A Nankai University-based team developed a small circular single-stranded DNA molecule that inhibits cancer growth in cells and mice by sequestering microRNAs (miRNAs) that silence tumor suppressor genes.
Preclinical deals in nucleic acid modalities over the past five years show increasing interest among pharmas in nucleic acid therapeutics, in particular for siRNA and mRNA. But interest in microRNA (miRNA) has tapered after discontinuations of miRNA candidates to treat HCV from Regulus Therapeutics Inc. (NASDAQ:RGLS) and Santaris Pharma A/S (see BioCentury Innovations, May 10).
In a paper in Science Translational Medicine, researchers first found that increased expression of tumor suppressor genes Kruppel-like factor 17 (KLF17), e-cadherin (CDH1; CD324) and ceramide synthase 2 (CERS2; LASS2) was associated with improved median survival times in breast, lung and ovarian cancer patients. Overexpressing the three genes in HeLa cells decreased cell proliferation, migration, invasion and colony formation and increased cell death.
The team then screened miRNA databases for common oncogenic miRNAs targeting the three genes. Of the screened miRNAs, transfecting microRNA-9 (miR-9) had the greatest inhibitory effect on expression of the three genes in HeLa cells.
Based on the finding, the researchers generated CSSD-9 -- a circular single-stranded DNA that mimics the stable, covalently closed loop of a circular RNA -- that contained four miR-9 binding sites. CSSD-9 inhibited cell invasion and migration and increased cell death in cervical, lung and liver cancer cell lines. In HeLa cells, nanoparticles loaded with CSSD-9 decreased cell proliferation, migration, invasion and colony formation and increased apoptosis.
In mouse xenograft models of cervical, lung and liver cancer, a mixture of CSSD-9 and nanoparticles to bind to the DNA molecules and prevent degradation by nucleases decreased tumor growth and lung metastatic nodules. CSSD-9 also decreased tumor growth in patient-derived xenograft mouse models of liver, lung, cervical, ovarian and breast cancer with high miR-9 expression, and the tumor inhibition rate was positively correlated with miR-9 expression and negatively correlated with expression of KLF17, CDH1 and CERS2.