Clinical Utility of IFIT Proteins in Human Malignancies

Abstract

Interferon (IFN)-induced proteins with tetratricopeptide repeats (IFITs) are key interferon-stimulated genes (ISGs), and in humans include IFIT1, IFIT2, IFIT3 and IFIT5. These proteins are primarily known for their role in the innate immune response to pathogens. However, growing evidence suggests that IFITs participate in a range of other cellular processes, including cancer development and progression. Notably, IFITs may behave in either a pro-oncogenic or tumor suppressive fashion depending on cancer types and emphasizing their potential dual function in tumorigenesis. Importantly, IFITs have shown potential to be utilized as clinical biomarkers in oncology. Their aberrant expression has been correlated with survival and other clinical outcomes, including resistance to radiotherapy, chemotherapy, targeted treatments and immunotherapy in various cancers. Additionally, they have also been reported to be a part of various clinical predictive models in cancers. This review provides an overview of the current understanding of IFIT proteins' involvement in cancers, with an emphasis on their emerging roles as clinically relevant biomarkers.

Keywords: IFIT1; IFIT2; IFIT3; IFIT5; biomarkers; cancer; interferon-induced protein with tetratricopeptide repeats.

Figure 1

Simplified schematic of IFITs induction by viral infections and IFITs anti-viral responses. Viral infection leads to recognition of their PAMPs by various PRRs and subsequent activation of signaling cascades, including IFNs. IFN signaling triggers the JAK/STAT pathway leading to a nuclear translocation of the transcription factor complex ISGF3, that in turn activates transcription of ISGs, including IFITs. In the IFN-independent pathway, direct activation of factors inducing ISGs transcription can take place. IFITs then assert their antiviral function through various mechanisms, such as interacting with viral RNA and cellular and viral proteins to inhibit protein translation (namely translational initiation) and viral replication and modulating immune and inflammatory responses to viral infection. Notably, the baseline expression of IFITs in tissues is generally low and is induced in response to their activation. In addition, IFITs interactions with each other play an important role in their function [1,2,13]. PAMPs—pathogen-associated molecular patterns; PRR-pattern recognition receptors; IFN—interferon; JAK—Janus kinase; STAT—signal transducer and activator of transcription; IRF3—IFN-regulatory factor 3; ISGs—IFN-stimulated genes; IFIT—interferon induced proteins with tetratricopeptide repeats.

Figure 2

IFITs’ Mechanisms in Cancer Pathogenesis. EMT—epithelial-mesenchymal transition; IFIT—interferon induced proteins with tetratricopeptide repeats.

Figure 3

Potential clinical utility of IFIT proteins in various malignancies. IFIT—interferon induced proteins with tetratricopeptide repeats; HCC—hepatocellular carcinoma; OSCC—oral squamous cell carcinoma; NSCLC—non-small cell lung cancer; SKCM—skin cutaneous melanoma. * denotes that controversies exist (see text).