MiR130b from Schlafen4⁺ MDSCs stimulates epithelial proliferation and correlates with preneoplastic changes prior to gastric cancer

Abstract

The myeloid differentiation factor Schlafen4 (Slfn4) marks a subset of myeloid-derived suppressor cells (MDSCs) in the stomach during Helicobacter-induced spasmolytic polypeptide-expressing metaplasia (SPEM).ObjectiveTo identify the gene products expressed by Slfn4+-MDSCs and to determine how they promote SPEM.DesignWe performed transcriptome analyses for both coding genes (mRNA by RNA-Seq) and non-coding genes (microRNAs using NanoString nCounter) using flow-sorted SLFN4+ and SLFN4– cells from Helicobacter-infected mice exhibiting metaplasia at 6 months postinfection. Thioglycollate-elicited myeloid cells from the peritoneum were cultured and treated with IFNα to induce the T cell suppressor phenotype, expression of MIR130b and SLFN4. MIR130b expression in human gastric tissue including gastric cancer and patient sera was determined by qPCR and in situ hybridisation. Knockdown of MiR130b in vivo in Helicobacter-infected mice was performed using Invivofectamine. Organoids from primary gastric cancers were used to generate xenografts. ChIP assay and Western blots were performed to demonstrate NFκb p65 activation by MIR130b.ResultsMicroRNA analysis identified an increase in MiR130b in gastric SLFN4+ cells. Moreover, MIR130b colocalised with SLFN12L, a human homologue of SLFN4, in gastric cancers. MiR130b was required for the T-cell suppressor phenotype exhibited by the SLFN4+ cells and promoted Helicobacter-induced metaplasia. Treating gastric organoids with the MIR130b mimic induced epithelial cell proliferation and promoted xenograft tumour growth.ConclusionTaken together, MiR130b plays an essential role in MDSC function and supports metaplastic transformation.

Hypoxia downregulated miR-4521 suppresses gastric carcinoma progression through regulation of IGF2 and FOXM1

“…One of the biggest challenges in developing miRNA-based therapeutics is to identify the best miRNA candidates or miRNA targets for each disease type. Although several GC-implicated miRNAs have been identified [ 6 , 19 ], the functions and mechanisms of miRNAs in GC progression and metastasis are still poorly understood. Thus, identification of novel miRNA candidates involved in this disease and understanding of their targets and downstream pathways are needed to develop effective miRNA-based therapeutics for gastric carcinoma.…”

Murine- and Human-Derived Autologous Organoid/Immune Cell Co-Cultures as Pre-Clinical Models of Pancreatic Ductal Adenocarcinoma

“…Recent characterization of the infiltrating PMN-MDSCs in response to Helicobacter infection in the stomach showed that these immunosuppressive cells have a unique signature. These Arg1+/NOS2+ PMN-MDSC population express the Schlafen (SLFN) family of proteins, a transcriptional target of GLI1, and the endogenous small, non-coding RNA, MiR130b [ 29 , 30 ]. SLFN12L + myeloid cells express VEGF, IL-1β and TNF-α, which are known factors associated with MDSC regulation, an immunosuppressive cell of relevance to immunotherapy-resistant gastric cancer [ 29 , 30 ].…”

Myeloid-derived suppressor cells in gastrointestinal cancers: A systemic review

“…These SLFN-expressing MDSCs secrete factors including microRNAs, which can be detected in the peripheral blood as a biomarker and promote epithelial cell growth. This sustained immune dysregulation creates a microenvironment capable of supporting GC development[ 46 ].…”