Chan Ti-Chun, Shiue Yow-Ling, Li Chien-Feng
Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan.
National Health Research Institutes, National Institute of Cancer Research, Tainan, Taiwan.
Front Oncol. 2023 Jan 27;13:1123776. doi: 10.3389/fonc.2023.1123776. eCollection 2023.
Urothelial carcinoma (UC), which includes urinary bladder urothelial carcinoma (UBUC) and upper tract urothelial carcinoma (UTUC), is one of the most common malignancies worldwide. Accordingly, a comprehensive understanding of the underlying mechanism governing UC development is compulsory. Aberrant CCAAT/enhancer-binding protein delta (CEBPD), a transcription factor, displays an oncogene or tumor suppressor depending on tumor type and microenvironments. However, CEBPD has been reported to possess a clear oncogenic function in UC through multiple regulation pathways. Genomic amplification of triggered by MYC-driven genome instability is frequently examined in UC that drives CEBPD overexpression. Upregulated CEBPD transcriptionally suppresses to stabilize MYC protein and further induces hexokinase II (HK2)-related aerobic glycolysis that fuels cell growth. Apart from the MYC-dependent pathway, CEBPD also downregulates the level of hsa-miR-429 to enhance HK2-associated glycolysis and induce angiogenesis driven by vascular endothelial growth factor A (VEGFA). Additionally, aggressive UC is attributed to the tumor metastasis regulated by CEBPD-induced matrix metalloproteinase-2 (MMP2) overexpression. Furthermore, elevated CEBPD induced by cisplatin (CDDP) is identified to have dual functions, namely, CDDP-induced chemotherapy resistance or drive CDDP-induced antitumorigenesis. Given that the role of CEBPD in UC is getting clear but pending a more systemic reappraisal, this review aimed to comprehensively discuss the underlying mechanism of CEBPD in UC tumorigenesis.
尿路上皮癌（UC），包括膀胱尿路上皮癌（UBUC）和上尿路尿路上皮癌（UTUC），是全球最常见的恶性肿瘤之一。因此，全面了解UC发生发展的潜在机制至关重要。异常的CCAAT/增强子结合蛋白δ（CEBPD）作为一种转录因子，根据肿瘤类型和微环境显示出癌基因或肿瘤抑制因子的作用。然而，据报道CEBPD通过多种调控途径在UC中具有明确的致癌功能。在由MYC驱动的基因组不稳定引发的UC中，经常检测到CEBPD的基因组扩增，这驱动了CEBPD的过表达。上调的CEBPD转录抑制[具体基因未提及]以稳定MYC蛋白，并进一步诱导与己糖激酶II（HK2）相关的有氧糖酵解，从而促进细胞生长。除了MYC依赖途径外，CEBPD还下调hsa-miR-429的水平，以增强与HK2相关的糖酵解，并诱导由血管内皮生长因子A（VEGFA）驱动的血管生成。此外，侵袭性UC归因于CEBPD诱导的基质金属蛋白酶-2（MMP2）过表达所调节的肿瘤转移。此外，顺铂（CDDP）诱导的CEBPD升高被确定具有双重功能，即CDDP诱导的化疗耐药性或驱动CDDP诱导的抗肿瘤作用。鉴于CEBPD在UC中的作用日益明确，但有待更系统的重新评估，本综述旨在全面讨论CEBPD在UC肿瘤发生中的潜在机制。
