标题：Distinguishing between cancer cell differentiation and resistance induced by all-trans retinoic acid using transcriptional profiles and functional pathway analysis
摘要：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.
