miRNA-1246 induces pro-inflammatory responses in mesenchymal stem/stromal cells by regulating PKA and PP2A

Bott, Alexander; Erdem, Nese; Lerrer, Shalom; Hotz‐Wagenblatt, Agnes; Breunig, Christian; Abnaof, Khalid; Wörner, Angelika; Wilhelm, Heike; Münstermann, Ewald; Ben‐Baruch, Adit; Wiemann, Stefan

doi:10.18632/oncotarget.14915

Cited by 65 publications

(60 citation statements)

References 102 publications

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“…Meanwhile, this study also demonstrated that miR-1246 induced secretion of key pro-inflammatory cytokines and chemokines (IL-6, CCL2 and CCL5) in MSCs was mediated via NF-κB signaling pathway [25]. At the functional level, miR-1246 had been shown to induce the proliferation, invasion and migration and enhance cell apoptosis of cervical or hepatocellular carcinoma cells [28, 29].…”

Section: Discussionmentioning

confidence: 99%

“…A number of studies dispalyed that different miRNAs could increase or decrease cell apoptosis in OA, such as miR-149 and miR-30b [23, 24]. miR-1246 is associated with inflammation, which is a positive regulator of the immune response of leukocytes, and is also involved in many cellular processes, such as tumor cell proliferation [25]. However, the mechanism of miR-1246 in OA has not been studied.…”

Section: Introductionmentioning

confidence: 99%

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MiR-1246 Promotes LPS-Induced Inflammatory Injury in Chondrogenic Cells ATDC5 by Targeting HNF4γ

Zhang

Wang

et al. 2017

Cell Physiol Biochem

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Background/Aims: Osteoarthritis (OA) is a common inflammatory joint disease. miRNAs are associated with OA and functionally implicated in the pathogenesis of the disease. In the present study, we investigated the role of miR-1246 in the lipopolysaccharide (LPS)-induced inflammatory injury of ATDC5 cells. Methods: ATDC5 cells were cultured and treated with LPS in a series of concentration (0, 1, 5, and 10 µg/ml) for 5 h. The cells were transfected with miR-1246-mimic, inhibitor, si-HNF4γ or negative control, then were assessed for cell viability using CCK8 assay, apoptosis by flow-cytometry and expressions of miR-1246 and pro-inflammatory cytokines by qRT-PCR and western blot analysis. Results: Cell viability was significantly reduced and cell apoptosis was added in ATDC5 cells injured with LPS at the dosage of 5 and 10 µg/ml. Relative mRNA expressions of pro-inflammatory cytokines (IL-1β, IL-6, IL-8 and TNF-α) were significantly increased. miR-1246 was up-regulated in ATDC5 cells treated with LPS. Moreover, miR-1246 overexpression aggravated LPS-induced decrease in cell viability, increase in apoptosis and overproduction of pro-inflammatory factors. mRNA and protein expressions of HNF4γ were significantly suppressed in cells transfected with miR-124-mimic. Further, miR-1246 knockdown alleviated LPS-induced inflammatory injury by up-regulating the expression of HNF4γ and activation of PI3K/AKT and JAK/STAT pathways. Conclusions: Suppression of miR-1246 alleviated LPS-induced inflammatory injury in chondrogenic ADTC5 cells by up-regulation of HNF4γ and activation of PI3K/AKT and JAK/STAT pathways. The findings of this study will provide a novel viewpoint regarding miR-1246 target for clinical.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

MiR-1246 Promotes LPS-Induced Inflammatory Injury in Chondrogenic Cells ATDC5 by Targeting HNF4γ

Zhang

Wang

et al. 2017

Cell Physiol Biochem

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“…Accumulating evidence has supported that MSCs play critical roles in tumor development and progression, by increasing stemness of tumor cells, stimulating tumor cell migration, promoting angiogenesis, supporting immune responses, and inducing drug resistance. Additionally, MSCs increase the metastatic potential of tumor cells by advancing their motility and invasiveness and thereby play a role in the nature of a metastatic niche at the secondary site (Bott et al, 2017; Donnarumma et al, 2017; Gonzalez et al, 2017; Luo et al, 2009; McAndrews et al, 2015; Wolfe et al, 2016). Therefore, a comprehensive knowledge on the biology and mechanism of interaction between MSCs and TME of breast and prostate cancer is essential for the development of therapeutics that capitalize on vulnerabilities in these tumor cell-MSC interplay.…”

