Project description:We generated liver-specific Dyrk2 knockout mice mating Dyrk2 flox mice with Alb-cre mice and co-introduced SB13-transposase-, myrAkt-, Myc- and mutant Hras-expressing plasmids with either HA- or Dyrk2-expressing plasmid into the knockout mice by HTVi. Dyrk2-expressing suppressed tumorigenesis compared with HA-expressing.
Project description:This is a Phase I safety study of a gene transfer drug for colorectal cancer that has spread to the liver. The main purpose of this study is to determine if it is safe to give this new intervention to persons with cancer, but we will also look for indications that the drug is effective. Although the findings in animals that have cancer are encouraging, this is the first time humans will receive this experimental gene transfer drug. A gene called cyclin G1 has been shown to play a very important part in cancer growth. In animal experiments, a genetically modified virus (or vector)carrying a modified cyclin G1 gene caused the cancerous tumors to grow much slower or even die. In this safety study, the drug will be injected through the liver artery to get it near the cancer that has spread to the liver. The way the gene gets into the cancer cells is by using a targeted vector that concentrates in the area of the cancer to improve the delivery of the killing gene into cancer cells. The vector we are using is a virus that has been changed so that the infectious genes have been removed and instead carries the modified cyclin G1 gene.
Project description:The Notch signaling pathway regulates fate decision, proliferation and differentiation of intestinal epithelial cells. However, the role of Notch signaling in colorectal cancer progression is largely unknown. Here we show that Notch signaling suppresses the progression of colorectal tumorigenesis, even though it augments tumor initiation. In contrast to adenomas of Apcmin mice, Notch-inactivated Apcmin adenomas showed more malignant characteristics, such as submucosal invasion and loss of glandular pattern. Conversely, Notch-activated Apcmin adenomas showed a reversion from high-grade to low-grade features, such as the restoration of adherent junctions. Expression profiling revealed that Notch signaling promotes the differentiation of tumor cells with down regulation of Wnt/beta-catenin target genes and inhibition of epithelial-mesenchymal transition. Comparison of mouse and human expression profiles also suggests the common role of Notch in inhibition of tumor progression. Interestingly, Notch signaling suppressed the expression of beta-catenin responsive genes through chromatin modification of Tcf4/beta-catenin binding sides. Our results suggest that Notch signaling has dual roles in colorectal tumorigenesis: promoting adenoma initiation, while inhibiting tumor progression to colorectal cancer. mRNAs from normal (WT, Notch-activated and Notch-inactivated) and tumor (WT, Notch-activated and Notch-inactivated) tissues were profiled.
Project description:NAD biosynthetic enzymes are widely considered oncogenic due to their frequent overexpression in cancer to support elevated metabolic demand. This dataset is in support of a manuscript where we identify a tumor-suppressive role for the deamidated NAD biosynthesis pathway in both mice and humans. Unlike the ubiquitously expressed amidated salvage enzyme, NAPRT the first enzyme of the deamidated pathway is selectively enriched in gut epithelial cells, where it sustains NAD levels during stress-induced acute depletion. Loss of NAPRT compromises PARP activity and DNA repair, increasing susceptibility to chemically induced colitis, tumorigenesis, and age-associated spontaneous tumors in mice. Consistently, low NAPRT expression correlates with poor prognosis across multiple human cancers. These findings demonstrate that endogenous deamidated NAD biosynthesis suppresses tumorigenesis, and that enhancing this pathway may offer a strategy for tumor prevention.