BK21 Plus KNU Multi-Omics Creative Drug Research Team, Kyungpook National University, Daegu 41566, Republic of Korea.
National Basic Research Laboratory of Vascular Homeostasis Regulation, College of Pharmacy, Kyungpook National University, Daegu 41566, Republic of Korea.
Int J Oncol. 2019 Apr;54(4):1327-1336. doi: 10.3892/ijo.2019.4713. Epub 2019 Feb 11.
Endothelial progenitor cells (EPCs) are bone marrow (BM)‑derived progenitor cells that can differentiate into mature endothelial cells, contributing to vasculogenesis in the blood vessel formation process. Runt‑related transcription factor 3 (RUNX3) belongs to the Runt domain family and is required for the differentiation of specific immune cells and neurons. The tumor suppressive role of RUNX3, via the induction of apoptosis and cell cycle arrest in a variety of cancers, and its deletion or frequent silencing by epigenetic mechanisms have been studied extensively; however, its role in the differentiation of EPCs is yet to be investigated. Therefore, in the present study, adult BM‑derived hematopoietic stem cells (HSCs) were isolated from Runx3 heterozygous (Rx3+/‑) or wild‑type (WT) mice. The differentiation of EPCs from the BM‑derived HSCs of Rx3+/‑ mice was found to be significantly increased compared with those of the WT mice, as determined by the number of small or large colony‑forming units. The migration and tube formation abilities of Rx3+/‑ EPCs were also observed to be significantly increased compared with those of WT EPCs. Furthermore, the number of circulating EPCs, defined as CD34+/vascular endothelial growth factor receptor 2 (VEGFR2)+ cells, was also significantly increased in Rx3+/‑ mice. Hypoxia‑inducible factor (HIF)‑1α was upregulated in Rx3+/‑ EPCs compared with WT EPCs, even under normoxic conditions. Furthermore, in a hindlimb ischemic mouse models, the recovery of blood flow was observed to be highly stimulated in Rx3+/‑ mice compared with WT mice. Also, in a Lewis lung carcinoma cell allograft model, the tumor size in Rx3+/‑ mice was significantly larger than that in WT mice, and the EPC cell population (CD34+/VEGFR2+ cells) recruited to the tumor was greater in the Rx3+/‑ mice compared with the WT mice. In conclusion, the present study revealed that Runx3 inhibits vasculogenesis via the inhibition of EPC differentiation and functions via the suppression of HIF‑1α activity.
内皮祖细胞（EPCs）是骨髓（BM）衍生的祖细胞，可分化为成熟的内皮细胞，有助于血管生成过程中的血管发生。Runt 相关转录因子 3（RUNX3）属于 Runt 结构域家族，是特定免疫细胞和神经元分化所必需的。RUNX3 的肿瘤抑制作用已通过在多种癌症中诱导细胞凋亡和细胞周期停滞得到广泛研究；然而，其在 EPC 分化中的作用尚未被研究。因此，在本研究中，从 Runx3 杂合（Rx3+/‑）或野生型（WT）小鼠中分离出 BM 来源的造血干细胞（HSCs）。与 WT 小鼠相比，Rx3+/‑ 小鼠 BM 来源 HSCs 分化的 EPCs 数量显著增加，小或大集落形成单位的数量表明。还观察到 Rx3+/‑ EPC 的迁移和管形成能力明显高于 WT EPC。此外，定义为 CD34+/血管内皮生长因子受体 2（VEGFR2）+细胞的循环 EPC 数量在 Rx3+/‑ 小鼠中也显著增加。与 WT EPC 相比，Rx3+/‑ EPC 中的缺氧诱导因子 1α（HIF-1α）即使在常氧条件下也上调。此外，在小鼠后肢缺血模型中，与 WT 小鼠相比，观察到 Rx3+/‑ 小鼠的血流恢复受到高度刺激。同样，在 Lewis 肺癌细胞同种异体移植模型中，Rx3+/‑ 小鼠的肿瘤体积明显大于 WT 小鼠，并且 Rx3+/‑ 小鼠中募集到肿瘤的 EPC 细胞群体（CD34+/VEGFR2+细胞）大于 WT 小鼠。综上所述，本研究表明，Runx3 通过抑制 EPC 分化和功能来抑制血管生成，通过抑制 HIF-1α 活性来抑制血管生成。
