The Second Affiliated Hospital, Dalian Medical University, Dalian, Liaoning 116044, P.R. China.
Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning 116044, P.R. China.
Int J Biol Sci. 2024 Sep 3;20(12):4767-4780. doi: 10.7150/ijbs.97861. eCollection 2024.
The important role of nucleobindin 2 (NUCB2) in various cancers has been recently recognized. However, its biological functions and regulatory mechanisms in hepatocellular carcinoma (HCC) remain unclear. The expression level of NUCB2 in HCC was assessed using public databases, immunohistochemistry, and Western blotting. The effects of NUCB2 on cell proliferation and metastasis were investigated using colony formation, EdU, Transwell assays, and an mouse xenograft model. Regulation of E2F4 by NUCB2 was identified by protein half-life and ubiquitylation assays. The relationship between E2F4 and prostaglandin reductase 1 (PTGR1) was investigated by qRT-PCR, RT-PCR, and chromatin immunoprecipitation assays. This study found that NUCB2 expression was significantly higher in HCC tissues than in normal liver tissues, and patients with high expression displayed shorter survival rates. Inhibition of NUCB2 reduced the proliferation and metastatic potential of HCC cells and . NUCB2 depletion reduced PTGR1 expression, which reduced cell proliferation and migration. Our findings suggested that NUCB2 suppressed E2F4 degradation by interacting with E2F4. Additionally, increased E2F4 levels facilitated PTGR1 transcription by directly binding to the PTGR1 promoter. This study demonstrated the oncogenic properties of NUCB2 in HCC and suggested that NUCB2 facilitates hepatocellular carcinoma progression by activating the E2F4/PTGR1 axis.
核结合蛋白 2（NUCB2）在各种癌症中的重要作用最近得到了认可。然而，其在肝细胞癌（HCC）中的生物学功能和调节机制尚不清楚。使用公共数据库、免疫组织化学和 Western blot 评估了 HCC 中 NUCB2 的表达水平。使用集落形成、EdU、Transwell 测定和小鼠异种移植模型研究了 NUCB2 对细胞增殖和转移的影响。通过蛋白半衰期和泛素化测定鉴定了 NUCB2 对 E2F4 的调节作用。通过 qRT-PCR、RT-PCR 和染色质免疫沉淀测定研究了 E2F4 和前列腺素还原酶 1（PTGR1）之间的关系。本研究发现，NUCB2 在 HCC 组织中的表达明显高于正常肝组织，高表达的患者生存率较低。抑制 NUCB2 降低了 HCC 细胞的增殖和转移潜能。NUCB2 耗竭降低了 PTGR1 的表达，从而降低了细胞增殖和迁移。我们的研究结果表明，NUCB2 通过与 E2F4 相互作用抑制 E2F4 的降解。此外，增加的 E2F4 水平通过直接结合 PTGR1 启动子促进 PTGR1 转录。本研究表明 NUCB2 在 HCC 中的致癌特性，并表明 NUCB2 通过激活 E2F4/PTGR1 轴促进肝细胞癌的进展。
