miRNA dynamics in tumor-infiltrating myeloid cells modulating tumor progression in pancreatic cancer

Abstract

Myeloid cells including tumor-associated macrophages (TAM) and myeloid-derived suppressor cells (MDSC) are known as important mediators of tumor progression in solid tumors such as pancreatic cancer. Infiltrating myeloid cells have been identified not only in invasive tumors, but also in early pre-invasive pancreatic intraepithelial precursor lesions (PanIN). The functional dynamics of myeloid cells during carcinogenesis is largely unknown. We aimed to systematically elucidate phenotypic and transcriptional changes in infiltrating myeloid cells during carcinogenesis and tumor progression in a genetic mouse model of pancreatic cancer. Using murine pancreatic myeloid cells isolated from the genetic mouse model at different time points during carcinogenesis, we examined both established markers of macrophage polarization using RT-PCR and FACS as well as transcriptional changes focusing on miRNA profiling. Myeloid cells isolated during carcinogenesis showed a simultaneous increase of established markers of M1 and M2 polarization during carcinogenesis, indicating that phenotypic changes of myeloid cells during carcinogenesis do not follow the established M1/M2 classification. MiRNA profiling revealed distinct regulations of several miRNAs already present in myeloid cells infiltrating pre-invasive PanIN lesions. Among them miRNA-21 was significantly increased in myeloid cells surrounding both PanIN lesions and invasive cancers. Functionally, miRNA-21-5p and -3p altered expression of the immune-modulating cytokines CXCL-10 and CCL-3 respectively. Our data indicate that miRNAs are dynamically regulated in infiltrating myeloid cells during carcinogenesis and mediate their functional phenotype by facilitating an immune-suppressive tumor-promoting micro-milieu.

ADAR1 attenuates allogeneic graft rejection by suppressing miR‐21 biogenesis in macrophages and promoting M2 polarization

“…During the development of schistosomiasis, significant up-regulation of miR-146a/b was reported in macrophages, which promoted the polarization of IFN-g-induced macrophages into M1 by targeting signal transducer and activator of transcription 1 (44). miR-21-5p and miR-21-3p altered the expression of chemokine (C-X-C motif) ligand 10 (CXCL-10) and chemokine (C-C motif) ligand 3 (CCL-3), respectively, which led to macrophage polarization to M1 (45). miR-21 also prevented macrophages from polarizing to M2 by interfering with prostaglandin E 2 production (46); however, the mechanism that underlies the regulation of miR-21 remains unclear.…”

MicroRNA‑153 suppresses human laryngeal squamous cell carcinoma migration and invasion by targeting the SNAI1 gene

“…Currently, an increasing number of reports have demonstrated the association between miRNA and tumor metastasis, which is regulated by miRNA mediating a number of signal pathways ( 40 , 41 ). Liu et al ( 42 ) indicated that miR-153 could enhance the therapeutic effects of gemcitabine, by targeting SNAI1 in pancreatic cancer and gastric carcinoma.…”

Curcumin inhibits migration and invasion of non-small cell lung cancer cells through up-regulation of miR-206 and suppression of PI3K/AKT/mTOR signaling pathway

“…MiRNA dysregulation widely occurred in NSCLC, which might contribute to tumor occurrence and progression (16). To verify whether curcumin could regulate the expression of miR-206 in A549 cells, we treated the A549 cells with 10 and 20 μmol L -1 curcumin for 24 h. Then the relative expression of miR-206 was detected by real-time RT-PCR.…”