Liu Song-Mei, Chen Weiping, Wang Jin
Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China.
Microarray Core, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Sci Rep. 2014 Jul 4;4:5577. doi: 10.1038/srep05577.
All-trans retinoic acid (ATRA) induces differentiation in various cell types and has been investigated extensively for its effective use in cancer prevention and treatment. Relapsed or refractory disease that is resistant to ATRA is a clinically significant problem. To identify the molecular mechanism that bridges ATRA differentiation and resistance in cancer, we selected the multidrug-resistant leukemia cell line HL-60[R] by exposing it to ATRA, followed by sequential increases of one-half log concentration. A cytotoxicity analysis revealed that HL-60[R] cells were highly resistant to ATRA, doxorubicin, and etoposide. A comparative genome hybridization analysis of HL-60[R] cells identified gains of 4q34, 9q12, and 19q13 and a loss of Yq12 compared with in the parental HL-60 cell line. Transcriptional profiles and functional pathway analyses further demonstrated that 7 genes (FEN1, RFC5, EXO1, XRCC5, PARP1, POLR2F, and GTF2H3) that were relatively up-regulated in HL-60[R] cells and repressed in cells with ATRA-induced differentiation were related to mismatch repair in eukaryotes, DNA double-strand break repair, and nucleotide excision repair pathways. Our results suggest that transcriptional time series profiles and a functional pathway analysis of drug resistance and ATRA-induced cell differentiation will be useful for identifying promyelocytic leukemia patients who are eligible for new therapeutic strategies.
全反式维甲酸（ATRA）可诱导多种细胞类型分化，并且因其在癌症预防和治疗中的有效应用而受到广泛研究。对ATRA耐药的复发或难治性疾病是一个具有临床意义的问题。为了确定在癌症中介导ATRA分化和耐药性的分子机制，我们通过将多药耐药白血病细胞系HL-60[R]暴露于ATRA，随后依次将浓度提高半对数，从而筛选出该细胞系。细胞毒性分析显示，HL-60[R]细胞对ATRA、阿霉素和依托泊苷具有高度耐药性。与亲本HL-60细胞系相比，对HL-60[R]细胞进行的比较基因组杂交分析确定了4q34、9q12和19q13区域的扩增以及Yq12区域的缺失。转录谱和功能通路分析进一步表明，在HL-60[R]细胞中相对上调而在ATRA诱导分化的细胞中受到抑制的7个基因（FEN1、RFC5、EXO1、XRCC5、PARP1、POLR2F和GTF2H3）与真核生物错配修复、DNA双链断裂修复和核苷酸切除修复通路有关。我们的结果表明，耐药性和ATRA诱导的细胞分化的转录时间序列谱和功能通路分析将有助于识别适合新治疗策略的早幼粒细胞白血病患者。
