Abstract

IFIT3 Modulates STAT1 Expression in sEVs Derived From Prostate Cancer Cells

NICOLE NARANJO, , THOMAS JEFFERSON UNIVRRSITY

We have previously shown that the alpha 5 beta 6 integrin plays a key role in promoting prostate cancer (PrCa) as it can be transferred to recipient cells via small extracellular vesicles (sEVs). Furthermore, we have reported in a proteomic analysis that alpha 5 beta 6 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 beta 6 integrin subunit, IFIT3 or STAT1. Our results show that IFIT3 and STAT1 are highly expressed in PrCa cells devoid of the beta 6 integrin subunit. However, IFIT3 but not STAT1, is present in sEVs derived from PrCa cells lacking the beta 6 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 PrCa derived sEVs and in intercellular communication in PrCa.