Type I interferons (IFN1, including IFN?/?) are anti-viral cytokines known for their ability to engage the IFNAR1/2 receptor and induce cell senescence and apoptosis. These direct effects of IFN1 on cancer cells along with ability to stimulate the immune system and inhibit angiogenesis shape the foundation for current paradigm that considers IFN1 as endogenous anti-tumorigenic cytokines and, accordingly, provides a rationale to use pharmaceutically produced recombinant IFN1 to treat the oncologic diseases. However, data from our and other groups are also suggestive that IFN1 may have pro-tumorigenic properties. These data include observations that (i) IFN1 can amplify the extent of DNA damage (thereby increasing a chance for oncogenic mutations), (ii) DNA damage-induced IFN1 activates the p53-p21 tumor suppressive pathway and elicits cell senescence that is dependent on p53 activities; (iii) IFN1 gene signature is increased in chemo-/radio-resistant cancers (often lacking p53 function); (iv) while downregulation of IFNAR1 in cancers can suppress the IFN1 pathway, tumors that preserved IFNAR1 levels and IFN1 signaling are often characterized by inactivated p53 pathway, (v) IFN1 signaling can stimulate growth of p53-null cells, and (vi) IFN1 plays an important role in tissue inflammation that is known to contribute to tumorigenesis. These and other data suggest a somewhat controversial, highly novel and paradigm-shifting hypothesis that, upon inactivation of the p53-dependent pathway, IFN1 signaling may exhibit pro-carcinogenic activities by diverse mechanisms including increasing the extent of DNA damage and promoting the inflammation-associated tumorigenesis. To test this hypothesis we will (1) determine the role of IFN1 signaling in regulating the extent of carcinogen-induced DNA damage and in controlling nuclear excision repair (NER) and guanine demethylation; (2) determine the procarcinogenic roles of IFN1 in development of colorectal cancer (CRC), and (3) determine the procarcinogenic roles of IFN1 in development of cutaneous melanoma. These experiments will use mouse models exhibiting diverse extent of IFN1 signaling and p53 functions in combination with treatment with environmental carcinogens and chemical carcinogenesis/genetic mouse models of colorectal cancers and melanoma. Status of p53/IFNAR1 will be also examined in human melanoma samples from patients that responded or not to high dose IFN1 therapy. Completion of these experiments should pave the road for future detailed studies on the role of IFN1 in various inflammation-associated cancers, gain the insights into regulation of DNA damage and repair by IFN1, and determine the role of IFN1 in counteracting or promoting the development and progression of CRC and melanoma.
Type I interferons (IFN1) are anti-viral cytokines that are known for their ability to suppress development and progression of cancers. However, our recent pilot results suggest that IFN1 can be induced by DNA damage and act to amplify the DNA damage response thereby potentially increasing the frequency of generating abnormal cells. Furthermore, when the senescence pathway employed by IFN1 to permanently block proliferation of damaged cells is inactivated, IFN1 may stimulate inflammation and promote tumor development. This proposal will delineate these paradoxical activities of IFN1 and will help to shed the light on the role of IFN1 in carcinogenesis and on the practicality of IFN1-modulating therapies in cancers.
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