Cancer-secreted hsa-miR-940 induces an osteoblastic phenotype in the bone metastatic microenvironment via targeting ARHGAP1 and FAM134A

Hashimoto, Kyoko; Ochi, Hiroki; Sunamura, Satoko; Kosaka, Nobuyoshi; Mabuchi, Yo; Fukuda, Tsuyoshi; Yao, Kenta; Kanda, Hiroaki; Ae, Keisuke; Okawa, Atsushi; Akazawa, Chihiro; Ochiya, Takahiro; Futakuchi, Mitsuru; Takeda, Satoshi; Sato, Shingo

doi:10.1073/pnas.1717363115

Cited by 204 publications

(173 citation statements)

References 38 publications

Supporting

Mentioning

167

Contrasting

Order By: Relevance

“…(10) These exosomes are enriched in proteins related to migration and invasion, compared to exosomes isolated from non-metastatic breast cancer cells. (10) Consistent with the ability of tumor cell-derived EVs to drive organotropism, Hashimoto and colleagues (11) found that hsa-miR-940 shuttled by prostate cancer EVs enhances human mesenchymal stem cell differentiation toward an osteoblastic phenotype by targeting ARHGAP1 and FAM134A. Moreover, forced expression of hsa-miR-940 in the osteotropic breast cancer cell line MDA-MB-231 reverts its propensity to induce osteolytic lesions toward an osteosclerotic phenotype, (11) thus indicating that the phenotype of bone metastases is also influenced by EV-shuttled miRNAs.…”

Section: Introductionmentioning

confidence: 81%

“…(10) Consistent with the ability of tumor cell-derived EVs to drive organotropism, Hashimoto and colleagues (11) found that hsa-miR-940 shuttled by prostate cancer EVs enhances human mesenchymal stem cell differentiation toward an osteoblastic phenotype by targeting ARHGAP1 and FAM134A. Moreover, forced expression of hsa-miR-940 in the osteotropic breast cancer cell line MDA-MB-231 reverts its propensity to induce osteolytic lesions toward an osteosclerotic phenotype, (11) thus indicating that the phenotype of bone metastases is also influenced by EV-shuttled miRNAs. Finally, a recent paper showed that exosomal release of L-plastin by MDA-MB-231 cells promotes their ability to induce osteolytic bone metastases in mouse models.…”

Section: Introductionmentioning

confidence: 81%

See 1 more Smart Citation

Extracellular Vesicles From Osteotropic Breast Cancer Cells Affect Bone Resident Cells

Loftus

Cappariello

George

et al. 2019

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

Extracellular vesicles (EVs) are emerging as mediators of a range of pathological processes, including cancer. However, their role in bone metastases has been poorly explored. We investigated EV-mediated effects of osteotropic breast cancer cells (MDA-MB-231) on bone resident cells and endothelial cells. Pretreatment of osteoblasts with conditioned medium (CM) of MDA-MB-231 (MDA) cells promoted pro-osteoclastogenic and pro-angiogenic effects by osteoblast EVs (OB-EVs), as well as an increase of RANKL-positive OB-EVs. Moreover, when treating osteoblasts with MDA-EVs, we observed a reduction of their number, metabolic activity, and alkaline phosphatase (Alp) activity. MDA-EVs also reduced transcription of Cyclin D1 and of the osteoblast-differentiating genes, while enhancing the expression of the pro-osteoclastogenic factors Rankl, Lcn2, Il1b, and Il6. Interestingly, a cytokine array on CM from osteoblasts treated with MDA-EVs showed an increase of the cytokines CCL3, CXCL2, Reg3G, and VEGF, while OPG and WISP1 were downregulated. MDA-EVs contained mRNAs of genes involved in bone metabolism, as well as cytokines, including PDGF-BB, CCL3, CCL27, VEGF, and Angiopoietin 2. In line with this profile, MDA-EVs increased osteoclastogenesis and in vivo angiogenesis. Finally, intraperitoneal injection of MDA-EVs in mice revealed their ability to reach the bone microenvironment and be integrated by osteoblasts and osteoclasts. In conclusion, we showed a role for osteoblast-derived EVs and tumor cell-derived EVs in the deregulation of bone and endothelial cell physiology, thus fueling the vicious cycle induced by bone tumors.n 396 LOFTUS ET AL. Osteoblast primary culturesCalvariae from 7-day-old WT CD1 mice were explanted, cleaned free of soft tissues, and digested three times with 1 mg/mL Clostridium histolyticum type IV collagenase and 0.25% trypsin, for 20 min at 37 C, with gentle agitation. Cells from the second and third digestions were plated following centrifugation at 200g for 7 min and grown in DMEM plus 10% FBS. At confluence, cells were trypsinized and plated according to the experimental protocol. The purity of the culture was evaluated by the transcriptional expression of the osteoblast markers alkaline phosphatase (Alp), Runt-related transcription factor 2 (Runx2), type I collagen, and osteocalcin and by the cytochemical evaluation of Alp activity. (14) Journal of Bone and Mineral Research BREAST CANCER CELL EVS AFFECT BONE RESIDENT CELLS 397 n Journal of Bone and Mineral Research n 398 LOFTUS ET AL.

