MiR-21/Smad 7 signaling determines TGF-β1-induced CAF formation

Li, Qiong; Zhang, Daoxiang; Wang, Yongbin; Sun, Pengfei; Hou, Xiaodan; Larner, J; Xiong, Wei; Mi, Jun

doi:10.1038/srep02038

Cited by 158 publications

(146 citation statements)

References 43 publications

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“…Through deep sequencing, miRNA profile showed that miR-186 was downregulated during CAF formation, of which the model was established previously (Li et al, 2013b). In the mean time, the protein level of Glut1 was upregulated.…”

Section: Downregulation Of Mir-186 Increases Glut1 Protein Level Durimentioning

confidence: 88%

miR-186 Regulates Glycolysis through Glut1 During the Formation of Cancer-associated Fibroblasts

Sun¹,

Hu²,

Xiong³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Emerging evidence has suggested that glycolysis is enhanced in cancer-associated fibroblasts (CAF), and miR-186 is downregulated during the CAF formation. However, it is not clear whether miR-186 is involved in the regulation of glycolysis and what the role of miR-186 plays during the CAF formation. In this study, quantitative PCR analysises show miR-186 is downregulated during the CAF formation. Moreover, miR-186 targets the 3' UTR of Glut1, and its overexpression results in the degradation of Glut1 mRNA, which eventually reduces the level of Glut1 protein. On the other hand, knockdown of miR-186 increased the expression of Glut1. Both time course and dose response experiments also demonstrated that the protein and mRNA levels of Glut1 increase during CAF formation, according to Western blot and quantitative PCR analyses, respectively. Most importantly, besides the regulation on cell cycle progression, miR-186 regulates glucose uptake and lactate production which is mediated by Glut1. These observations suggest that miR-186 plays important roles in glycolysis regulation as well as cell cycle checkpoint activation.

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Section: Downregulation Of Mir-186 Increases Glut1 Protein Level Durimentioning

confidence: 88%

miR-186 Regulates Glycolysis through Glut1 During the Formation of Cancer-associated Fibroblasts

Sun¹,

Hu²,

Xiong³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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“…The regulation of microRNA expression controls key pathways involved in acquisition of a CAF phenotype. For example, up-regulation of miR-21 in fibroblasts results in deregulation of TGF-β1 signaling and TGF-β1-induced conversion to CAFs through inhibition of translation of the TGF-β inhibitor Smad 7 (Li et al 2013). Up-regulation of the hypoxia-induced miR-210 in young fibroblasts triggers senescence and conversion into CAFs able to promote EMT in cancer cells, support angiogenesis, and recruit monocytes/macrophages .…”

Section: Caf: Cell or State?mentioning

confidence: 99%

Carcinoma-associated fibroblasts: orchestrating the composition of malignancy

2016

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The tumor stroma is no longer seen solely as physical support for mutated epithelial cells but as an important modulator and even a driver of tumorigenicity. Within the tumor stromal milieu, heterogeneous populations of fibroblast-like cells, collectively termed carcinoma-associated fibroblasts (CAFs), are key players in the multicellular, stromal-dependent alterations that contribute to malignant initiation and progression. This review focuses on novel insights into the contributions of CAFs to disease progression, emergent events leading to the generation of CAFs, identification of CAF-specific biomarkers predictive of disease outcome, and recent therapeutic approaches aimed at blunting or reverting detrimental protumorigenic phenotypes associated with CAFs.

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“…We propose that this phenotypic evolution to CAF, exemplified by the formation of actin stress fibers and a massive cytokine release, is, to a large extent, driven by a complex mixture of small RNAs and proteins contained by CLL exosomes. Among the cargoes identified in exosomes, tetraspanins can promote cell activation, growth, and motility, 50 and the most abundant miRNAs (miR-21 and -146a) are known critical regulators of CAF induction, 51,52 MSC proliferation, 53 and EC angiogenic activities. 54 On uptake of CLL exosomes, cell signaling pathways are activated, and gene expression is altered in target cells.…”

Section: Cll Exosomes Induce Caf Formation 1113mentioning

confidence: 99%

Exosomes released by chronic lymphocytic leukemia cells induce the transition of stromal cells into cancer-associated fibroblasts

Paggetti

Haderk

Seiffert

et al. 2015

Blood

400

397

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Luxembourg Key Points• CLL-derived exosomes are internalized by stromal cells, deliver functional microRNA and proteins, and activate key signaling pathways.• Stromal cells exposed to CLLderived exosomes demonstrate a CAF-like phenotype and secrete factors promoting CLL cell survival.Exosomes derived from solid tumor cells are involved in immune suppression, angiogenesis, and metastasis, but the role of leukemia-derived exosomes has been less investigated. The pathogenesis of chronic lymphocytic leukemia (CLL) is stringently associated with a tumorsupportive microenvironment and a dysfunctional immune system. Here, we explore the role of CLL-derived exosomes in the cellular and molecular mechanisms by which malignant cells create this favorable surrounding. We show that CLL-derived exosomes are actively incorporated by endothelial and mesenchymal stem cells ex vivo and in vivo and that the transfer of exosomal protein and microRNA induces an inflammatory phenotype in the target cells, which resembles the phenotype of cancer-associated fibroblasts (CAFs). As a result, stromal cells show enhanced proliferation, migration, and secretion of inflammatory cytokines, contributing to a tumor-supportive microenvironment. Exosome uptake by endothelial cells increased angiogenesis ex vivo and in vivo, and coinjection of CLL-derived exosomes and CLL cells promoted tumor growth in immunodeficient mice. Finally, we detected a-smooth actin-positive stromal cells in lymph nodes of CLL patients. These findings demonstrate that CLL-derived exosomes actively promote disease progression by modulating several functions of surrounding stromal cells that acquire features of cancer-associated fibroblasts. (Blood. 2015;126(9):1106-1117

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MiR-21/Smad 7 signaling determines TGF-β1-induced CAF formation

Cited by 158 publications

References 43 publications

miR-186 Regulates Glycolysis through Glut1 During the Formation of Cancer-associated Fibroblasts

miR-186 Regulates Glycolysis through Glut1 During the Formation of Cancer-associated Fibroblasts

Carcinoma-associated fibroblasts: orchestrating the composition of malignancy

Exosomes released by chronic lymphocytic leukemia cells induce the transition of stromal cells into cancer-associated fibroblasts

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