Abstract
BackgroundPlasma microRNA (miRNA) has become a promising biomarker for detecting cancer; however, it remains uncertain whether miRNA expression levels in plasma reflect those in tumor cells. Our aim was to determine the biological relevance of miR-92a, which has been implicated as an oncomiR in both plasma and leukemia cells in patients with acute leukemia and to evaluate whether it could be a novel biomarker for monitoring these patients.ResultsWe quantified the expression level of miR-92a in both cells and plasma by reverse transcription polymerase chain reaction in 91 patients with acute leukemia. We also determined miR-92a expression levels in peripheral blood mononuclear cells (PBMNC) from normal controls. We compared miR-92a expression in plasma with its expression in leukemia cells. Synthetic anti-miR-92a inhibitor was transfected into Raji and OM9;22 cells, and apoptosis was assessed. For in vivo assessment, 6-week-old female nude mice were injected with U937 cells, and miR-92a expression in plasma and tumors was measured. The level of miR-92a expression in fresh leukemia cells was highly variable compared with PBMNC, but significantly lower compared with CD34-positive cells obtained from healthy volunteers. We also noticed that miR-92a was preferentially expressed in acute lymphoblastic leukemia (ALL) cells in comparison with acute myeloid leukemia (AML) cells. More specifically, cellular miR-92a expression was significantly increased in a subset of ALL cells, and ALL patients with overexpressed miR-92a had poor prognoses. The anti-miR-92a inhibitor-treated Raji and OM9;22 cells revealed an increase of apoptotic cells. Notably, the cell to plasma ratio of miR-92a expression was significantly higher in both AML and ALL cells compared with PBMNC from healthy volunteers. In tumor-bearing mice, the plasma miR-92a level was significantly decreased in accordance with tumor growth, while tumor tissue was strongly positive for miR-92a.ConclusionsThe miR-92a expression in leukemia cells could be a prognostic factor in ALL patients. The inverse correlation of miR-92a expression between cells and plasma and the cell to plasma ratio may be important to understanding the clinical and biological relevance of miR-92a in acute leukemia.
Highlights
Plasma microRNA has become a promising biomarker for detecting cancer; it remains uncertain whether miRNA expression levels in plasma reflect those in tumor cells
We found that the miR-92a plasma expression level was significantly lower–approximately only 1/ 100th–in both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) compared with normal controls
We show that the cell to plasma ratio of miR-92a expression is significantly higher for both AML and ALL compared with the ratio based on peripheral blood mononuclear cells (PBMNC) from healthy volunteers
Summary
Plasma microRNA (miRNA) has become a promising biomarker for detecting cancer; it remains uncertain whether miRNA expression levels in plasma reflect those in tumor cells. MicroRNAs (miRNAs) are a class of small noncoding RNAs of 19 to 25 nucleotides in size that are endogenously expressed in mammalian cells [1,2,3]. They regulate gene expression by repressing mRNA translation or cleaving target mRNA. Evidence suggests that certain tumor-derived circulating miRNAs, such as miR-155, miR-21, miR-15b, miR16, and miR-24, are detected in cell-free specimens, such as plasma and serum of cancer patients, regardless of the high RNAse activity in plasma; this may reflect tumor-derived miRNA [5,6]. The question has arisen regarding why the level of miR-92a is down-regulated in acute leukemia cells
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