show abstract

Section: Introductionmentioning

confidence: 81%

Section: Introductionmentioning

confidence: 81%

Extracellular Vesicles From Osteotropic Breast Cancer Cells Affect Bone Resident Cells

Loftus

Cappariello

George

et al. 2019

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

show abstract

“…microRNAs (miRNAs) are short (20‐24 nt) non‐coding RNAs involved in the post‐transcriptional regulation of gene expression in multicellular organisms by affecting both mRNA stability and translation . During recent decades, suppressive miRNAs have been shown to exert regulatory functional effects through targeting osteogenic genes involved in osteoblast growth, osteoclast‐mediated bone absorption processes and bone balance .…”

Section: Introductionmentioning

confidence: 99%

IL‐10 induces MC3T3‐E1 cells differentiation towards osteoblastic fate in murine model

Xiong

Yan

Chen

et al. 2019

J Cellular Molecular Medi

View full text Add to dashboard Cite

Interleukin‐10 (IL‐10) displays well‐documented anti‐inflammatory effects, but its effects on osteoblast differentiation have not been investigated. In this study, we found IL‐10 negatively regulates microRNA‐7025‐5p (miR‐7025‐5p), the down‐regulation of which enhances osteoblast differentiation. Furthermore, through luciferase reporter assays, we found evidence that insulin‐like growth factor 1 receptor (IGF1R) is a miR‐7025‐5p target gene that positively regulates osteoblast differentiation. In vivo studies indicated that the pre‐injection of IL‐10 leads to increased bone formation, while agomiR‐7025‐5p injection delays fracture healing. Taken together, these results indicate that IL‐10 induces osteoblast differentiation via regulation of the miR‐7025‐5p/IGF1R axis. IL‐10 therefore represents a promising therapeutic strategy to promote fracture healing.

show abstract

“…In recent decades, miRNAs have been reported to serve as important regulatory factors in the context of osteogenic differentiation, and the underlying mechanisms have been the focus of substantial research [26][27][28][29]. We therefore sought to identify miRNAs with differential expression between intact control bone and calluses of post-fracture mice, leading to our selection of miR-6979-5p from the GEO database.…”

Section: Discussionmentioning

confidence: 99%

The lncRNA Rhno1/miR-6979-5p/BMP2 Axis Modulates Osteoblast Differentiation

Xiong¹,

Chen²,

Yan³

et al. 2020

Int. J. Biol. Sci.

View full text Add to dashboard Cite

The roles of long non-coding RNAs (lncRNAs) and micro RNAs (miRNAs) as regulators of mRNA expression in various diseases have recently been reported. Osteoblast differentiation is the vital process which mediates bone formation and fracture healing. In present study, we found microRNA-6979-5p (miR-6979-5p) to be the most differentially expressed miRNA between normal bone and calluses of mice, and overexpression of miR-6979-5p was negatively associated with osteoblast differentiation. Through luciferase assays, we found evidence that bone morphogenetic protein 2 (BMP2) is a miR-6979-5p target gene that positively regulates osteoblast differentiation. We further identified the lncRNA Rhno1 as a competing endogenous RNA (ceRNA) of miR-6979-5p, and we verified that it was able to influence osteoblast differentiation both in vitro and in vivo. In summary, our data indicates that the lncRNA Rhno1/miR-6979-5p/BMP2 axis is a significant regulatory mechanism controlling osteoblast differentiation, and it may thus offer a novel therapeutic strategy for fracture healing.

show abstract

Cancer-secreted hsa-miR-940 induces an osteoblastic phenotype in the bone metastatic microenvironment via targeting ARHGAP1 and FAM134A

Cited by 204 publications

References 38 publications

Extracellular Vesicles From Osteotropic Breast Cancer Cells Affect Bone Resident Cells

Extracellular Vesicles From Osteotropic Breast Cancer Cells Affect Bone Resident Cells

IL‐10 induces MC3T3‐E1 cells differentiation towards osteoblastic fate in murine model

The lncRNA Rhno1/miR-6979-5p/BMP2 Axis Modulates Osteoblast Differentiation

Contact Info

Product

Resources

About