Dataset Information

MiR-155-deficient bone marrow promotes tumor metastasis.

ABSTRACT: Infiltration of immune cells in primary tumors and metastatic sites is known to influence tumor progression and metastasis. Macrophages represent the most abundant immune cells in the tumor microenvironment, and evidence has shown that macrophages promote seeding, extravasation, and persistent growth of tumor cells at metastatic sites. miR-155 plays an essential role in immune cell development/function, and its aberrant expression is associated with lymphomas and several solid tumor types. However, it is unknown how miR-155 expression in immune cells affects solid tumor growth and metastasis. To this end, bone marrow transplantation was performed using miR-155-deficient mice as bone marrow donors and wild-type (WT) mice as recipients, and the chimeric mice were inoculated with tumor cells. We demonstrate that bone marrow lacking miR-155 significantly enhanced lung metastasis without a substantial effect on primary tumor growth. Relative to mice with WT bone marrow, miR-155-deficient bone marrow accumulated more macrophages in the spleen and lungs. Further analysis revealed that miR-155-deficient macrophages in metastatic sites exhibited a tumor-promoting M2 phenotype. In vitro study suggested that miR-155-null macrophages were prone to M2 polarization upon incubation with tumor cell-conditioned medium, due to elevated expression of C/EBP?, an identified miR-155 target. These data, for the first time, demonstrate that miR-155 in host immune cells plays a vital role in modulating solid tumor metastasis by affecting the recruitment and polarization of bone marrow-derived macrophages.Targeted inhibition of miR-155 delays tumor development but inhibition in host immune cells may encourage metastasis.

SUBMITTER: Yu F

PROVIDER: S-EPMC3748167 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

miR-155-deficient bone marrow promotes tumor metastasis.

Yu Fang F Jia Xuemei X Du Fen F Wang Junfeng J Wang Yuzhen Y Ai Walden W Fan Daping D

Molecular cancer research : MCR 20130510 8

<h4>Unlabelled</h4>Infiltration of immune cells in primary tumors and metastatic sites is known to influence tumor progression and metastasis. Macrophages represent the most abundant immune cells in the tumor microenvironment, and evidence has shown that macrophages promote seeding, extravasation, and persistent growth of tumor cells at metastatic sites. miR-155 plays an essential role in immune cell development/function, and its aberrant expression is associated with lymphomas and several solid ...[more]

PMID: 23666369

Similar Datasets

Project description:BackgroundWe previously reported an inverse relationship between B cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1) and Raf kinase inhibitory protein (RKIP), which is associated with the prognosis of gastric cancer (GC). In this study, we further explored the microRNA (miRNA) regulatory mechanism between Bmi-1 and RKIP.MethodsMicroarray analysis was first carried out to identify miRNA profiles that were differentially expressed in cells overexpressing Bmi-1. Then, miRNAs that could regulate RKIP were identified. Quantitative real-time PCR (qRT-PCR) and Western blotting were performed to measure the expression of Bmi-1, miR-155, miR-27a and RKIP. RKIP was confirmed as a target of miR-27a and miR-155 through luciferase reporter assays, qRT-PCR and Western blotting. The effects of the Bmi-1/miR-27a/RKIP and Bmi-1/miR-155/RKIP axes on tumor growth, proliferation, migration, invasion, colony-formation ability, metastasis and chemoresistance were investigated both in vitro and in vivo.ResultsThe downregulation of RKIP by Bmi-1 occurred at the protein but not mRNA level. This indicates probable posttranscriptional regulation. miRNA expression profiles of cells with ectopic expression of Bmi-1 were analyzed and compared to those of control cells by microarray analysis. A total of 51 upregulated and 72 downregulated miRNAs were identified. Based on publicly available algorithms, miR-27a and miR-155 were predicted, selected and demonstrated to target RKIP. Bmi-1, miR-27a and miR-155 are elevated in human GC and associated with poor prognosis of GC, while RKIP is expressed at lower levels in GC and correlated with good prognosis. Then, in vitro tests shown that in addition to regulating RKIP expression via miR-27a and miR-155, Bmi-1 was also able to regulate the migration, invasion, proliferation, colony-formation ability and chemosensitivity of GC cells through the same pathway. Finally, the in vivo test showed similar results, whereby the knockdown of the Bmi-1 gene led to the inhibition of tumor growth, metastasis and chemoresistance through miR-27a and miR-155.ConclusionsBmi-1 was proven to induce the expression of miR-27a and miR-155 and thus promote tumor metastasis and chemoresistance by targeting RKIP in GC. Overall, miR-27a and miR-155 might be promising targets for the screening, diagnosis, prognosis, treatment and disease monitoring of GC.

Project description:BackgroundBone metastasis is the leading cause of death in patients with prostate cancer (PCa) and currently has no effective treatment. Disseminated tumor cells in bone marrow often obtain new characteristics to cause therapy resistance and tumor recurrence. Thus, understanding the status of disseminated prostate cancer cells in bone marrow is crucial for developing a new treatment.MethodsWe analyzed the transcriptome of disseminated tumor cells from a single cell RNA-sequencing data of PCa bone metastases. We built a bone metastasis model through caudal artery injection of tumor cells, and sorted the tumor hybrid cells by flow cytometry. We performed multi-omics analysis, including transcriptomic, proteomic and phosphoproteomic analysis, to compare the difference between the tumor hybrid cells and parental cells. In vivo experiments were performed to analyze the tumor growth rate, metastatic and tumorigenic potential, drug and radiation sensitivity in hybrid cells. Single cell RNA-sequencing and CyTOF were performed to analyze the impact of hybrid cells on tumor microenvironment.ResultsHere, we identified a unique cluster of cancer cells in PCa bone metastases, which expressed myeloid cell markers and showed a significant change in pathways related to immune regulation and tumor progression. We found that cell fusion between disseminated tumor cells and bone marrow cells can be source of these myeloid-like tumor cells. Multi-omics showed the pathways related to cell adhesion and proliferation, such as focal adhesion, tight junction, DNA replication, and cell cycle, were most significantly changed in these hybrid cells. In vivo experiment showed hybrid cells had a significantly increased proliferative rate, and metastatic potential. Single cell RNA-sequencing and CyTOF showed tumor-associated neutrophils/monocytes/macrophages were highly enriched in hybrid cells-induced tumor microenvironment with a higher immunosuppressive capacity. Otherwise, the hybrid cells showed an enhanced EMT phenotype with higher tumorigenicity, and were resistant to docetaxel and ferroptosis, but sensitive to radiotherapy.ConclusionTaken together, our data demonstrate that spontaneous cell fusion in bone marrow can generate myeloid-like tumor hybrid cells that promote the progression of bone metastasis, and these unique population of disseminated tumor cells can provide a potential therapeutic target for PCa bone metastasis.

Dataset Information

MiR-155-deficient bone marrow promotes tumor metastasis.

Publications

miR-155-deficient bone marrow promotes tumor metastasis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets