About Nephroblastoma Overexpressed (NOV):
NOV (nephroblastoma overexpressed) is also known as CCN3, a matricellular protein that is encoded as the NOV gene in humans.
NOV regulates multiple cellular activities such as cell adhesion, proliferation, differentiation, migration and survival. It works by directly binding itself to integrin receptors and other receptors like NOTCH1 and fibulin 1c (FBLN1). NOV is expressed during wound healing and induces angiogenesis in vivo. It’s essential for the self-renewal of CD34+ hematopoietic stem cells from umbilical cord blood.
NOV can also bind BMP2 and inhibit its functions in promoting osteogenic differentiation. IT can also stimulate osteoclastogenesis through a process that could involve calcium flux. Overexpression of NOV in transgenic mice in osteoblasts antagonizes both BMP and Wnt-signaling and result in osteopenia.
It has also been reported that the NOV protein was involved in regulatory T cell-mediated oligodendrocyte differentiation in the regeneration of myelin following damage to the myelin sheath. These findings revealed a new function for regulatory T cells and is distinct from the role they have in immunomodulation.
The human NOV protein contains 357 amino acids with an N-terminal secretory signal peptide, followed by four distinct domains with homologies to insulin-like growth factor binding protein (IGFBP), thrombospondin type 1 repeat (TSR), von Willebrand type C repeats (vWC) and a cysteine knot motif within the C-terminal (CT) domain.
NOV-null mice are viable and largely normal, which contrasts with the lethality of Cyr61 (CCN1) and Ctgf (CCN2) genetic knockout. They only exhibit modest and transient sexually dimorphic skeletal abnormalities. However, NOV-null mice do show enhanced blood vessel neointimal thickening when challenged with vascular injury. This indicates that NOV inhibits neointimal hyperplasia.
Despite inhibiting the proliferation of cancer cells, NOV does appear to promote metastasis. Nov overexpression results in reduced tumoru size in glioma cells xenografts, but it does enhance metastatic potential in xenotransplanted melanoma cells. NOV expression is often associated with an increased risk of metastasis and worse prognosis in patients with cancers like melanoma, breast cancer and Ewing’s sarcoma. In chronic myeloid leukaemia (CML), NOV is downregulated as a consequence of kinase activity of BCR-ABL, a chimeric protein which is generated through the chromosomal translocation between chromosome 9 and 22. When forced, NOV expression inhibits proliferation and restores growth control in CML cells. This suggests that NOV could be used as an alternate target for novel therapeutics against CML.