MicroRNA-15a Carried by Mesenchymal Stem Cell-Derived Extracellular Vesicles Inhibits the Immune Evasion of Colorectal Cancer Cells by Regulating the KDM4B/HOXC4/PD-L1 Axis

Abstract

The relevance of microRNA-15a (miR-15a) to autoimmunity has been reported. Herein, we intended to probe the potential roles of miR-15a shuttled by adipose-derived mesenchymal stem cells (adMSCs)-derived extracellular vesicles (Evs) in colorectal cancer (CRC). Initially, CRC cells were treated with interferon gamma (IFN-γ) to screen out differentially expressed genes by transcriptome sequencing. Following a 24-h co-culture with 20 μM adMSCs-derived Evs, CRC cell viability, migration, invasion, and apoptosis were assessed. After the determination of histone lysine demethylase 4B (KDM4B) as our target, its regulatory miRNA was predicted by the bioinformatics websites and verified by dual-luciferase and RNA pull-down assays. Intriguingly, KDM4B downregulated homeobox C4 (HOXC4) expression, while HOXC4 bound to the promoter sequence of programmed death-ligand 1 (PD-L1). Thus, we conducted rescue experiments to study the role of KDM4B and HOXC4. Finally, we evaluated the effects of adMSCs on CRC cell growth and immune evasion through in vivo tumorigenesis experiments. AdMSCs-derived Evs overexpressing miR-15a repressed proliferation, migration, and invasion, while it promoted the apoptosis of CRC cells via downregulation of KDM4B. These in vivo findings were reproduced in vitro on CRC immune evasion. Collectively, adMSCs-derived Evs overexpressing miR-15a restricted the immune evasion of CRC via the KDM4B/HOXC4/PD-L1 axis.

Large-Scale Analysis and Clinical Samples Reveals the Specific Clinical and Immune Features of KDM4B in UCEC

“…The present study demonstrated a signi cant positive correlation between KDM4B and CTLA4 and SIGLEC15 respectively, which may inhibit the immune response of UCEC patients through excessive immunosuppression leading to immunologic escape of malignant tumor cells resulting in poor prognosis of malignant tumor. Mesenchymal stem cell-derived extracellular vesicles overexpressing miR-15a limit immunologic escape in colorectal cancer (CRC) via the KDM4B/Hoxc4/PD-L1 axis, and this study con rms our ndings (12). In addition, immune checkpoint blockade using anti-PD1/PD-L1/CTLA4 antibodies improved the prognosis of patients with refractory solid tumors.…”

“…Recent studies have suggested that KDM4B facilitates in the regulation of PI3K(8), TGF-β, Notch, and Wnt/βcatenin pathways (9) during malignant transformation of cancer and researches also indicated that KDM4B was a potential biomarker for targeted therapy of these cancers (10,11). Encouragingly, recent studies have reported that KDM4B-HOXC4-PD-L1 axis played an indispensable role in immune evasion of colorectal cancer cells (12). Therefore, the immune function of KDM4B in gynecological malignancies, especially in UCEC, has aroused great interest for us.…”

Analysis of miR-375-3p, miR-197-3p, and miR-15a-5p Expression and Their Clinical Relevance as Biomarkers in Lung Cancer

“…At the same time, extracellular vesicles overexpressing miR-15a inhibited the immune evasion of colorectal cancer cells via the KDM4B/HOXC4/PD-L1 axis. 24 Since PD-L1 is highly expressed in lung tumors 25 , 26 and we recently found differential expression of PD-L1 regulatory miRNAs in the serum of NSCLC patients, 14 we decided further to analyze their expression in the lung tumor tissues to ascertain whether these miRNAs have any clinical utility as prognostic and predictive biomarkers. To confirm the same, we correlated the expression patterns of the miRNAs mentioned above with survival outcomes, therapeutic response, and various clinicopathological parameters, including clinical stage and histology.…”

The Roles of Mesenchymal Stem Cells in Gastrointestinal Cancers

“…Exosome miR-424 from BMSCs could inhibit the malignant behavior of CRC cells by targeting TGFBR3 (102). Liu et al found that miR-15a derived from MSCs could inhibit the immune escape of CRC cells by modulating the KDM4B/HOXC4/ PD-L1 axis (103). In addition, Zhao et al also discovered that microRNA-34a-5p derived from tumorigenesis of CRC could be inhibited by MSC-derived extracellular vesicles through the c-MYC/ DNMT3a/PTEN axis (104).…”