260. LOW BLOOD LEVEL OF TUMOR SUPPRESSOR MIR-3619 AS A TARGET OF NUCLEIC ACID THERAPY TO PIM-1 IN ESOPHAGEAL CANCER

Abstract

Background Numerous studies have attempted to understand the molecular mechanisms of tumorigenesis and identify clinical biomarkers and molecular targets for esophageal squamous cell carcinoma (ESCC). However, there are still only a few biomarkers and targets. We focused on tumor suppressor micro-RNA (miR)s in the plasma of ESCC patients, and we investigated the usefulness of these tumor suppressor miRs as biomarkers and therapeutic agents for ESCC. Methods: Plasma samples of 94 ESCC patients and 86 healthy volunteers were analyzed in this study. Among the group of 2600 miRs candidates registered in miRbase, we selected 25 miRs candidates which are low expressed in ESCC tissues, have tumor suppressive functions, and unreported as a body fluid biomarker. We selected 5 miRs (miR-564/ 637/ 1182/ 3178/ 3619), whose signals were detectable in the blood of healthy volunteers by microarray analysis. By test-scale analysis using TaqMan assay and validation analysis, we identified miR-3619, which showed the most significant difference in ESCC patients compared to healthy volunteers (p < 0.001). Results: 1) Prognostic analysis revealed that a low miR-3619 plasma level was significantly associated with advanced stage and recurrence rate, and was an independent factor predicting poor prognosis in ESCC patients (p = 0.028, HR = 2.09). 2) Overexpression of miR-3619 mimic inhibited the proliferation of ESCC cells, induced the accumulation of apoptosis or G1/S phase cells, and reduced the cell migration and invasion abilities compared with negative control mimic. 3) We tested PIM-1xas candidate putative target genes for miR-3619 using microRNA database. PIM-1 protein expression levels were decreased in miR-3619-5p transfectants compared with NC. 4) In vivo, subcutaneous injection of miR-3619 could significantly inhibit tumor growth in mice. Administration of miR-3619 did not cause any clinical adverse events or side effects in blood-based parameters reflecting organ disorders. Conclusion: These results suggest that depleted tumor-suppressor miR-3619 in plasma could be one of blood-based biomarkers for predicting malignant potential of ESCC.