Department of Stem Cell Sciences, Graduate School of Health Sciences, Center for Stem Cell Research and Development, Hacettepe University, Sihhiye, 06100, Ankara, Turkey.
Blood Bank, Burhan Nalbantoglu State Hospital, Nicosia, North Cyprus.
Mol Biol Rep. 2019 Feb;46(1):669-678. doi: 10.1007/s11033-018-4522-z. Epub 2018 Dec 4.
HOX and TALE transcription factors are important regulators of development and homeostasis in determining cellular identity. Deregulation of this process may drive cancer progression. The aim of this study was to investigate the expression of these transcription factors in the bone marrow derived mesenchymal stem cells (BM-MSCs) of Fanconi anemia (FA) patients, which is a cancer-predisposing disease. Expression levels of HOX and TALE genes in BM-MSCs were obtained from FA patients and healthy donors by RT-qPCR and highly conserved expression levels were observed between patient and donor cells, except PKNOX2, which is a member of TALE class. PKNOX2 was significantly downregulated in FA cells compared to donors (P < 0.05). PKNOX2 expression levels did not change with diepoxybutane (DEB), a DNA crosslinking agent, in either donor or FA cells except one patient's with a truncation mutation of FANCA. A difference of PKNOX2 protein level was not obtained between FA patient and donor BM-MSCs by western blot analysis. When human TGF-β1 (rTGF-β1) recombinant protein was provided to the cultures, PKNOX2 as well as TGF-β1 expression increased both in FA and donor BM-MSCs in a dose dependent manner. 5 ng/mL rTGF-β stimulation had more dominant effect on the gene expression of donor BM-MSCs compared to FA cells. Decreased PKNOX2 expression in FA BM-MSCs may provide new insights into the molecular pathophysiology of the disease and TGF-β1 levels of the microenvironment may be the cause of PKNOX2 downregulation.
HOX 和 TALE 转录因子是决定细胞身份的发育和稳态的重要调节剂。该过程的失调可能会推动癌症的进展。本研究旨在研究范可尼贫血（FA）患者骨髓间充质干细胞（BM-MSCs）中这些转录因子的表达情况，FA 是一种易患癌症的疾病。通过 RT-qPCR 从 FA 患者和健康供体中获得 BM-MSCs 中 HOX 和 TALE 基因的表达水平，除了 TALE 类的 PKNOX2 外，患者和供体细胞之间观察到高度保守的表达水平。与供体相比，FA 细胞中 PKNOX2 的表达明显下调（P < 0.05）。除了一名具有 FANCA 截断突变的患者外，DEB（一种 DNA 交联剂）在供体或 FA 细胞中均未改变 PKNOX2 的表达水平。FA 患者和供体 BM-MSCs 之间通过 Western blot 分析未获得 PKNOX2 蛋白水平的差异。当提供人 TGF-β1（rTGF-β1）重组蛋白时，PKNOX2 以及 TGF-β1 在 FA 和供体 BM-MSCs 中的表达均呈剂量依赖性增加。与 FA 细胞相比，5ng/mL rTGF-β 刺激对供体 BM-MSCs 的基因表达具有更显著的影响。FA BM-MSCs 中 PKNOX2 表达的降低可能为该疾病的分子病理生理学提供新的见解，并且微环境中 TGF-β1 的水平可能是 PKNOX2 下调的原因。
