Exosome miR‐3184‐5p inhibits gastric cancer growth by targeting XBP1 to regulate the AKT, STAT3, and IRE1 signalling pathways

Abstract

MicroRNAs can regulate the transcription of protein-coding genes associated with the development and progression of cancer. In this study, we explored the potential diagnostic function of exosome miR-3184-5p in gastric cancer. This exosome was isolated from the blood samples of 150 patients with gastric cancer and 60 healthy participants.The mean particle size and concentration of serum exosome in the patients with gastric cancer were 104.6 nm (93.97-115.84) and 6.21e+009 particles/ml (5.15e+009-7.12e+009), respectively. miR-3184-5p expression was substantially downregulated in the patients with gastric cancer compared with that in the healthy participants.The gastric cancer cell line HGC-27 was cultured and transfected with the mimic and an inhibitor to overexpress and inhibit miR-3184-5p expression. miR-3184-5p strongly suppressed cell proliferation, migration, and invasion but induced cell apoptosis. Luciferase reporter assay revealed that XBP1 was the target of miR-3184-5p. miR-3184-5p substantially downregulated the expression of CD44, cyclin D1, MMP2, p65, p-AKT, and p-STAT3 but upregulated that of GRP78, IRE1, p-JNK, and CHOP. Moreover, miR-3184-5p cleaved caspase-12 and inhibited BCL-2 expression. These results suggested that the downregulation of miR-3184-5p in patients with gastric cancer might regulate the AKT, STAT3, and IRE1 pathways to promote the vitality of gastric cancer cells.

Decoding contextual crosstalk: revealing distinct interactions between non-coding RNAs and unfolded protein response in breast cancer

“…This, in turn, results in the suppression of the ATF6 branch of the UPR and the development of gastric cancer SGC7901 and BGC-823 Mice Human In vitro and in vivo miR-1291 In silico predictions and experimental validation suggest that miR-1291 represses the expression of IRE1α mRNA HuH7 cells In vitro [ 136 ] miR-424 miR-424 appears to be intricately involved in the regulation of UPR by influencing the expression of ATF6, PERK signaling, and RIDD, with its downregulation being a part of the response to ER stress, mediated by PERK MEFs, H9c2, and HEK 293T cells Mice In vitro and in vivo [ 137 ] miR-322 The ER oxidoreductase PDIA6 and miR-322 are identified as key regulators of IRE1α activity. The reduction in ER Ca2+ levels and activation of store-operated Ca2+ entry led to decreased miR-322 abundance, subsequently stabilizing PDIA6 mRNA and amplifying IRE1α activity during ER stress embryonic fibroblasts and COS-1 cells Mice In vitro and in vivo [ 56 ] miR-199a-5p The research suggests that the protective impact of HUVEC-derived miR-199a-5p on neural cells occurs through exosome-mediated transfer, leading to the inhibition of ER stress-induced apoptosis and inflammation by targeting BIP HUVECs, SH-SY5Y cells In vitro [ 138 ] miR-3184-5p XBP1 has identified as a target gene for miR-3184-5p, and downstream molecular effects implicate the regulation of CD44, cyclin D1, MMP2, p65, p-AKT, p-STAT3, GRP78, IRE1, p-JNK, CHOP, caspase-12, and BCL-2 HGC-27 cells Human In vitro [ 139 ] miR-30c-2-3p The research demonstrates that miR-30c-2-3p inhibits the expression of XBP1, leading to a decrease in the ER folding capacity and an intensification of ER stress, as evidenced by Thioflavin T staining. The study further reveals that miR-30c-2-3p up-regulates pro-apoptotic proteins CHOP and BIM while down-regulating the ER stress response protein BIP/GRP78 OVCAR3 (C430) and SKOV3 (C209) cells In vitro ...…”

New Possible Ways to Use Exosomes in Diagnostics and Therapy via JAK/STAT Pathways

“…Lin et al, found that exosome-derived miR-3184-5p expression levels were lowered in gastric cancer (GC) patients. miR-3184-5p has been shown to bind X-box binding protein 1 (XBP-1), a potential transcription activator of STAT3 that plays a critical role in cancer transformation and carcinogenesis [ 25 ]. Thus, downregulated miR-3184-5p may inhibit gastric cancer cell proliferation ( Figure 2 ).…”

“…Thus, downregulated miR-3184-5p may inhibit gastric cancer cell proliferation ( Figure 2 ). However, silencing of XBP-1 was also shown to decrease the expression of p65, p-AKT, and p-STAT3, thereby inducing cell apoptosis ( Table 1 ) [ 23 , 24 , 25 ]. TDEs advance pro-tumor inflammation via toll-like receptor (TLR) signaling ( Figure 2 ).…”

“…Membrane-associated Hsp72 from TDEs mediates STAT3-dependent immunosuppressive function of myeloid-derived suppressor cells (MDSC) [ 54 ]. miR-3184-5p expression was downregulated in gastric cancer (GC) patients, resulting in increased cell proliferation, migration, and invasion and reduced cell apoptosis [ 25 ]. CXCL10 produced by HPV-positive cervical squamous cell carcinoma (CSCC) stimulates exosomal PDL1 expression by fibroblasts via CXCR3 and JAK-STAT pathways, forming an immune escape response pathway that leads to tumor emergence [ 53 ].…”

Suppression of gastric cancer cell proliferation by miR-494-3p inhibitor-loaded engineered exosomes

“…These engineered exosomes have high encapsulation efficiency and can slow tumor growth in vivo [ 32 ]. They have been used to block the malignant behavior of glioblastoma multiforme cells, induce apoptosis in ovarian cancer cells, and inhibit gastric cancer progression [ [33] , [34] , [35] , [36] , [37] , [38] , [39] ]. Additionally, few studies also focused on delivering of exosomes loaded with inhibitors of miRNA for disease treatment [ 40 , 41 ].…”