miR‐2909 regulates ISGylation system via STAT1 signalling through negative regulation of SOCS3 in prostate cancer

Abstract

One of the well-document strategies adopted by tumour cells for progression is to evade immune surveillance mechanisms. An understanding of the tight interaction between immunity and progression of cancer can provide novel treatment options for different malignancies including prostate cancer (PCa). Here, we have shown that AATF genome encoded miR-2909, known to play role both in immunity and cancer upregulates various interferon stimulating genes (ISGs) including ISGylation system through STAT1. Our results revealed that miR-2909 up-regulates STAT1 through negative regulation of SOCS3 and not through up-regulation of Type 1 interferon (IFN) production. It was observed that inhibition of ISGylation reduced the proliferation potential of PCa cells. Furthermore, androgens were found to negatively regulate ISGylation in LNCaP cells through androgen receptor signalling independently of miR-2909. TGF-β mediated SMAD3 signalling was also seen to be suppressed by miR-2909 through induction of SMAD7 via enhanced STAT1 expression. Collectively, these studies suggest that miR-2909 could play a vital role in prostate carcinogenesis through modulation of ISGylation system and TGFβ signalling via STAT1.

Cancer cells govern miR‐2909 exosomal recruitment through its 3′‐end post‐transcriptional modification

“…Further internalization of miR‐2909 enriched exosomes by the target cells may contribute to the regulation of genes encoding tumour suppressors/oncogenes or involved in immune surveillance within such cells. This view is in conformity with our earlier reported findings regarding the role of cellular miR‐2909 RNomics in the regulation of genes coding for tumour suppressors/oncogenes as well as those that govern immunity . By making use of archetype cellular models (ie, T‐24 and PC‐3 cell lines), the present study revealed that increased post‐transcriptional 3′‐end uridylation of miR‐2909 is the driving force for the recruitment of this miRNA to the exosomes secreted by the prostate cancer cells (PC‐3, Figure C).…”

“…Human AATF genome, located on the chromosome 17, has evolved to hold AATF protein coding transcript and regulatory noncoding microRNA (miRNA, miR‐2909) within its fold in a fashion that ensures their mutual cooperative regulation . This interplay between AATF and miR‐2909 is responsible for governing of various cellular processes especially cell cycle progression, checkpoint control, and cellular autophagy/apoptosis . The complexity of this genome does not end here because AATF genome‐encoded miR‐2909 has been shown to govern genes that play crucial role in cancer and immunity, thereby behaving like a double‐edged sword.…”

“…[1][2][3] This interplay between AATF and miR-2909 is responsible for governing of various cellular processes especially cell cycle progression, checkpoint control, and cellular autophagy/apoptosis. [4][5][6][7][8] The complexity of this genome does not end here because AATF genome-encoded miR-2909 has been shown to govern genes that play crucial role in cancer and immunity, 3,7,8 thereby behaving like a double-edged sword. Several findings have indicated that cancer cells have the ability to secrete exosomes containing constituents (including miRNAs) of their cell of origin, and these exosomes ensure immune privilege to the tumour growth.…”

The Effect of SH2B1 Variants on Expression of Leptin- and Insulin-Induced Pathways in Murine Hypothalamus

“…Another downstream effector of STAT1 is ISG15 , an ubiquitin-like modifier that binds to cytoplasmic and nuclear proteins ISGylating them. ISG15 has not only an anti-viral role, as assumed at the beginning, but also an oncogenic role [36,37]. In our study, both direct STAT1 interaction partners showed nominally increased expression for different mutations.…”

Role of miR-2909 in Prostate Carcinogenesis

“…Further, it was observed that miR-2909 overexpression modulated ISGylation through STAT1 mediated via negative regulation of SOCS3. A significant upregulation of STAT1 phosphorylation and downregulation of SOCS3 was detected in miR-2909-overexpressing PC3 cells whereas miR-2909 plasmid coupled with antagomiR-2909 treatment significantly downregulated phosphorylated STAT1 and upregulated SOCS3 expression [29]. The SOCS3 is a welldocumented inhibitor of JAK/STAT pathway and STAT1 phosphorylation is always reported as inversely correlated with SOCS3 expression [30].…”