The Department of Laboratory Medicine and Medical Research Center, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Foshan, Chongqing 528308, P.R. China.
Department of Laboratory Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, P.R. China.
Oncol Rep. 2021 Jul;46(1). doi: 10.3892/or.2021.8082. Epub 2021 May 20.
Macrophage migration inhibitory factor (MIF) has been confirmed as an oncogene in solid tumor development, and its overexpression causes cell proliferation in T acute lymphoblastic leukemia (T‑ALL); however, the underlying mechanisms remain unclear. The overexpression of MIF promotes cellular transformation and proliferation, in part, through interaction with UHRF1. Nevertheless, overexpression of UHRF1 cannot upregulate expression in T‑ALL. New insights into MIF regulation in T‑ALL are imperative to offer the opportunity for therapeutic intervention. In the present study, using RT‑qPCR, western blot analysis, confocal microscopy and RNA sequence, we report the identification and validation of UHRF1 as a negative regulator of , which functions to downregulate MIF expression by binding to the CATT repeat sequence of the promoter. By contrast, HMG‑box protein 1 () functions as a positive regulator of MIF. Moreover, we demonstrated that HBP1 suppressive signaling is reduced by UHRF1 through promotion of the interaction between MIF and HBP1. deficiency caused by knockdown resulted in enhanced apoptosis in T‑ALL as compared with that caused by decreased MIF or increased HBP1 expression alone. These results identify UHRF1 as a key regulator of transcription in T‑ALL, although these transcription factors possess opposite regulatory functions. Thus, this mechanism may provide insight into how to effectively prevent MIF‑dependent oncogenic activity. Finally, T‑ALL mice possessing high HBP1 or low UHRF1 expression levels are associated with longer survival as compared with control mice, with ‑knockdown mice living the longest. Taken together, these findings indicate that MIF and its regulators are potential treatment targets and biomarkers for the prediction of prognosis in T‑ALL.
巨噬细胞移动抑制因子（MIF）已被证实是实体瘤发展中的癌基因，其过表达导致 T 急性淋巴细胞白血病（T-ALL）中的细胞增殖；然而，其潜在机制尚不清楚。MIF 的过表达促进细胞转化和增殖，部分原因是与 UHRF1 相互作用。然而，UHRF1 的过表达不能上调 T-ALL 中的表达。深入了解 MIF 在 T-ALL 中的调控对于提供治疗干预的机会至关重要。在本研究中，我们通过 RT-qPCR、western blot 分析、共聚焦显微镜和 RNA 测序，报告了 UHRF1 作为的负调节剂的鉴定和验证，其通过结合的 CATT 重复序列来下调的表达。相比之下，HMG-框蛋白 1（）作为 MIF 的正调节剂。此外，我们证明了 UHRF1 通过促进 MIF 和 HBP1 之间的相互作用来减少 HBP1 抑制信号。与单独降低 MIF 或增加 HBP1 表达相比，敲低导致的缺乏导致 T-ALL 中的凋亡增加。这些结果表明 UHRF1 是 T-ALL 中转录的关键调节剂，尽管这些转录因子具有相反的调节功能。因此，该机制可能为如何有效预防 MIF 依赖性致癌活性提供了深入了解。最后，与对照小鼠相比，具有高 HBP1 或低 UHRF1 表达水平的 T-ALL 小鼠具有更长的生存时间，并且敲低小鼠存活时间最长。总之，这些发现表明 MIF 及其调节剂是 T-ALL 潜在的治疗靶点和预后预测的生物标志物。
