E2F family participates in most human malignancies by activating the transcription of the cell cycle-related genes. Whereas, as a specifical atypical member of this family, E2F7 was described as a repressor against its downstream genes and exerted oscillatory and controversial functions in cancers. Our previous study identified a molecular interaction promoting hepatocellular carcinoma (HCC) growth induced by SOX4 and Anillin. Meanwhile, we preliminarily identified SP1 as the upstream activator of SOX4. Intriguingly, we observed that the repressive E2F7 presents a remarkable high expression in HCC, and is positively correlated and involved in the same pathway with the potentially SP1/SOX4/Anillin axis. However, their exact interaction or mechanism controlling tumor progress between these genes has not been illustrated. Thus, we focused on this point in this study and attempted to improve the potential regulating axis in HCC cell proliferation and tumor growth for promoting tumor prevention and control. The expression profile of E2F7 in HCC tissues and tumor cells was detected along with the related candidate genes, through real-time quantitative polymerase chain reaction assay, the Western blot analysis, and the immunohistochemistry assay, combined with bioinformatics analysis of the HCC information from the the Cancer Genome Altas and Gene Expression Omnibus data sets. The correlation between E2F7 and HCC patients' clinicopathologic features was explored. Gain-of and loss-of-function assays were conducted both in vitro and in vivo along with the rescue experiment, for revealing the relative genes' functions in HCC progress. The ChIP and the dual-luciferase reporter assays were performed to verify the transcriptional regulating profile between E2F7 and SP1/SOX4/Anillin axis. E2F7 was upregulated in HCC and significantly correlated with SP1/SOX4/Anillin axis. High E2F7 expression is associated with dismal clinicopathologic features and poor survival of the patients. E2F7 depletion potently impaired SP1/SOX4/Anillin expression and significantly inhibited HCC growth. Furthermore, intensive exploration demonstrated that E2F7 preserves high SP1 levels by abrogating miR-383-5p in a transcriptional way. Atypical E2F7 is an important repressive transcription factor commonly upregulated in the HCC environment. E2F7 facilitates HCC growth by repressing miR-383-5p transcription and sequentially promoting SP1/SOX4/Anillin axis. Our findings provide us with probable targets for HCC prevention and therapeutic treatment.

中文翻译：

---

E2F7 通过抑制 miRNA-383-5p 转录来保留 SP1/SOX4/Anillin 轴，从而增强肝细胞癌的生长


E2F家族通过激活细胞周期相关基因的转录参与大多数人类恶性肿瘤。然而，作为该家族的一个特殊非典型成员，E2F7 被描述为对其下游基因的抑制因子，并在癌症中发挥振荡和有争议的功能。我们之前的研究发现了 SOX4 和 Anillin 诱导的促进肝细胞癌 (HCC) 生长的分子相互作用。同时，我们初步鉴定SP1是SOX4的上游激活子。有趣的是，我们观察到抑制性 E2F7 在 HCC 中呈现显着的高表达，并且与潜在的 SP1/SOX4/Anillin 轴呈正相关并参与相同的通路。然而，这些基因之间的确切相互作用或控制肿瘤进展的机制尚未得到阐明。因此，本研究围绕这一点，试图改善肝癌细胞增殖和肿瘤生长的潜在调控轴，以促进肿瘤的防治。通过实时定量聚合酶链式反应检测、Western blot分析和免疫组化检测，结合HCC信息的生物信息学分析，检测E2F7在HCC组织和肿瘤细胞中的表达谱以及相关候选基因。癌症基因组 Altas 和基因表达综合数据集。探讨了E2F7与HCC患者临床病理特征之间的相关性。与救援实验一起在体外和体内进行功能获得和功能丧失测定，以揭示相关基因在 HCC 进展中的功能。 进行 ChIP 和双荧光素酶报告基因测定以验证 E2F7 和 SP1/SOX4/Anillin 轴之间的转录调控谱。 E2F7 在 HCC 中表达上调，并且与 SP1/SOX4/Anillin 轴显着相关。 E2F7 高表达与患者的临床病理特征不佳和生存率低相关。 E2F7 耗竭会严重损害 SP1/SOX4/Anilin 表达，并显着抑制 HCC 生长。此外，深入的探索表明，E2F7 通过以转录方式消除 miR-383-5p 来保留高 SP1 水平。非典型 E2F7 是一种重要的抑制性转录因子，在 HCC 环境中通常上调。 E2F7 通过抑制 miR-383-5p 转录并依次促进 SP1/SOX4/Anillin 轴来促进 HCC 生长。我们的研究结果为我们提供了 HCC 预防和治疗的可能目标。