Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, 81744-176, Isfahan, Iran.
Diagnostic Laboratory Sciences and Technology Research Center, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran.
Med Oncol. 2022 Jun 8;39(8):117. doi: 10.1007/s12032-022-01709-9.
Acute lymphoblastic leukemia (ALL) is the most common malignancy in children and relapsed B-ALL is the leading cause of mortality in children with leukemia due to a lack of response to treatment. S100A8 is a low molecular weight calcium-binding intracellular protein that is expressed in certain cells, and its increased expression is seen in most tumors as well as in relapsed childhood B-ALL cases. The present study indicates the important role of S100A8 in improving viability and resistance to chemotherapy in relapsed B-ALL lymphoblasts. S100A8 levels were compared in B-ALL and relapsed B-ALL lymphoblasts that were sensitive and resistant to Vincristine, respectively. S100A8 was inhibited in the lymphoblasts of two patients by antisense locked nucleic acid (LNA) GapmeRs and the decreased expression of S100A8 was evaluated using quantitative real-time PCR and ELISA. Then, the S100A8 antisense LNA GapmeRs-transfected cells were treated with Vincristine and the expression levels of S100A8 mRNA and S100A8 protein were re-determined. At all of these stages, cell viability and LC50 were assessed by MTT assay. The results showed that S100A8 levels in relapsed B-ALL lymphoblasts were significantly higher than B-ALL lymphoblasts. Moreover, the increase in S100A8 expression was proportionate to the increase in Vincristine resistance in these cells. The S100A8 knockdown procedure using antisense LNA GapmeRs decreased the cell viability and increased vincristine sensitivity in lymphoblasts of two patients, and it also increased the sensitivity to chemotherapy in relapsed B-ALL lymphoblasts. According to the findings of the present study, S100A8 is effective in developing lymphoblast resistance to chemotherapy, and its enhanced expression may contribute to shifting B-ALL into the relapse phase of the illness. As a result, S100A8 may be a valuable target for managing and improving relapses B-ALL.
急性淋巴细胞白血病（ALL）是儿童中最常见的恶性肿瘤，由于对治疗无反应，复发的 B-ALL 是导致白血病患儿死亡的主要原因。S100A8 是一种低分子量的钙结合细胞内蛋白，在某些细胞中表达，其在大多数肿瘤以及复发的儿童 B-ALL 病例中表达增加。本研究表明，S100A8 在提高复发 B-ALL 淋巴母细胞的活力和对化疗的耐药性方面发挥着重要作用。分别比较了对长春新碱敏感和耐药的 B-ALL 和复发的 B-ALL 淋巴母细胞中的 S100A8 水平。用反义锁核酸（LNA）GapmeR 抑制两名患者的淋巴母细胞中的 S100A8，并通过定量实时 PCR 和 ELISA 评估 S100A8 的表达下调。然后，用长春新碱处理转染 S100A8 反义 LNA GapmeR 的细胞，并重新测定 S100A8mRNA 和 S100A8 蛋白的表达水平。在所有这些阶段，通过 MTT 测定法评估细胞活力和 LC50。结果表明，复发的 B-ALL 淋巴母细胞中的 S100A8 水平明显高于 B-ALL 淋巴母细胞。此外，S100A8 表达的增加与这些细胞中长春新碱耐药性的增加成正比。用反义 LNA GapmeR 进行 S100A8 敲低程序降低了两名患者的淋巴母细胞活力并增加了长春新碱的敏感性，并且还增加了复发的 B-ALL 淋巴母细胞对化疗的敏感性。根据本研究的结果，S100A8 可有效增强淋巴母细胞对化疗的耐药性，其表达增强可能导致 B-ALL 进入疾病复发阶段。因此，S100A8 可能是管理和改善复发 B-ALL 的有价值的靶点。
