Abstract 5323: Innovative bridged nucleic acid (BNA)-based cellular reprogramming medicine towards extermination of gastrointestinal cancer.

Abstract

Abstract Background. Considering that cancer is a disease with genetic and epigenetic origins, we have examined the possible effects of cellular reprogramming by induction or inhibition of cancer-related genes and immature status-related genes including that of induced pluripotent stem (iPS) cell genes. Viral-mediated introduction of iPS cell genes was necessary for inducing the expression of immature status-related proteins in gastrointestinal cancer (GIC) cells. We reprogrammed successfully mouse and human cells to pluripotency by direct transfection of mature double-stranded microRNAs (miRNAs) as a combination, and then studied the underlying mechanism of miRNA-based reprogramming and the possible application for cancer cell reprogramming as a novel therapeutic approach. Given that induced GIC cells showed slow proliferation and were sensitized to differentiation-inducing treatment, and in vivo tumorigenesis was reduced in immunodeficient mice, it is naturally expected that pharmacogenomics of targeting iPS cell genes may sensitize cancer cell populations that were largely refractory to conventional chemotherapy, which may open an avenue to treat gastrointestinal cancers that are difficult to cure. To development of nucleic acid medicine for extermination of cancer, we screened the sets of bridged nucleic acid (BNAs) for cell reprogramming. Materials and Methods. We designed 20 kinds of chemically modified BNA to each miRNAs (has-mir-200c, has-mir-302s, has-mir-369). The BNAs were transfected into the cells and examined the efficiency of reprogramming. To inactivate cancer cells, we transfected a small set of BNAs by in vitro experiments, including cell growth, invasion, sphere formation, differentiation assay (three germs) and immunocytochemistry; and in vivo ones, such as chemo-sensitivity, teratoma assay and tumorigenesis. Result. We identified the most efficient sets of BNAs for cell reprogramming. These sets of BNAs were able to reprogram colorectal cancer cells in vitro, as shown by microscopic analysis and qRT-PCR: three germ cell line differentiation, reduced proliferation and suppressed invasion. Cell fate analysis in vitro demonstrated that colorectal cancer cells reprogrammed, while remaining cells were subjected to apoptosis induction. The reprogrammed cells were sensitized to chemotherapy (fluorouracil). Conclusion. We identified the most efficient sets of chemically modified BNAs for reprogramming. In vitro and in vivo assay demonstrated clearly that cancer-reprogramming therapy using synthesized BNAs could modurate the cancer cell malignancy. In the future BNAs-mediated cancer reprogramming should be a promising potion for innovative cancer treatment. Citation Format: Masamitsu Konno. Innovative bridged nucleic acid (BNA)-based cellular reprogramming medicine towards extermination of gastrointestinal cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5323. doi:10.1158/1538-7445.AM2013-5323