IFNγ-Induced IFIT5 Promotes Epithelial-to-Mesenchymal Transition in Prostate Cancer via miRNA Processing

Abstract

IFNg, a potent cytokine known to modulate tumor immunity and tumoricidal effects, is highly elevated in patients with prostate cancer after radiation. In this study, we demonstrate that IFNg can induce epithelial-to-mesenchymal transition (EMT) in prostate cancer cells via the JAK-STAT signaling pathway, leading to the transcription of IFN-stimulated genes (ISG) such as IFN-induced tetratricopeptide repeat 5 (IFIT5). We unveil a new function of IFIT5 complex in degrading precursor miRNAs (pre-miRNA) that includes pre-miR-363 from the miR-106a-363 cluster as well as pre-miR-101 and pre-miR-128, who share a similar 5 0 -end structure with pre-miR-363. These suppressive miRNAs exerted a similar function by targeting EMT transcription factors in prostate cancer cells. Depletion of IFIT5 decreased IFNg-induced cell invasiveness in vitro and lung metastasis in vivo. IFIT5 was highly elevated in high-grade prostate cancer and its expression inversely correlated with these suppressive miRNAs. Altogether, this study unveils a prometastatic role of the IFNg pathway via a new mechanism of action, which raises concerns about its clinical application.Significance: A unique IFIT5-XRN1 complex involved in the turnover of specific tumor suppressive microRNAs is the underlying mechanism of IFNg-induced epithelial-tomesenchymal transition in prostate cancer.See related commentary by Liu and Gao, p. 1032

Emerging Functions of Human IFIT Proteins in Cancer

“…Although IFITs are involved in the host immune response and antiviral defense, emerging research studies have shown their involvement in malignant progression (Lai et al, 2008(Lai et al, , 2013Niess et al, 2015;Zhang et al, 2016;Ohsugi et al, 2017;Yang et al, 2017;Zhao et al, 2017;Chen et al, 2018;Lo et al, 2018Lo et al, , 2019Nushtaeva et al, 2018;Shen et al, 2018;Huang et al, 2019). The epithelial-mesenchymal transition (EMT) is a biological mechanism in which epithelial cells convert into a mesenchymal phenotype to acquire increased cell invasion and migration capacity as well as resistance to apoptosis (Kalluri and Weinberg, 2009), which lead to metastasis (Yilmaz and Christofori, 2009).…”

“…IFIT5 expression was also inversely correlated with miR-363 expression in prostate cancer. IFIT5 is involved in the degradation of miR-363 and can form a complex with miR-101 and miR-128 to promote prostate cancer progression by inducing EMT (Lo et al, 2018).…”

“…Furthermore, IFIT5 colocalized with MAVS (Zhang et al, 2013;Zheng et al, 2015). Recent research has shown that IFIT5 promoted the progression of various cancers, including renal cancer, prostate cancer, and bladder cancer (Lo et al, 2018(Lo et al, , 2019Huang et al, 2019). Hence, it would be interesting to investigate whether IFIT5 may also have anti-apoptotic functions.…”

“…Over the past decade, an increasing number of HPV E6-associated proteins have contributed to cellular malignant transformation, with human telomerase as one of the best examples (Narisawa-Saito and Kiyono, 2007). Recently, human IFIT5 has been implicated in cancer progression (Lo et al, 2018(Lo et al, , 2019Huang et al, 2019). Therefore, the correlation between human IFIT5 and HVP E6 might contribute to OSCC malignancy, and further investigation is warranted to explore the reason for their association.…”

The Prospect of Identifying Resistance Mechanisms for Castrate-Resistant Prostate Cancer Using Circulating Tumor Cells: Is Epithelial-to-Mesenchymal Transition a Key Player?

“…IFN-c can induce epithelial-tomesenchymal transition (EMT) in PCa cells via the JAK-STAT signaling pathway [75], and STAT3 may directly mediate EMT progression and regulate ZEB1 expression in CRC [76] PCa progression, cell proliferation, and inhibition of apoptosis [51,52] No direct analysis of these pathways in CTCs Wnt/ β-catenin Dysregulation of Wnt/β-catenin signaling has been implicated in the development of cancer in different tissues such as lung, skin, liver, and prostate [52], via regulating Zeb1 in CRC [77] Wnt/β-catenin pathway promotes the metastatic spread of prostate cancer cells by inducing EMT [78] Epithelial type CTCs and activation of Wnt/β-catenin signaling in lung cancer cells [79]. No report in PCa CTCs Notch Crosstalk between the Jagged1/Notch and JAK/STAT3 signaling pathways by promoting EMT through Jagged-1 in ovarian cancer [80] Notch signaling results in prostate tumor recurrence via EMT [81] Increased production of ROS results in the upregulation of Notch1 in CTCs in metastatic breast and melanoma cancer [82].…”