Roles of N-Myc and STAT interactor in cancer: From initiation to dissemination

Pruitt, Hawley C.; Devine, Daniel J.; Samant, Rajeev S.

The importance of viral infection in cancer biology was solidified fifty years ago with the discovery of the Rous sarcoma virus and the first proto-oncogene, Src. 68, 69 Since then, this connection has only been strengthened with the discoveries of human viruses initiating carcinogenesis such as HPV in cervical cancer and EBV in Burkitt's lymphoma. In addition, the pivotal role of the host immune system in eliminating cancer cells has been garnered for treatment. Based on its ability to influence JAK/STAT signaling, it is feasible that NMI plays a role in the host's viral response. Indeed, NMI has been independently identified by groups studying viral infection as a mediator of host-viral response. 70 NMI was proposed to facilitate apoptosis through interaction with FMDV 2C, a key protein from a virus that causes foot and mouth disease in swine. 71 The FMDV 2C-NMI complexes were speculated to associate with the endoplasmic reticulum. In an independent study, microarray data from cells overexpressing HIV viral proteins showed a twofold decrease of NMI mRNA, suggesting it may have a mechanism in host cell viral defense during HIV infection. 72 Most recently however, NMI was identified as a binding partner of the severe acute respiratory syndrome (SARS) coronavirus non-structural protein 6. 70,73 Protein 6 is a transmembrane protein that localizes to the cytosolic side of the endoplasmic reticulum and is assembled into a replication complex that facilitates viral replication. Interestingly, it inhibits the host's innate immune response by binding and preventing nuclear import of STAT1. 74 The NMI protein 6 interaction led to the destabilization of NMI. 70 Although these studies were conducted independently it is intriguing to speculate that degradation or sequestration of NMI by SARS coronavirus protein 6 could contribute to the inhibitory effect on STAT1.