Inhibition of Embryonic Genes to Control Colorectal Cancer Metastasis.

摘要

Embryonic core transcription factors (TFs), primarily the retrogene NanogP8, are the master regulators of cancer stem cells (CSC) in human colorectal carcinoma (CRC). The corollary is that inhibition of NanogP8 will inhibit neoplastic progression of CRC. During the second year of funding we confirmed that NANOG is expressed in the majority of primary human colon carcinomas and that its expression is a significant prognostic factor, especially when associated with expression of the cell adhesion scaffold protein NEDD9. We also elucidated that inhibition of NANOGP8 and/or NANOG induces apoptosis through inhibition of MCL-1 as well as proof of the principle that vector-delivered shRNA to NANOGP8 and/or NANOG complements inhibition of BCL-2 and BCL-XL as a means to inhibit and kill human colorectal cells. Finally we have demonstrated that intralesional injection of LV-delivered shRNA to NANOGP8 or NANOG transduces tumor cells within xenografts growing in vivo in NOD/SCID mice as well as the probable need to create a conditionally replicating adenovirus.