Abstract
Under pathological conditions like inflammation, ischemia or in solid tumors, parameters of the microenvironment like local oxygenation and extracellular pH show marked changes when compared to healthy tissue. The altered microenvironment affects cellular phenotype of omnipresent fibroblasts and immune cells. Recently, the impact of the microenvironment on the expression patterns of microRNAs, small non-coding RNAs that regulate gene expression on a post-transcriptional level, was discussed. Therefore, microRNAs might be the link between altered microenvironmental parameters and changes in cellular phenotype. In this study, the effect of hypoxia-induced extracellular acidosis (24 h pH 6.6) on microRNA expression in fibroblasts and macrophages was analyzed. MicroRNAs in rat fibroblasts (NRK-49F) were examined with the miScript miRNA PCR Array and changes in the expression validated by TaqMan qPCR. Subsequently, the identified microRNAs were analyzed in RAW 264.7 mouse macrophages. Nine out of 84 tested microRNAs were found to be acidosis-regulated in fibroblasts by miRNA PCR array, most of them up-regulated. Of those, the pH dependency could be validated by TaqMan qPCR for five of these nine microRNAs. When comparing these microRNAs in terms of their expression in macrophages, profound differences were observed. Thus, acidosis-induced alterations in the expression of microRNAs seem to be cell-type specific. Only the up-regulation of the miR-133b by low pH was seen in all normal cells, but not in tumor cells. As the identified microRNAs are involved in the regulation of proliferation, cell death and migration (amongst others), acidosis-induced changes in their expression might affect cellular behavior of fibroblasts and macrophages under pathological conditions. For instance the proto-oncogene c-Jun, which is a target of the miR-133b, was shown to be acidosis-regulated. Acidosis could regulate the biological behavior via miRNA-133b and c-Jun.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Adams J, Difazio L, Rolandelli R et al (2009) HIF-1: a key mediator in hypoxia (Review). Acta Physiol Hung 96:19–28
Riemann A, Schneider B, Ihling A et al (2011) Acidic environment leads to ROS-Induced MAPK signaling in cancer cells. PLoS One 6:e22445
Lujambio A, Lowe SW (2012) The microcosmos of cancer. Nature 482:347–355
Eulalio A, Huntzinger E, Izaurralde E (2008) Getting to the root of miRNA-mediated gene silencing. Cell 132:9–14
Ambros V (2004) The functions of animal microRNAs. Nature 431:350–355
Wei Y, Schober A (2016) MicroRNA regulation of macrophages in human pathologies. Cell Mol Life Sci 73:3473–3495
Olejniczak M, Kotowska-Zimmer A, Krzyzosiak W (2017) Stress-induced changes in miRNA biogenesis and functioning. Cell Mol Life Sci 75:177–191
Nallamshetty S, Chan SY, Loscalzo J (2013) Hypoxia: a master regulator of microRNA biogenesis and activity. Free Radic Biol Med 64:20–30
Bao B, Azmi AS, Li Y et al (2014) Targeting CSCs in tumor microenvironment: the potential role of ROS-associated miRNAs in tumor aggressiveness. Curr Stem Cell Res Ther 9:22–35
Schetter AJ, Heegaard NHH, Harris CC (2009) Inflammation and cancer: interweaving microRNA, free radical, cytokine and p53 pathways. Carcinogenesis 31:37–49
Riemann A, Reime S, Thews O (2017) Hypoxia-related tumor acidosis affects microRNA expression pattern in prostate and breast tumor cells. Adv Exp Med Biol 977:119–124
Dweep H, Gretz N (2015) miRWalk2.0: a comprehensive atlas of microRNA-target interactions. Nat Methods 12:697
Reimand J, Arak T, Adler P et al (2016) g:profiler—a web server for functional interpretation of gene lists (2016 update). Nucleic Acids Res 44:W83–W89
Ye R-S, Xi Q-Y, Qi Q et al (2013) Differentially expressed miRNAs after GnRH treatment and their potential roles in FSH regulation in porcine anterior pituitary cell. PLoS One 8:e57156
Esquela-Kerscher A, Slack FJ (2006) Oncomirs – microRNAs with a role in cancer. Nat Rev Cancer 6:259–269
Mitchelson KR, Qin W-Y (2015) Roles of the canonical myomiRs miR-1, −133 and −206 in cell development and disease. World J Biol Chem 6:162–208
Sturrock A, Mir-Kasimov M, Baker J et al (2014) Key role of MicroRNA in the regulation of granulocyte macrophage colony-stimulating factor expression in murine alveolar epithelial cells during oxidative stress. J Biol Chem 289:4095–4105
Doldi V, Callari M, Giannoni E et al (2015) Integrated gene and miRNA expression analysis of prostate cancer associated fibroblasts supports a prominent role for interleukin-6 in fibroblast activation. Oncotarget 6:31441–31460
Acknowledgments
This work was supported by Wilhelm-Roux program of the medical faculty, Martin Luther University Halle-Wittenberg (FKZ 29/12) and the Deutsche Forschungsgemeinschaft DFG (grant TH-482/6-1).
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2018 Springer International Publishing AG, part of Springer Nature
About this chapter
Cite this chapter
Riemann, A., Reime, S., Wollny, P., Sangerhausen, C., Gekle, M., Thews, O. (2018). Expression of MicroRNAs in Fibroblasts and Macrophages Is Regulated by Hypoxia-Induced Extracellular Acidosis. In: Thews, O., LaManna, J., Harrison, D. (eds) Oxygen Transport to Tissue XL. Advances in Experimental Medicine and Biology, vol 1072. Springer, Cham. https://doi.org/10.1007/978-3-319-91287-5_33
Download citation
DOI: https://doi.org/10.1007/978-3-319-91287-5_33
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-91285-1
Online ISBN: 978-3-319-91287-5
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)