Section: Tumor Cell Interactions With the Mesenchymementioning

confidence: 99%

“…A recent study shows that MSCs in the TME has an impact on breast cancer progression by creating a pro-inflammatory milieu within the tumor (Bott et al, 2017). This study identified six putative oncomiRs, strongly correlating with poor overall patient survival.…”

Section: Tumor Cell Interactions With the Mesenchymementioning

confidence: 99%

Tumor Microenvironment Heterogeneity: Challenges and Opportunities

et al. 2017

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The tumor microenvironment (TME) has been recognized as an integral component of malignancies in breast and prostate tissues, contributing in confounding ways to tumor progression, metastasis, therapy resistance and disease recurrence. Major components of the TME are immune cells, fibroblasts, pericytes, endothelial cells, mesenchymal stroma/stem cells (MSCs), and extracellular matrix (ECM) components. Herein, we discuss the molecular and cellular heterogeneity within the TME and how this presents unique challenges and opportunities for treating breast and prostate cancers.

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“…miRNAs regulate signaling pathways at the post‐transcriptional level and are frequently deregulated in breast cancer. It has been shown that aberrantly expressed miRNAs promote cancer development, metastasis formation, and potently induce drug resistance in both tumor cells and cells of the tumor microenvironment (Bott et al ., 2017; Breunig et al ., 2017; Dvinge et al ., 2013; Tang et al ., 2012; Zhu et al ., 2011). In a previous study, we have identified a tumor‐suppressive function of the miR‐520/miR373 family by targeting TGFBR2 in breast cancer cells (Keklikoglou et al ., 2012).…”

Section: Introductionmentioning

confidence: 99%

TGFβ1 regulates HGF‐induced cell migration and hepatocyte growth factor receptor MET expression via C‐ets‐1 and miR‐128‐3p in basal‐like breast cancer

et al. 2018

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Breast cancer is the most common cancer in women worldwide. The tumor microenvironment contributes to tumor progression by inducing cell dissemination from the primary tumor and metastasis. TGFβ signaling is involved in breast cancer progression and is specifically elevated during metastatic transformation in aggressive breast cancer. In this study, we performed genomewide correlation analysis of TGFBR2 expression in a panel of 51 breast cancer cell lines and identified that MET is coregulated with TGFBR2. This correlation was confirmed at the protein level in breast cancer cell lines and human tumor tissues. Flow cytometric analysis of luminal and basal‐like breast cancer cell lines and examination of 801 tumor specimens from a prospective cohort of breast cancer patients using reverse phase protein arrays revealed that expression of TGFBR2 and MET is increased in basal‐like breast cancer cell lines, as well as in triple‐negative breast cancer tumor tissues, compared to other subtypes. Using real‐time cell analysis technology, we demonstrated that TGFβ1 triggered hepatocyte growth factor (HGF)‐induced and MET‐dependent migration in vitro. Bioinformatic analysis predicted that TGFβ1 induces expression of C‐ets‐1 as a candidate transcription factor regulating MET expression. Indeed, TGFβ1‐induced expression of ETS1 and breast cancer cell migration was blocked by knockdown of ETS1. Further, we identified that MET is a direct target of miR‐128‐3p and that this miRNA is negatively regulated by TGFβ1. Overexpression of miR‐128‐3p reduced MET expression and abrogated HGF‐induced cell migration of invasive breast cancer cells. In conclusion, we have identified that TGFβ1 regulates HGF‐induced and MET‐mediated cell migration, through positive regulation of C‐ets‐1 and negative regulation of miR‐128‐3p expression in basal‐like breast cancer cell lines and in triple‐negative breast cancer tissue.

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miRNA-1246 induces pro-inflammatory responses in mesenchymal stem/stromal cells by regulating PKA and PP2A

Cited by 65 publications

References 102 publications

MiR-1246 Promotes LPS-Induced Inflammatory Injury in Chondrogenic Cells ATDC5 by Targeting HNF4γ

MiR-1246 Promotes LPS-Induced Inflammatory Injury in Chondrogenic Cells ATDC5 by Targeting HNF4γ

Tumor Microenvironment Heterogeneity: Challenges and Opportunities

TGFβ1 regulates HGF‐induced cell migration and hepatocyte growth factor receptor MET expression via C‐ets‐1 and miR‐128‐3p in basal‐like breast cancer

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