 信号通路，从而促进 OSCC 和 HSCC 的进展，表明 UBE2L3 可能是治疗 HNSCC 的潜在治疗靶点。
