IFIT3 (interferon induced protein with tetratricopeptide repeats 3) modulates STAT1 expression in small extracellular vesicles.

Nicole M Naranjo,Lucia R Languino,Maisha A Harris,Israa Salem

doi:10.1042/bcj20210580

Abstract

We have previously shown that the αvβ6 integrin plays a key role in promoting prostate cancer (PrCa) and it can be transferred to recipient cells via small extracellular vesicles (sEVs). Furthermore, we have reported in a proteomic analysis that αvβ6 integrin down-regulation increases the expression of IFIT3 (interferon induced protein with tetratricopeptide repeats 3) in PrCa cells and their derived sEVs. IFIT3 is a protein well known for being an antiviral effector, but recently its role in cancer has also been elucidated. To study the relationship between IFIT3 and STAT1 (signal transducer and activator of transcription 1), an upstream regulator of IFIT3, in PrCa cells and their released sEVs, we used CRISPR/Cas9 techniques to down-regulate the expression of the β6 integrin subunit, IFIT3 or STAT1. Our results show that IFIT3 and STAT1 are highly expressed in PrCa cells devoid of the β6 integrin subunit. However, IFIT3 but not STAT1, is present in sEVs derived from PrCa cells lacking the β6 integrin subunit. We demonstrate that loss of IFIT3 generates sEVs enriched in STAT1 but reduces the levels of STAT1 in the cells. As expected, IFIT3 is not detectable in STAT1 negative cells or sEVs. We thus propose that the observed STAT1 enrichment in sEVs is a compensatory mechanism for the loss of IFIT3. Overall, these results provide new insights into the intrinsic role of IFIT3 as a regulator of STAT1 expression in sEVs and in intercellular communication in PrCa.

Highlights

Prostate cancer (PrCa) is the most common cancer affecting men in the United States, with a relative survival time of approximately 5 years [1]
We find that compared with the NS siRNA treatment, the levels of interferon-induced protein with tetratricopeptide repeat 3 (IFIT3) and signal transducer and activator of transcription 1 (STAT1) are upregulated upon treatment with the D2 siRNA
Our study reveals that downregulation of the β6 integrin subunit via siRNA (D2) or CRISPR/Cas9 techniques in PrCa cells results in increased protein expression of IFIT3 and STAT1 in PrCa cells

Summary

Introduction

Prostate cancer (PrCa) is the most common cancer affecting men in the United States, with a relative survival time of approximately 5 years [1]. The occurrence of PrCa has been attributed to the deregulation of various signaling pathways, including the androgen receptor (AR) signaling pathway [2, 3]. Integrin signaling cascades are deregulated in PrCa [5, 6]. Integrins are transmembrane receptors that drive the related processes of cell survival, adhesion, and proliferation [7, 8]. The αvβ integrin, which is not detectable in healthy human and mouse tissue [10, 11], is associated with metastatic phenotypes and poor survival in various malignancies, including breast [12], cervical [13], and colorectal [14] cancers. The αvβ integrin acts as a receptor for extracellular matrix proteins, where it can bind to different ligands, such as fibronectin, tenascin-C, LAP-TGF-β and vitronectin, all which have been implicated in mediating cell adhesion and migration in vitro [15]. As well as other groups, have shown that the αvβ integrin plays a key role in promoting tumor growth in vivo [10, 12, 16]

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Conclusion