Department of General Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Department of General Surgery, The Affiliated Luoyang Central Hospital of Zhengzhou University, Luoyang, China.
Curr Cancer Drug Targets. 2023;23(10):817-828. doi: 10.2174/1568009623666230511100246.
Hepatocellular carcinoma (HCC), one of the world's most prevalent malignancies, accounts for 90% of primary liver cancer cases. Recent studies have shown an increased expression of denticles E3 ubiquitin protein ligase homolog (DTL) in several different tumor types, but its function and regulatory mechanisms remain unclear.
This study aimed to investigate the expressions of the Cullin4 (CUL4) complex in HCC and elucidate the roles of DTL in HCC cells.
The relative expression of the CUL4 complex and its clinical significance were analyzed with The Cancer Genome Atlas (TCGA) data, and the level of DTL was confirmed by immunohistochemistry. The functions of DTL1 and upstream E2F1 were evaluated by a Western blot, MTT, transwell, and xenograft in HCC cell lines.
The elevated mRNA expression of the CUL4 complex, including CUL4B, DDB1 (Damage Specific DNA Binding Protein 1), and DTL, was associated with the overall survival of HCC patients. We also found that the DTL protein was elevated in HCC tissues, and patients with highly expressed DTL and nucleus-located DTL had a poorer survival time. DTL knockdown significantly inhibited cancer proliferation, migration, and invasion. Further experiments showed that E2F1 was an upstream regulatory molecule of DTL, which was bound to the promoter of DTL, promoting the expression of DTL.
The study results demonstrate that E2F1-DTL signaling promotes the growth, migration, and invasion of HCC cells, which provides new insights and a potential biological target for future HCC therapies.
肝细胞癌（HCC）是世界上最常见的恶性肿瘤之一，占原发性肝癌病例的 90%。最近的研究表明， denticles E3 泛素蛋白连接酶同源物（DTL）在几种不同的肿瘤类型中表达增加，但它的功能和调节机制尚不清楚。
本研究旨在探讨 Cullin4（CUL4）复合物在 HCC 中的表达，并阐明 DTL 在 HCC 细胞中的作用。
利用癌症基因组图谱（TCGA）数据分析 CUL4 复合物的相对表达及其临床意义，并通过免疫组织化学法验证 DTL 的水平。通过 Western blot、MTT、transwell 和 HCC 细胞系异种移植实验评估 DTL1 和上游 E2F1 的功能。
CUL4 复合物的 mRNA 表达升高，包括 CUL4B、DDB1（损伤特异性 DNA 结合蛋白 1）和 DTL，与 HCC 患者的总生存率相关。我们还发现 DTL 蛋白在 HCC 组织中升高，且 DTL 高表达和核定位的患者生存时间更差。DTL 敲低显著抑制了癌症的增殖、迁移和侵袭。进一步的实验表明，E2F1 是 DTL 的上游调节分子，它与 DTL 的启动子结合，促进 DTL 的表达。
研究结果表明，E2F1-DTL 信号促进了 HCC 细胞的生长、迁移和侵袭，为未来的 HCC 治疗提供了新的见解和潜在的生物学靶点。
