Low levels of tumor suppressor miR-3619 in plasma contribute to malignant outcomes and a target for nucleic acid therapy in esophageal cancer.

Recent studies indicate that reduced levels of certain tumor-suppressing microRNAs (miRNAs) circulating in the blood are linked to tumor progression and poor prognosis across various types of malignancies. Identified from a comprehensive analysis of the NCBI and miRNA databases, we tested tumor suppressor miR-3619-5p in esophageal squamous cell carcinoma (ESCC). Both test-scale and large-scale analyses demonstrated that plasma levels of miR-3619-5p were markedly lower in ESCC patients than in healthy volunteers. Lower plasma levels of miR-3619-5p showed a strong association with advanced pathological stages and were recognized as an independent prognostic marker. Overexpression of miR-3619-5p in ESCC cells inhibited cell proliferation, migration and invasion through the direct suppression of novel target protein, proviral insertion site in Moloney murine leukemia virus 1 (PIM1). PIM1 is overexpressed in various solid and hematological cancers including ESCC, and has proven to be a promising target of inhibitors in recent clinical trials. In vivo, increased plasma 3619-5p levels following subcutaneous injection in mice bearing ESCC tumors significantly inhibited tumor growth, with low expression of PIM1 in tumor. Until now, no study has demonstrated that the secretory-type miRNA such as miR- 3619-5p could contribute to nucleic acid therapy to PIM1. Reduced blood levels of miR-3619-5p are linked to ESCC progression and poor prognosis, suggesting that miR-3619-5p could act as a novel therapeutic focus for nucleic acid-based treatment targeting PIM1 in ESCC patients.