# Role of HOS in Cell Transformation and Apoptosis

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $344,138

## Abstract

Type I interferons (IFN1, including IFNα/β) 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.

## Key facts

- **NIH application ID:** 9828072
- **Project number:** 5R01CA092900-18
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Serge Y Fuchs
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $344,138
- **Award type:** 5
- **Project period:** 2001-03-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9828072

## Citation

> US National Institutes of Health, RePORTER application 9828072, Role of HOS in Cell Transformation and Apoptosis (5R01CA092900-18). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9828072. Licensed CC0.

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