CCN3: Doctor Jekyll and Mister Hyde

Abstract

CCN proteins are key regulators of signaling pathways that are essential for the control of normal life, from birth to death. As such, they make use of their unique mosaic structure to interact with several other regulatory proteins and ligands that control the fate of living cells. The various functions attributed to the CCN proteins may sometimes appear contradictory, but this situation reflects the complexity of the multimolecular scaffolds in which CCN proteins are engaged and the critical impact of the microenvironment that dictates the bioavailability of the elementary building blocks. CCN3 is one of the best examples of a CCN protein showing biological properties which may at first glance appear opposite or contradictory. Indeed, CCN3 acts both as a tumor suppressor and is associated with higher metastatic potential. Furthermore, the physical interaction of CCN3 with VEGF and its potential antiangionenic activity in glioma cells are in apparent contradiction with its proangiogenic activity in rabbit cornea. In this communication, I am revisiting the observations that led us to these apparent contradictions. After pointing out how the methodologies that were employed might have contributed to the confusion, I briefly discuss the dual biological activities of CCN3 in the context of tumor cell engineering and survival prognosis.

Nephroblastoma overexpressed (NOV/CCN3) gene: a paired-domain-specific PAX3-FKHR transcription target that promotes survival and motility in alveolar rhabdomyosarcoma cells

“…A simple explanation would be that the effect of CCN3 on RMS differentiation is subtype-specific, as aRMS and eRMS are genetically distinct. Like most CCN proteins, CCN3 function is complex as its effects on both normal and tumor cells are context-dependent (Perbal, 2004; Holbourn et al , 2008; Perbal, 2008a). Alternatively, CCN3 might be kept at a concentration below a certain threshold required for myogenesis, but high enough to facilitate other pro-tumorogenic activities in aRMS.…”

CCN2 expression and localization in melanoma cells

“…Intriguingly, evidence suggests that CCN1 may be a tumor suppressing gene in melanoma (Dobroff et al 2009), consistent with our observation that CCN1 mRNA expression was less than that of CCN2, CCN3 and CCN4. The situation with CCN3 appears to be complicated and context-dependent (Perbal 2008), nonetheless the preponderance of data suggests that anti-CCN2 antibody and counterstained with DAPI as described in methods. Experiments were performed thrice, a representative photograph is shown CCN3 is most commonly associated with negative growth regulation and reduced proliferation and invasion including in melanoma/melanocytes (Planque and Perbal 2003;Fukunaga-Kalabis et al 2008;McCallum et al 2009).…”

CCN3/NOV gene expression in human prostate cancer is directly suppressed by the androgen receptor

“…16 NOV has been implicated in a range of cancers including gliomas, melanoma, Ewing's sarcoma, leukemia and breast cancer. 14,17–19 It has been reported to exhibit both tumor-suppressive or oncogenic roles depending on the cellular context. 14,17,20 A majority of studies showed that NOV inhibits cell proliferation in cancer cells such as Ewing's sarcoma, melanoma and breast cancer, while conflicting reports are also abundant.…”